CRISPR-Associated Protein 9 ; Gene Editing ; CRISPR-Cas Systems/genetics*

OBJECTIVE: Appraisal of treatment outcomes in integrative medicine is a challenge due to a gap between the concepts of Western medicine (WM) disease and traditional Chinese medicine (TCM) syndrome. This study presents an approach for the appraisal of integrative medicine that is based on targeted metabolomics. We use non-alcoholic fatty liver disease with spleen deficiency syndrome as a test case. METHODS: A patient-reported outcome (PRO) scale was developed based on literature review, Delphi consensus survey, and reliability and validity test, to quantitatively evaluate spleen deficiency syndrome. Then, a metabonomic foundation for the treatment of non-alcoholic fatty liver disease with spleen deficiency syndrome was identified via a longitudinal interventional trial and targeted metabolomics. Finally, an integrated appraisal model was established by identifying metabolites that responded in the treatment of WM disease and TCM syndrome as positive outcomes and using other aspects of the metabonomic foundation as independent variables. RESULTS: Ten symptoms and signs were included in the spleen deficiency PRO scale. The internal reliability, content validity, discriminative validity and structural validity of the scale were all qualified. Based on treatment responses to treatments for WM disease (homeostasis model assessment of insulin resistance) or TCM syndrome (spleen deficiency PRO scale score) from a previous randomized controlled trial, two cohorts comprised of 30 participants each were established for targeted metabolomics detection. Twenty-five metabolites were found to be involved in successful treatment outcomes to both WM and TCM, following quantitative comparison and multivariate analysis. Finally, the model of the integrated appraisal system was exploratively established using binary logistic regression; it included 9 core metabolites and had the prediction probability of 83.3%. CONCLUSION This study presented a new and comprehensive research route for integrative appraisal of treatment outcomes for WM disease and TCM syndrome. Critical research techniques used in this research included the development of a TCM syndrome assessment tool, a longitudinal interventional trial with verified TCM treatment, identification of homogeneous metabolites, and statistical modeling.
Humans ; Drugs, Chinese Herbal ; Integrative Medicine ; Medicine, Chinese Traditional/methods* ; Non-alcoholic Fatty Liver Disease/therapy* ; Reproducibility of Results ; Spleen ; Syndrome ; Treatment Outcome ; Clinical Trials as Topic

BACKGROUND: Syndrome is one of the most important concepts in Chinese medicine (CM) theory. However, it was not well accounted in most of randomized controlled trials (RCTs). OBJECTIVES: To determine whether CM syndrome differentiation affects the treatment results, functional constipation (FC) was selected as a target disease, and MaZiRenWan (, MZRW), a classic CM formula commonly used for constipation with excessive heat syndrome, was selected for study. METHODS: It is an 18-week prospective double-blinded, doubledummy RCT, including 2-week run-in, 8-week treatment and 8-week post treatment follow-up. A total of 120 FC patients diagnosed as excessive heat syndrome will be recruited from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and the Baokang Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. Patients will be randomly allocated into fixed MZRW (f_MZRW) granule group, modified MZRW (m_MZRW) granule group or bisacodyl group. For m_MZRW group, no more than two herbal granules can be added according to the syndrome differentiation for individual participants. The primary end point is the mean of complete spontaneous bowel movements (CSBMs) per week during the treatment period. Secondary end points include mean of CSBMs per week during follow-up, stool form, global symptom improvement, constipation and constipation-related symptoms assessment, CM syndrome change, and reported adverse events. DISCUSSION This trial is designed to evaluate the effectiveness of these three interventions for FC patients with the CM syndrome of excessive heat, and to determine the change of CM syndrome and the progress of disease during the treatment course. The results are important to explore whether syndrome differentiation is important for the therapeutic effect of a formula on a disease. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-TRC-13003742); protocol version: MZRW/NSFC-81173363 (2015.05.04)].
Constipation ; diagnosis ; drug therapy ; Double-Blind Method ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; Outcome Assessment (Health Care) ; Prospective Studies ; Randomized Controlled Trials as Topic

