Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

BACKGROUND:Numerous clinical and basic studies have shown that electroacupuncture can improve the function of neurogenic bladder after suprasacral spinal cord injury. OBJECTIVE:To observe the effects of electroacupuncture on bladder function and connective tissue growth factor expression in rats with suprasacral spinal cord injury. METHODS:Forty-eight female Sprague-Dawley rats were randomly divided into four groups(n=12 per group):the blank group did not receive any treatment;the sham-operated group only exposed the T8 subvertebral spinal cord;in the model group established,a T8 subvertebral spinal cord transection injury model was established;in the electroacupuncture group,the T8 subvertebral spinal cord transection injury model was established,and electroacupuncture intervention at Ciliao(BL32),Zhongji(RN03)and Sanyinjiao(SP06)was given at 19 days after modeling,20 minutes once a day,for 10 continuous days.After the intervention,the relevant indicators were detected. RESULTS AND CONCLUSION:Urodynamics:Compared with the blank group,the leakage point pressure,maximum bladder capacity and maximum bladder pressure of rats in the model group increased(P<0.05).Compared with the model group,the leakage point pressure,maximum bladder capacity and maximum bladder pressure of rats in the electroacupuncture group decreased(P<0.05).Hematoxylin-eosin staining:Compared with the blank group,the bladder epithelial cells in the model group were arranged in a disordered manner,the lamina propria was destroyed,the detrusor muscle bundles were hypertrophied,the muscle fibers were arranged in a disordered manner,and the tissue edema was obvious.Compared with the model group,the bladder epithelial cells in the electroacupuncture group were arranged in a regular and orderly manner,and the degree of bladder fibrosis and tissue edema was relatively reduced.Masson staining:The degree of bladder detrusor muscle fibrosis was severe in the model group and it was lighter in the electroacupuncture group than in the model group.Transmission electron microscopy:Mitochondria in the bladder tissue in the model group were swollen and vacuolated,the morphology of the detrusor muscle was twisted and distorted,and the muscle gap was widened.Compared with the model group,mitochondria in the electroacupuncture group had a slightly clearer contour and were less vacuolated,and the muscle gap was narrowed.Western blot detection:The protein expression of connective tissue growth factor in the detrusor muscle of the bladder was elevated in the model group compared with the blank group(P<0.05).Compared with the model group,the protein expression of connective tissue growth factor in the bladder detrusor muscle was decreased in the electroacupuncture group(P<0.05).To conclude,electroacupuncture at Ciliao(BL32),Zhongji(RN03)and Sanyinjiao(SP06)acupoints can improve the morphology,structure and function of the bladder in rats with suprasacral spinal cord injury,and the mechanism of action may be related to the down-regulation of connective tissue growth factor protein expression in the detrusor muscle.

OBJECTIVE: To investigate and analyze the risk factors of massive hemorrhage in patients with renal cell carcinoma and venous tumor thrombus undergoing radical nephrectomy and removal of venous tumor thrombus. METHODS: From January 2014 to June 2020, 241 patients with renal cancer and tumor thrombus in a single center of urology at Peking University Third Hospital were retrospectively analyzed. All patients underwent radical nephrectomy and removal of venous tumor thrombus. The relevant preoperative indicators, intraoperative conditions, and postoperative data were statistically analyzed by using statistical software of SPSS 18.0. The main end point of the study was intraoperative bleeding volume greater than 2 000 mL. Logistic regression analysis was used to determine the relevant influencing factors. First, single factor Logistic regression was used for preliminary screening of influencing factors, and variables with single factor Logistic regression analysis P < 0.05 were included in multivariate Logistic regression. In all statistical analyses, P < 0.05 is considered statistically significant. RESULTS: Among the 241 patients included, there were 60 cases of massive hemorrhage, 48 males and 12 females, with a median age of 62 years. The number of non-massive hemorrhage was 181. There were 136 males and 45 females, with a median age of 59 years. Univariate analysis showed that the clinical symptoms (both systemic and local symptoms, OR 2.794, 95%CI 1.087-7.181, P=0.033), surgical approach (open surgery, OR 9.365, 95%CI 4.447-19.72, P < 0.001), Mayo grade (Mayo 3-4, OR 5.257, 95%CI 2.806-10.886, P < 0.001), American Society of Anesthesiologists (ASA) score (ASA level 3, OR 2.842, 95%CI 1.338-6.036, P=0.007), preoperative hemoglobin (OR 0.978, 95%CI 0.965-0.991, P=0.001), preoperative platelet count (OR 0.996, 95%CI 0.992-1.000, P=0.037), maximum tumor thrombus width (OR 1.061, 95%CI 1.033-1.091, P < 0.001), Complicated with bland thrombus (OR 4.493, 95%CI 2.264-8.915, P < 0.001), adrenalectomy (OR 3.101, 95%CI 1.614-5.958, P=0.001), segmental resection of the inferior vena cava (OR 2.857, 95%CI 1.395-5.852, P=0.004). There was a statistically significant difference in these aspects(P < 0.05). Multivariate Logistic regression analysis showed that there was a statistically significant difference in surgical approach (open surgery, OR 6.730, 95%CI 2.947-15.368;P < 0.001), Mayo grade (Mayo 3-4, OR 2.294, 95%CI 1.064-4.948, P=0.034), Complicated with bland thrombus (OR 3.236, 95%CI 1.492-7.020, P=0.003). CONCLUSION Combining the results of univariate and multivariate Logistic regression analysis, the surgical approach, Mayo grade, and tumor thrombus combined with conventional thrombus were associated risk factors for massive hemorrhage during surgery for renal cell carcinoma with tumor thrombus. Patients who undergo open surgery, high Mayo grade, and tumor thrombus combined with conventional thrombus are at a relatively higher risk of massive hemorrhage.
Male ; Female ; Humans ; Middle Aged ; Carcinoma, Renal Cell/pathology* ; Retrospective Studies ; Thrombosis/etiology* ; Kidney Neoplasms/pathology* ; Vena Cava, Inferior/surgery* ; Nephrectomy/methods* ; Thrombectomy/methods* ; Risk Factors ; Hemorrhage

