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Whole-cell biosensors based on transcriptional regulators are powerful tools for rapid measurement, high-throughput screening, dynamic metabolic regulation, etc. To optimize the biosensing performance of transcriptional regulator, its effector-binding domain is commonly engineered. However, this strategy is encumbered by the limitation of diversifying such a large domain and the risk of affecting effector specificity. Molecular dynamics simulation of effector binding of LysG (an LysR-type transcriptional regulator, LTTR) suggests the crucial role of the short linker helix (LH) connecting effector- and DNA-binding domains in protein conformational change. Directed evolution of LH efficiently produced LysG variants with extended operational range and unaltered effector specificity. The whole-cell biosensor based on the best LysG

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. The effect of Chinese medicine (CM) on mortality during acute exacerbation of COPD is unclear. We evaluated the real-world effectiveness of add-on personalized CM in hospitalized COPD patients with acute exacerbation.This is a retrospective cohort study with new-user design. All electronic medical records of hospitalized adult COPD patients (n = 4781) between July 2011 and November 2019 were extracted. Personalized CM exposure was defined as receiving CM that were prescribed, and not in a fixed form and dose at baseline. A 1:1 matching control cohort was generated from the same source and matched by propensity score. Primary endpoint was mortality. Multivariable Cox regression models were used to estimate the hazard ratio (HR) adjusting the same set of covariates (most prevalent with significant inter-group difference) used in propensity score calculation. Secondary endpoints included the change in hematology and biochemistry, and the association between the use of difference CMs and treatment effect. The prescription pattern was also assessed and the putative targets of the CMs on COPD was analyzed with network pharmacology approach.4325 (90.5%) patients were included in the analysis. The mean total hospital stay was 16.7 ± 11.8 days. In the matched cohort, the absolute risk reduction by add-on personalized CM was 5.2% (3.9% vs 9.1%). The adjusted HR of mortality was 0.13 (95% CI: 0.03 to 0.60, p = 0.008). The result remained robust in the sensitivity analyses. The change in hematology and biochemistry were comparable between groups. Among the top 10 most used CMs, Poria (Fu-ling), Citri Reticulatae Pericarpium (Chen-pi) and Glycyrrhizae Radix Et Rhizoma (Gan-cao) were associated with significant hazard reduction in mortality. The putative targets of the CM used in this cohort on COPD were related to Jak-STAT, Toll-like receptor, and TNF signaling pathway which shares similar mechanism with a range of immunological disorders and infectious diseases.Our results suggest that add-on personalized Chinese medicine was associated with significant mortality reduction in hospitalized COPD patients with acute exacerbation in real-world setting with minimal adverse effect on liver and renal function. Further randomized trials are warranted.

Abnormal platelet activation plays an important role in the development of sepsis. The effect of antiplatelet drugs on the outcome of patients with sepsis remains unclear. This meta-analysis aimed to determine the effect of antiplatelet drugs on the prognosis of patients with sepsis.PubMed, Cochrane Library, CBM, and Embase were searched for all related articles published from inception to April 2018. The primary end point was mortality. Adjusted data were used and statistically analysed.Ten cohort studies were included. The total number of patients with sepsis was 689,897. Data showed that the use of antiplatelet drugs could effectively reduce the mortality of patients with sepsis (odds ratio (OR) = 0.82, 95% CI: 0.81-0.83, p 0.05). Seven studies used aspirin for antiplatelet therapy, and subgroup analysis showed that aspirin effectively reduced ICU or hospital mortality in patients with sepsis (OR = 0.60, 95% CI: 0.53-0.68, p 0.05). A subgroup analysis on the timing of anti-platelet drug administration showed that antiplatelet drugs can reduce mortality when administered either before (OR = 0.78, 95% CI: 0.77-0.80) or after sepsis (OR = 0.59, 95% CI: 0.52-0.67).Antiplatelet drugs, particularly aspirin, could be used to effectively reduce mortality in patients with sepsis.