OBJECTIVE: To explore the molecular-level mechanism on the hematopoiesis effect of Angelicae sinensis Radix (ASR) with systems-based interactome analysis. METHODS: This systems-based interactome analysis was designed to enforce the workflow of "ASR (herb)→compound→target protein→internal protein actions→ending regulated protein for hematopoiesis". This workflow was deployed with restrictions on regulated proteins expresses in bone marrow and anemia disease and futher validated with experiments. RESULTS: The hematopoiesis mechanism of ASR might be accomplished through regulating pathways of cell proliferation towards hemopoiesis with cross-talking agents of spleen tyrosine kinase (SYK), Janus kinase 2 (JAK2), and interleukin-2-inducible T-cell kinase (ITK). The hematopoietic function of ASR was also validated by colony-forming assay performed on mice bone marrow cells. As a result, SYK, JAK2 and ITK were activated. CONCLUSION This study provides a new approach to systematically study and predict the therapeutic mechanism for ASR based on interactome analysis towards biological process with experimental validations.

BACKGROUND:No retrievable and repositionable second generation transcatheter aortic valve is available in China. Here, we report the first-in-man implantation of the retrievable and repositionable VenusA-Plus valve. METHODS:A 76-year-old patient with symptomatic severe aortic stenosis and high surgical risk (STS 13.8％) was recommended for transcatheter aortic valve replacement (TAVR) by heart valve team. Type 0 bicuspid aortic valve with asymmetric calcification was identified by dual source computed tomography, and the unfavorable anatomies increased the possibility of malposition and paravalvular leakage during TAVR. Therefore, we used the retrievable and repositionable VenusA-Plus valve for the patient. RESULTS:Transfemoral TAVR was performed under local anesthesia with sedation, and a 26-mm VenusA-Plus valve was successful y implanted. No transvalvular pressure gradient and trace paravalvular leakage were found. CONCLUSION:The successful first-in-man implantation indicates the retrievable and repositionable VenusA-Plus valve is feasible in complicated TAVR cases such as bicuspid aortic valve.

Objective To understand the changing resistance proifle ofProteus,Serratia,Citrobacter,Morganella andProvidencia in hospitals across China according to the data from CHINET Antimicrobial Resistance Surveillance Program 2005-2014.Methods Antimicrobial susceptibility was tested by using Kirby-Bauer method or automatic minimum inhibitory concentration determination according to a uniifed protocol.Results A total of 21 663 clinical isolates were collected from January 2005 to December 2014. The proportion ofProteus andSerratia isolates increased with time from 1.41% in 2005 to 2.09% in 2014, and from 0.99% in 2005 to 1.28% in 2014 among all the isolates. No change was found for the proportion ofCitrobacter,Morganella, orProvidencia. Less than 10% of theProteus isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, ceftazidime, cefoxitin, amikacin and tigecycline. Less than 10% of theSerratia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, amikacin and tigecycline. Less than 20% of theCitrobacter isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 10% of theMorganella isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 20% of theProvidencia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, cefoxitin and tigecycline.Conclusions The antibiotic resistance ofProteus,Serratia, Citrobacter,Morganella andProvidencia isolates in hospitals across China is growing during the period from 2005 to 2014. Strengthening infection control and rational antibiotic use are effective to slow the growth of drug resistance.