AIM: To evaluate the necessity of slit-lamp biomicroscopy(referred to here as “slit-lamp”)training from the student's perspective and reach a consensus on slit-lamp training in medical students during ophthalmology clerkship.METHODS: A controlled before-after clerkship study was performed on 117 students of the class of 2017 enrolled in clinical medicine at Sun Yat-sen University. All medical students underwent slit-lamp training during ophthalmology clerkship. We evaluated the students' cognition, perceived need and recommendations for slit-lamp teaching, using a self-completed questionnaire survey and compared the students' scores in these aspects before and after their ophthalmology clerkships. Additionally, the efficiency of slit-lamp training was evaluated by subjective student assessment after the ophthalmology clerkship. Each item was scored on a five-point Likert Scale. Statistical analysis was performed by IBM SPSS(Version 20.0; SPSS Inc., Chicago, IL, USA).RESULTS: A total of 116(99.1%)medical students completed the survey. The average score before clerkship was 19.99±3.03, which indicated a high level of cognition regarding slit-lamp utility; However, this score significantly increased to 22.97±2.37 after clerkship(P<0.001). The average score regarding perceived need was also higher for post-clerkship students than for pre-clerkship students(24.62±3.15 vs. 23.60±2.36, P=0.009). Moreover, 86.2% of post-clerkship students reported that hands-on slit-lamp practice could help promote clerkship quality. More than three-quarters of the surveyed students tended to agree that slit-lamp practice time should be increased(76.7% and 77.6% before and after clerkship, respectively).CONCLUSION: A hands-on approach to slit-lamp training is more favored by medical students in ophthalmology clerkships, and this training should be recommended in ophthalmology clerkships given its potential usefulness for improving clerkship quality.

COVID-19 is caused by a novel coronavirus-severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which has being spreading around the world, posing a serious threat to human health and lives. Neutralizing antibodies and small molecule inhibitors for virus replication cycle are the main antiviral treatment for novel coronavirus recommended in China. To further promote the rational use of antiviral therapy in clinical practice, the National Center for Infectious Diseases (Beijing Ditan Hospital Capital Medical University and the First Affiliated Hospital, Zhejiang University School of Medicine) invited experts in fields of infectious diseases, respiratory and intensive care to develop an Expert Consensus on Antiviral Therapy of COVID-19 based on the Diagnosis and Treatment Guideline for COVID-19 ( trial version 10) and experiences in the diagnosis and treatment of COVID-19 in China. The consensus is concise, practical and highly operable, hopefully it would improve the understanding of antiviral therapy for clinicians and provide suggestions for standardized medication in treatment of COVID-19.