Graphical abstract, We formulated a traditional Chinese medicine (TCM) prescription, Hanshiyi Formula (HSYF), which was approved and promoted by the Wuhan Municipal Health Commission for treating mild and moderate coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of HSYF on the progression to severe disease in mild and moderate COVID-19 patients. We conducted a retrospective cohort study of patients with mild and moderate COVID-19 in a quarantine station in Wuchang District, Wuhan. Using the real-time Internet information collection application and Centers for Disease Control for the Wuchang District, patient data were collected through patient self-reports and follow-ups. HSYF intervention was defined as the exposure. The primary outcome was the proportion of patients who progressed to a severe disease status, and a stratification analysis was performed. Univariate and multivariate regression analyses were performed to identify influencing factors that may affect the outcome. Further, we used propensity score matching (PSM) to assess the effect of HSYF intervention on the conversion of mild and moderate to a severe disease status. Totally, 721 mild and moderate COVID-19 patients were enrolled, including 430 HSYF users (exposed group) and 291 non-users (control group). No cases in the exposed group and 19 (6.5 %, P < 0.001) cases in the control group progressed to severe disease, and the difference between the two groups (exposed group-control group) was −6.5 % [95 % confidence interval (CI): (−8.87 %, −4.13 %)]. Univariate regression analysis revealed sex (male), age, fever, cough, and fatigue as risk factors for progression to severe disease. After PSM, none of the HSYF users and 7 (4.7 %, P = 0.022) non-users transitioned to severe disease, and the difference between the two groups (exposed group-control group) was −4.7 % [95 % CI: (−8.2 %, −1.2 %)]. Multivariate regression analysis revealed that sex (male) [OR: 3.145; 95 % CI: 1.036–9.545; P = 0.043] and age (> 48 years) [odds ratio (OR): 1.044; 95 % CI: 1.001–1.088; P = 0.044] were independent risk factors for conversion to severe disease. Therefore, HSYF can significantly reduce the progression to severe disease in patients with mild and moderate COVID-19, which may effectively prevent and treat the disease. However, further larger clinical studies are required to verify our results.

To evaluate the efficacy and safety of electroacupuncture vs pelvic floor muscle training (PFMT) plus solifenacin for women with mixed urinary incontinence (MUI).This randomized controlled noninferiority trial was conducted at 10 hospitals in China between March 1, 2014, and October 10, 2016. Participants were randomized 1:1 to receive electroacupuncture (36 sessions) over 12 weeks with 24 weeks of follow-up or PFMT-solifenacin (5 mg/d) over 36 weeks. The primary outcome was percentage change from baseline to week 12 in mean 72-hour incontinence episode frequency (IEF) measured by the 72-hour bladder diary. It was analyzed in the per-protocol set with a prespecified noninferiority margin of 15%.Of 500 women with MUI who were randomized, 467 (239 in the electroacupuncture group and 228 in the PFMT-solifenacin group) completed treatment per protocol and were included in the primary outcome analysis. At weeks 1 through 12, the percentage of reduction from baseline in mean 72-hour IEF was 37.83% in the electroacupuncture group and 36.49% in the PFMT-solifenacin group (between-group difference, -1.34% [95% CI, -9.78% to 7.10%]; P.001 for noninferiority), which demonstrates noninferiority; the treatment effect persisted throughout follow-up. Statistically significant improvements were found for secondary outcomes in both groups, with no meaningful difference between treatments.In women with moderate to severe MUI, electroacupuncture was not inferior to PFMT-solifenacin in decreasing the 72-hour IEF and shows promise as an effective alternative for the treatment of MUI.clinicaltrials.gov Identifier: NCT02047032.