Objective To investigate the distribution and antibiotic resistance proifle of clinicalEnterobacter isolates using the data from CHINET during the period from 2005 through 2014.Methods A total of 20 558 clinical strains ofEnterobacter spp. were collected from 2005 to 2014 in CHINET Antimicrobial Resistance Surveillance Program. Antimicrobial susceptibility testing was performed with Kirby-Bauer or minimum inhibitory concentration method. The results were analyzed according to CLSI 2014 breakpoints.ResultsEnterobacter cloacae andEnterobacter aerogenes accounted for 71.1% (14 617/20558) and 20.1% (4 129/20 558) of all theEnterobacterisolates, respectively. The proportion ofEnterobacter spp. increased with time from 3.5% in 2005 to 4.3% in 2014. The main source of the isolates was respiratory tract, accounting for 55.2% (11 358/20 558). More than 90% of theEnterobacterisolates were resistant to cefazolin and cefoxitin, but less than 30% of the strains were resistant to cefepime, piperacillin-tazobactam, cefoperazone-sulbactam, amikacin, gentamicin, ciprolfoxacin, meropenem, imipenem and ertapenem. TheEnterobacterisolates showed a trend of declining resistance to most antibiotics except ertapenem and meropenem. The resistance proifle ofEnterobacterisolates varied with departments where they were isolated. The strains from ICU and Department of Surgery were relatively more resistant to antibiotics. The prevalence of multi-drug resistant (MDR) strains was decreasing, but the prevalence of carbapenem-resistantEnterobacter (CRE, resistant to any of imipenem, meropenem or ertapenem) was increasing. The MDR and CRE strains were primarily isolated from ICU and Department of Surgery. At least 30% of the MDREnterobacter strains were resistant to any of the antimicrobial agents tested except meropenem, imipenem and ertapenem and at least 35% of the CRE strains were resistant to any of the antimicrobial agents tested except amikacin and ciprolfoxacin.Conclusions TheEnterobacter isolates in CHINET Antimicrobial Resistance Surveillance Program showed decreasing resistance to most of the antimicrobial agents tested since 2011, but the prevalence of CRE strains increased progressively. Effective measures should be carried out to prevent the spread of CRE strains in hospitals.

Objective To evaluate the changing pattern of antibiotic resistance inKlebsiella strains isolated from the patients in 19 hospitals across China based on the data from CHINET Antimicrobial Resistance Surveillance Program during the period from 2005 through 2014.Methods Kirby-Bauer disk diffusion and automated susceptibility testing methods were used to test the susceptibility ofKlebsiella isolates to the commonly used antibiotics. The results were interpreted according to the criteria of the Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing (CLSI-2014).Results A total of 61 406Klebsiella strains were identified between 2005 and 2014, includingK. pneumoniae (56 281 strains), K. oxytoca(4 779),Klebsiella pneumoniae subsp.Ozaenae (300) and otherKlebsiella species (46). Most (89.0%, 54 664/61 406) of theKlebsiella strains were isolated from inpatients, and 60.0% (36 835/61 406) were from respiratory tract speciems. About 16.7% (10 248/61 406) of the strains were isolated from pediatric patients aged 0-17 years and 83.3% (51 158/61 406) from adult patients. The prevalence ofKlebsiella spp. increased with time from 10.1% in 2005 to 14.3% in 2014. Based on the surveillance data during the 10-year period, we found a marked increase of resistance to imipenem (2.9% to 10.5%) and meropenem (2.8% to 13.4%) inKlebsiella spp. The prevalence of ESBLs-producing isolates inK. pneumoniae andK. oxytoca decreased from 39.0% in 2005 to 30.1% in 2014. The resistance to amikacin, ceftazidime, ciprolfoxacin, pipracillin-tazobactam and cefoperazone-sulbactam was on decline. The resistance rate to cefotaxime remained high about 49.5%. Carbapenem resistantance was identiifed in 5 796 (9.4%) of the isolates, including 5 492 strains ofK. pneumoniae and 280 strains ofK. oxytoca. Overall, 4 740 (7.8%) strains were identiifed as extensively-drug resistant (XDR), including 4 520 strains ofK. pneumoniae and 202 strains ofK. oxytoca. The carbapenem-resistant strains showed high (>60%) resistance rate to majority of the antimicrobial agents tested, but relatively low resistance to tigecycline (16.8%), amikacin (54.4%), and trimethoprim-sulfamethoxazole (55.5%).Conclusions During the 10-year period from 2005 through 2014, carbapenem resistance amongKlebsiella isolates has increased dramatically in the hospitals across China. The level of resistance to other antibiotics remains stable.