Objective:To report the results of national surveillance on the distribution and antimicrobial resistance profile of clinical bacterial isolates from bloodstream infections in China in 2021.Methods:The clinical bacterial strains isolated from blood culture from member hospitals of Blood Bacterial Resistant Investigation Collaborative System (BRICS) were collected during January 2021 to December 2021. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical Laboratory Standards Institute (CLSI). WHONET 5.6 was used to analyze data.Results:During the study period, 11 013 bacterial strains were collected from 51 hospitals, of which 2 782 (25.3%) were Gram-positive bacteria and 8 231 (74.7%) were Gram-negative bacteria. The top 10 bacterial species were Escherichia coli (37.6%), Klebsiella pneumoniae (18.9%), Staphylococcus aureus (9.8%), coagulase-negative Staphylococci (6.3%), Pseudomonas aeruginosa (3.6%), Enterococcus faecium (3.6%), Acinetobacter baumannii (2.8%), Enterococcus faecalis (2.7%), Enterobacter cloacae (2.5%) and Klebsiella spp (2.1%). The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus aureus were 25.3% and 76.8%, respectively. No glycopeptide- and daptomycin-resistant Staphylococci was detected; more than 95.0% of Staphylococcus aureus were sensitive to ceftobiprole. No vancomycin-resistant Enterococci strains were detected. The rates of extended spectrum B-lactamase (ESBL)-producing isolated in Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis were 49.6%, 25.5% and 39.0%, respectively. The prevalence rates of carbapenem-resistance in Escherichia coli and Klebsiella pneumoniae were 2.2% and 15.8%, respectively; 7.9% of carbapenem-resistant Klebsiella pneumoniae was resistant to ceftazidime/avibactam combination. Ceftobiprole demonstrated excellent activity against non-ESBL-producing Escherichia coli and Klebsiella pneumoniae. Aztreonam/avibactam was highly active against carbapenem-resistant Escherichia coli and Klebsiella pneumoniae. The prevalence rate of carbapenem-resistance in Acinetobacter baumannii was 60.0%, while polymyxin and tigecycline showed good activity against Acinetobacter baumannii (5.5% and 4.5%). The prevalence of carbapenem-resistance in Pseudomonas aeruginosa was 18.9%. Conclusions:The BRICS surveillance results in 2021 shows that the main pathogens of blood stream infection in China are gram-negative bacteria, in which Escherichia coli is the most common. The MRSA incidence shows a further decreasing trend in China and the overall prevalence of vancomycin-resistant Enterococci is low. The prevalence of Carbapenem-resistant Klebsiella pneumoniae is still on a high level, but the trend is downwards.

Aim Human TMPRSS2 is a transmembrane serine protease.In this paper, the structure and func¬tion of the protein were systematically analyzed by bioinformatics, the codon was optimized and the pro- karvotie expression vector was constructed to explore the molecular mechanism of SARS-CoV-2 infecting host cells.Methods The recombinant expression vector pET-22b-TMPRSS2 was generated by molecular clo¬ning technology.The homology, functional sites, sub¬cellular localization, three-dimensional structure and evolutionary characteristics of TMPRSS2 protein were systematically analyzed by using analytical tools such as Protparam, NetPhos3.1, Blast, Clustal X2 and MEGA7.0.Results The prokarvotic expression plas- mid was constructed correctly; TMPRSS2 belongs to medium molecular weight protein, which is composed of 492 amino acid residues.The theoretical isoelectric point is 8.12, the molecular extinction coefficient is 118 145 L • mol~1 • cm"1 , and the half-life is 30 h; TMPRSS2 has 15 potential glycosylation sites and 49 possible phosphorylation sites.It is a transmembrane hydrophilie protein without signal sequenee.In addi¬tion, the protein has 13 potential B-cell epitopes and 7 T-eell epitopes.Seeondarv structure analysis showed that random coil accounted for the highest proportion of TMPRSS2 protein ( 0.453 3) , followed by extended strand (0.252 0).Sequence comparison and evolu¬tionary analysis showed that the highest sequence con¬sistency and closest genetic relationship with human TMPRSS2 was Pan troglodytes, followed by gorilla.Conclusions Human-derived TMPRSS2 protein is ev- olutionarilv conserved and functionally important.Hie results of this study can help to reveal the structure and mechanism of action of TMPRSS2 protein, provide ide¬as for the diagnosis and treatment of COYID-19, and accelerate the research and development process of new drugs targeting TMPRSS2 protein.

Advances in science and technology promote the rapid development of toxicological detection technologies. However, there is still a lack of decision-making tools for toxicological risk assessment, such as the lack of transparent schemes to evaluate current toxicological research and practice and the lag of toxicological testing tools to evaluate toxicity, resulting in difficulties in toxicity verification and hindering the transformation of toxicological research paradigm. Some scholars have proposed to integrate the concept of evidence-based medicine with the toxicological practice to improve the technical methods of toxicological research concept and risk assessment decision-making. With the promotion of relevant scholars and academic organizations, the concept and connotation of evidence-based toxicology have gradually become clear and a framework for research and practice has been initially formed. Although there are still many challenges, it also provides a new idea for the toxicity risk assessment and safe medication decision-making of traditional Chinese medicine(TCM). The era of digital intelligence has brought new opportunities and broad space for the development of TCM evidence-based toxicology. The exploration of TCM evidence-based toxicology from concept to method is an important embodiment of the development of TCM evidence-based toxicology, and will also promote the continuous enrichment and improvement of the research and practice system of TCM evidence-based toxicology.
Drugs, Chinese Herbal/toxicity* ; Evidence-Based Medicine ; Medicine, Chinese Traditional ; Research Design

We aimed to confirm the predictive ability of the presence of intraductal carcinoma of the prostate (IDC-P) for prognosis and the associations between IDC-P and clinicopathological parameters. Studies were identified in PubMed, Cochrane Library, EMBASE, Web of Science, and SCOPUS up to December 1, 2019. Hazard ratios (HRs) for survival data and odds ratios for clinicopathological data with 95% confidence intervals (CIs) were extracted. Heterogeneity was evaluated by the I