Platelet activation plays an important role in the development of sepsis. During sepsis, platelet activation leads to endothelial cell injury and promotes neutrophil extracellular trap and microthrombus formation, exacerbating septic coagulation and inflammatory reactions. The resultant induction or aggravation of disseminated intravascular coagulation (DIC) leads to organ damage. Antiplatelet drugs can inhibit coagulation and inflammatory reactions in models of sepsis, reducing damage to organ function. Clinical studies suggest that aspirin may improve the prognosis of patients with sepsis. In conclusion, antiplatelet drugs are promising agents that can improve the prognosis of sepsis patients and are expected to become a new line of treatment. However, further clinical studies are required for validation.

Introduction In the pathogenesis of sepsis-induced acute lung injury (ALI), the crosstalk between inflammation and coagulation plays a pivotal role. The aim of this study was to investigate the role of Rho kinase (ROCK) inhibitor in alleviating pulmonary inflammation and coagulation in lipopolysaccharide (LPS)-induced acute lung injury (ALI) models. Methods In the in vivo study, mice were randomized to four different groups: Control, Y-27632 (Y), LPS, and LPS + Y-27632 (LPS + Y). ALI was induced by intranasally administering LPS (10 μg in 50 μL PBS). Y-27632 (10 mg/kg body weight,) was injected intraperitoneally at 18 h and 1 h before LPS challenge. Mice were euthanized at 3 h or 8 h post LPS challenge (N = 8 per group). In the in vitro study, human pulmonary microvascular endothelial cells (HPMECs) were incubated with LPS alone (1 μg/mL) or in combination with 10 μM Y-27632 or 50 μM BAY11-7082. Cells were pretreated with the inhibitors 30 min before exposure to LPS. Three hours later, cells were isolated for subsequent analysis. Results The myeloperoxidase (MPO) activity and fibrinogen deposits in the lung tissue significantly decreased and the lung damage in ALI mouse was attenuated. Pretreatment with Y-27632 markedly reduced the LPS-induced expression of interleukins 1β and 6, and the activation of nuclear factor (NF)-κB. Furthermore, ROCK inhibitor treatment antagonized the expression of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue and HPMECs. Conclusions ROCK inhibition protects against the endotoxin-induced pulmonary inflammation and coagulation via NF-kappaB pathway modulation.

Premature ovarian insufficiency (POI) affects seriously physical and mental health of the patients. Studies show that acupuncture may be promising in treating POI, yet evidence is insufficient. International patient registry, one form of observational study, is designed for evaluating effectiveness and safety of acupuncture in real-world clinical settings. We will face a series of opportunities and challenges. The opportunities are as follows: (1) Interdisciplinary cooperation can improve the effect of acupuncture for POI. (2) The protocol for acupuncture to treat POI has room for improvement. (3) The patient registry study can make up the shortcomings of randomized controlled trials. (4) The patient registry study can collect real-world data and explore responses of different populations to acupuncture and can be the foundation for the successive studies. International patient registry may face technological, ethical and financial challenges, while the established International Patient Registry Platform of Acupuncture-Moxibustion ( www.amreg.org:8082/v3 ) is actively responding to these challenges. Till now there have been more than 300 patients of POI enrolled on this platform.

Based on extensive accumulated evidence and using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, we have developed clinical practice guidelines for the use of acupuncture to treat low back pain (LBP). In the guidelines, we considered the objective and scope of this guide, the diagnostic criteria and syndrome differentiation standards of traditional Chinese medicine and western medicine for LBP, the treatment principles of acupuncture, intervention opportunities for acupuncture, and recommendations for use of different acupuncture therapies for acute/subacute and chronic LBP.

This is the third paper of the series about “Dynamics of algae growth and nutrients in experimental enclosures culturing bighead carp and common carp”. In this paper, phosphorus dynamics were investigated under the condition of culturing bighead carp and common carp with added fish food (nitrogen dynamics is discussed in the second paper because their behaviors are so different from each other). Nearly fifty days’ observation results indicated that the reservoir water was typical of “phosphorus limited” water, and soluble reactive phosphorus (SRP) was the main constituent of measured total phosphorus (TP). The presence of fish food resulted in significantly higher SRP, dissolved total phosphorus (DTP) and TP concentrations in contrast with the reservoir water. Moreover, continuous supply of fish food led to the decline of total nitrogen to total phosphorus (TN:TP) from more than 100 to less than 5. Variations in the ratio of TN to TP favored the growth of blue-green algae. Fish species affected phosphorus concentrations, and culturing bait-eating common carp contributed more to reducing the SRP, DTP and TP concentrations than culturing planktivorous bighead carp. 0.5%, 4.1% and 3.1% TP can be removed in enclosures with culturing bighead carp, common carp and mixed bighead carp and common carp, respectively. Abundant phosphorus in the fish culturing activities may be present as the uneaten food, algae cells, and within the water column and sediment, which should be taken into serious consideration for the target of future water eutrophication prevention and safety of the drinking water supply.

Identifying the symptom clusters (two or more related symptoms) with shared underlying molecular mechanisms has been a vital analysis task to promote the symptom science and precision health. Related studies have applied the clustering algorithms (e.g. k-means, latent class model) to detect the symptom clusters mostly from various kinds of clinical data. In addition, they focused on identifying the symptom clusters (SCs) for a specific disease, which also mainly concerned with the clinical regularities for symptom management. Here, we utilized a network-based clustering algorithm (i.e., BigCLAM) to obtain 208 typical SCs across disease conditions on a large-scale symptom network derived from integrated high-quality disease-symptom associations. Furthermore, we evaluated the underlying shared molecular mechanisms for SCs, i.e., shared genes, protein-protein interaction (PPI) and gene functional annotations using integrated networks and similarity measures. We found that the symptoms in the same SCs tend to share a higher degree of genes, PPIs and have higher functional homogeneities. In addition, we found that most SCs have related symptoms with shared underlying molecular mechanisms (e.g. enriched pathways) across different disease conditions. Our work demonstrated that the integrated network analysis method could be used for identifying robust SCs and investigate the molecular mechanisms of these SCs, which would be valuable for symptom science and precision health.

More and more attention has been paid to the standardization of clinical research data. International clinical data standards mainly include four categories, which are the File Format, Exchange Standard, Analysis Standard and Terminology Standard. Clinical Data Interchange Standards Consortium (CDISC) is the main criteria of exchanging standard and analyzing standard currently. Backwardness of quality and level of the data management have become one of the most important factors that affect the sustained, rapid and healthy development of domestic clinical trials. How to apply international standards of clinical data to narrow the gap of clinical research of Chinese medicine with the international advanced level is a topic which needs to be continuously explored. This paper firstly introduced the CDISC and its two standards, then analyzed the significance of data standardization in clinical research of traditional Chinese medicine (TCM), and finally discussed problems existed in the process of TCM clinical research using CDISC standards. It was suggested that the strengthening on research of relevant TCM semantic structure and its terminology standard is the key problem. The only way to solve this problem is to use the CDISC standards.

Objective Allergic rhinitis (AR) is a common health problem. Summer acupoint application treatment (SAAT) is reported to effectively treat and prevent AR from seasonal onset. In the present study, we aimed to evaluate its effects, especially on the course of AR, through a retrospective study. Method A cross-sectional multicenter study was performed based on patients treated between 2008 and 2009 in 13 clinical centers in China. A total of 1058 outpatients aged ≥2 years with documented AR and ≥1 year SAAT were eligible for enrollment. A case report form (CRF) was completed by both patient and doctor. The CRF was designed to collect data on the patient's history of SAAT, AR condition, and self-reported health condition. The outcomes (dependent variables) were incidence and intensity of AR and concomitant medications used. Data were analyzed with ordinal logistic regression (OLR). Results Treatment course and seasonal pattern of AR were related to all dependent variables positively. After controlling for sample bias and confounding factors, the findings suggested that a 3-year treatment course had better efficacy (OR/incidence of AR: 2.57, 95% CI: 1.76–3.76; OR/intensity of AR: 2.17, 95%CI: 1.50–3.17; OR/concomitant medications: 2.20, 95% CI: 1.50–3.23) compared with a 2-year or less treatment course. Conclusion The results showed that: 1) the length of treatment course was positively associated with the efficacy of SAAT (the longer the treatment course, the better the efficacy); and 2) SAAT was more efficacious in treating seasonal AR than non-seasonal AR.

Ethnopharmacological relevance Traditional Chinese Medicine (TCM) has a history of thousands of years and has made great contributions to the health and well-being of the people. Integrative medicine (IM) treatment, combing TCM and conventional medicine, has been the most representative characteristic for coronary artery disease (CAD) patients in China, especially those in IM hospitals. However, the secondary prevention status of CAD and the potential benefit of IM therapy in improving CAD prognosis remains unclear. Materials and methods By means of a unified clinical and research information platform, we collected clinical information of hospitalized patients with CAD in cardiovascular department of 9 IM hospitals in Beijing and Tianjin from January 2003 to September 2006. The primary endpoints were major adverse cardiac events (MACEs) which include all-cause death in hospital and during one-year follow-up, acute myocardial infarction (AMI), percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). The diagnostic and therapeutic status of CAD patients was evaluated based on the latest available clinical guidelines. Meanwhile, a logistic stepwise regression analysis was also used to identify independent prognostic factors. Results 5284 hospitalized patients with CAD were registered. The top five TCM patterns were in turn blood stasis 79.3%, Qi deficiency 56.5%, phlegm-turbidness 41.1%, Yin deficiency 24.8%, Yang deficiency 11.3%. The standard-reaching rate of CAD patients with hyperlipidemia was 85.6% for total cholesterol, 31.2% for triglyceride, 21.4% for low-density lipoprotein cholesterol, 52.5% for high-density lipoprotein cholesterol, while it was 61.9% and 80.9% in systolic and diastolic blood pressure of CAD with hypertension respectively. The top five commonly used herbs by functions were Qi-tonifying agents 89.25%, blood-activating agents 86.04%, Qi-regulating agents 77.60%, heat-clearing agents 67.50%, dampness-draining agents 65.95%. The herbs commonly used were Salvia miltiorrhiza Bunge 63.10%, Poria 59.99%, Raidx Astragali 49.67%, Radix Paeoniae Rubra 48.71%, peach seed 47.32%, angelica 46.82%, Radix Ligustici Chuanxiong 46.36%, safflower 45.40%, Pinellia 45.30%, glycyrrhiza 41.36%. 90 patients (1.7%) died in hospital, and the overall incidence of endpoints was 6.1% (322/5284). The logistic stepwise regress analysis showed that AMI (OR, 5.62, 95% CI = 2.56–12.33), heart failure (OR, 2.68, 95% CI = 1.67–4.29), age ≥ 60 years (OR, 2.01, 95% CI = 1.22–3.30), and medication of phosphodiesterase inhibitors (OR, 1.67, 95% CI = 1.15–2.42) were independent risk factors for in-hospital mortality and one-year follow-up MACEs, while statins (OR, 0.23, 95% CI = 0.06–0.91) and IM therapy (OR, 0.69, 95% CI = 0.49–0.97) were protective factors. Conclusion There was still certain gap between the usage of conventional medicine and clinical guideline in IM hospitals of China. Integrative Medicine might have potential benefit for CAD patients in reducing MACEs. However, the scheme of IM intervention and the mechanism of action are still needed to be further determined.

Background Acupuncture has been used for women during menopause transition, but evidence is limited. Objective We sought to evaluate the efficacy of electroacupuncture on relieving symptoms of women during menopause transition. Study Design We conducted a prospective, multicenter, randomized, participant-blinded trial in China mainland. Subjects were randomized to receive 24 treatment sessions of electroacupuncture at traditional acupoints or sham electroacupuncture at nonacupoints over 8 weeks with 24 weeks’ follow-up. Primary outcome was the change from baseline in the total score of Menopause Rating Scale at week 8. Secondary outcomes included the changes from baseline in the average 24-hour hot flash score, the Menopause Rating Scale subscale scores, the total score of Menopause-Specific Quality of Life Questionnaire and its subscales, and serum female hormones. All analyses were performed with a 2-sided P value of Results A total of 360 women (180 in each group) with menopause-related symptoms during menopause transition were enrolled from June 9, 2013, through Dec 28, 2015. At week 8, the reduction from baseline in the Menopause Rating Scale total score was 6.3 (95% confidence interval, 5.0–7.7) in the electroacupuncture group and 4.5 (95% confidence interval, 3.2–5.8) in the sham electroacupuncture group with a between-group difference of 1.8 (95% confidence interval, 0.9–2.8; P = .0002), less than the minimal clinically important difference of 5 points’ reduction. For secondary outcomes, the between-group differences for the decrease in the mean 24-hour hot flash score were significant at weeks 8, 20, and 32, but all were less than the minimal clinically important difference in previous reports. Interestingly, the between-group differences for the Menopause-Specific Quality of Life Questionnaire total score reduction were 5.7 at week 8, 7.1 at week 20, and 8.4 at week 32, greater than the minimal clinically important difference of 4 points. Changes from baseline in follicle-stimulating hormone, luteinizing hormone, and estradiol levels at weeks 8 and 20 (P > .05 for all), with the exception of follicle-stimulating hormone/luteinizing hormone ratios (P = .0024 at week 8 and .0499 at week 20), did not differ between groups. Conclusion Among women during menopause transition, 8 weeks’ electroacupuncture treatment did not seem to relieve menopausal symptoms, even though it appeared to improve their quality of life. Generalizability of the trial results may be limited by mild baseline menopausal symptoms in the included participants.

Objective: Traditional Chinese medicine (TCM) is a scientific discipline, which develops the related theories from the long-term clinical practices. The large-scale clinical data are the core empirical knowledge source for TCM research. This paper introduces a clinical data warehouse (CDW) system, which incorporates the structured electronic medical record (SEMR) data for medical knowledge discovery and TCM clinical decision support (CDS). Materials and methods: We have developed the clinical reference information model (RIM) and physical data model to manage the various information entities and their relationships in TCM clinical data. An extraction-transformation-loading (ETL) tool is implemented to integrate and normalize the clinical data from different operational data sources. The CDW includes online analytical processing (OLAP) and complex network analysis (CNA) components to explore the various clinical relationships. Furthermore, the data mining and CNA methods are used to discover the valuable clinical knowledge from the data. Results: The CDW has integrated 20,000 TCM inpatient data and 20,000 outpatient data, which contains manifestations (e.g. symptoms, physical examinations and laboratory test results), diagnoses and prescriptions as the main information components. We propose a practical solution to accomplish the large-scale clinical data integration and preprocessing tasks. Meanwhile, we have developed over 400 OLAP reports to enable the multidimensional analysis of clinical data and the case-based CDS. We have successfully conducted several interesting data mining applications. Particularly, we use various classification methods, namely support vector machine, decision tree and Bayesian network, to discover the knowledge of syndrome differentiation. Furthermore, we have applied association rule and CNA to extract the useful acupuncture point and herb combination patterns from the clinical prescriptions. Conclusion: A CDW system consisting of TCM clinical RIM, ETL, OLAP and data mining as the core components has been developed to facilitate the tasks of TCM knowledge discovery and CDS. We have conducted several OLAP and data mining tasks to explore the empirical knowledge from the TCM clinical data. The CDW platform would be a promising infrastructure to make full use of the TCM clinical data for scientific hypothesis generation, and promote the development of TCM from individualized empirical knowledge to large-scale evidence-based medicine.