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Abstract Diabetic kidney disease (DKD) is more prevalent with an increase in diabetes mellitus. Oxidative stress is a major factor in the occurrence and progression of DKD. Defending against oxidative stress and restoring antioxidant defense might be key to preventing and treating DKD. The purpose of this article is to provide an explanation of how oxidative stress affects DKD, conduct a systematic review and meta-analysis on DKD, and examine the effect of antioxidants on the disease. An analysis of 19 randomized controlled trials showed that the use of antioxidants could reduce UAE (albumin excretion rate) in patients with DKD (SMD: − 0.31; 95% CI [− 0.47, − 0.14], I2 = 0%), UACR (urine albumin/creatinine ratio) (SMD: − 0.60; 95% CI [− 1.15, − 0.06], I2 = 89%), glycosylated hemoglobin (hbA1c) (MD: − 0.61; 95% CI [− 1.00, − 0.21], I2 = 93%) and MDA (malonaldehyde) (SMD:-1.05; 95% CI [− 1.87, − 0.23], I2 = 94%), suggesting that antioxidants seemed to have therapeutic effects in patients with DKD, especially in reducing proteinuria and hbA1c. The purpose of this study is to provide new targets and ideas for drug research and clinical treatment of DKD.

Background: Inflammation has a significant role in the onset and progression of inflammatory bowel disease (IBD). Increasing attention has been paid to the use of acupuncture in IBD patients; however, its regulatory effects on inflammatory factors in IBD still require validation. Here, we systematically evaluated the effects of acupuncture on inflammatory factors in IBD patients. Methods: Eight electronic databases were searched for studies that met the inclusion criteria. After evaluating the quality of the studies selected by two reviewers, the meta-analysis was performed to assess the efficacy of acupuncture in IBD patients and the impact on inflammatory factors (TNF-α, IL-1, IL-8 and IL-10). Results: Four randomized controlled trials with a total of 228 patients satisfied the inclusion criteria. Acupuncture has a positive therapeutic impact on IBD (MD = 1.22, 95% CI [1.07, 1.39], P = 0.003). Moreover, it regulates the levels of TNF-α (MD =−60.58, 95% CI [−100.30, −20.89], P = 0.003), IL-8 (MD =−56.40, 95% CI [−60.02, −52.14], P

BackgroundPrevious studies found that Jinlida granules could significantly reduce blood glucose levels and enhance the low-glucose action of metformin. However, the role of Jinlida in the standard-reaching rate of blood glucose and improving clinical symptoms has yet to be studied. We aimed to elaborate on the efficacy of Jinlida in type 2 diabetes (T2D) patients who experience clinical symptoms based on secondary analysis of a randomized controlled trial.MethodsData were analyzed from a 12-week, randomized, placebo-controlled study of Jinlida. The standard-reaching rate of blood glucose, the symptom disappearance rate, the symptom improvement rate, the efficacy of single symptoms, and the total symptom score were evaluated. The correlation between HbA1c and the improvement of clinical symptoms was analyzed.ResultsFor 12 weeks straight, 192 T2D patients were randomly assigned to receive either Jinlida or a placebo. The treatment group showed statistically significant differences in the standard-reaching rate of HbA1c < 6.5% (p = 0.046) and 2hPG (< 10 mmol/L, 11.1 mmol/L) (p < 0.001), compared with the control group. The standard-reaching rate of HbA1c < 7% (p = 0.06) and FBG < 7.0 mmol/L (p = 0.079) were not significantly different between the treatment and control groups. Five symptoms exhibited a statistical difference in symptom disappearance rate (p < 0.05). All the symptoms exhibited a significant difference in symptom improvement rate (p < 0.05). The mean change in total symptom score from baseline to week 12 was −5.45 ± 3.98 in the treatment group and −2.38 ± 3.11 in the control group, with statistically significant differences (p < 0.001). No significant correlations were noted between symptom improvement and HbA1c after 12 weeks of continuous intervention with Jinlida granules or placebo.ConclusionJinlida granules can effectively improve the standard-reaching rate of blood glucose and clinical symptoms of T2D patients, including thirst, fatigue, increased eating with rapid hungering, polyuria, dry mouth, spontaneous sweating, night sweat, vexing heat in the chest, palms, and soles, and constipation. Jinlida granules can be used as an effective adjuvant treatment for T2D patients who experience those symptoms.

The severe acute respiratory syndrome coronavirus - 2 (SARS - CoV - 2) was reported to cause the Wuhan outbreak of the corona virus disease 2019(COVID-19). To date, the COVID-19 has infected more than 600 million people gloabally. As a growing number of patients recover from acute infections and are discharged from hospitals, the proportion of patients in the recovery period is gradually increasing. Many of these individuals have been reported to experience multiple symptoms during the convalescence, such as fatigue, dyspnea and pain which are designated as “long-COVID”, “post-COVID syndrome” or “recovery sequelae. We searched for recent articles published in PubMed on COVID-19 convalescence and found that the pathogenesis of COVID-19 convalescence is not yet well recognized. It may be associated with incomplete recovery of immune system, parenchymal organ damage (liver or lung), coagulation abnormalities, “second hit” caused by viral infection, and Phenomenon of Cell Senescence-Associated Secretory Phenotype (SASP). Some drugs and psychological factors of patients also play a non-negligible role in it. We also found that the effect of traditional Chinese medicine (TCM) is effective in the treatment of the COVID-19 recovery phase, which can not only relieve the corresponding symptoms, but also improve the indicators and pulmonary fibrosis. Bufei Huoxue Capsule, as the only drug explicitly mentioned for COVID-19 recovery period, can exert strong rehabilitative effects on physiological activity in patients recovering from COVID-19. In addition, in previous studies, traditional Chinese medicine has been confirmed to have the ability to resist cytokine storms, as well as improve coagulation and myocardial damage, which makes it have potential therapeutic advantages in targeting the hyperimmune response, coagulation abnormalities and myocardial damage existing in the recovery period. In conclusion, the clinical symptoms of patients convalescing from COVID-19 are complex, and its pathogenesis has not been elucidated. traditional Chinese medicine, as a traditional treatment, its specific action and mechanism need to be confirmed by more studies, so that it can play a better role.

Abstract Since the outbreak of coronavirus disease 2019 (COVID-19), traditional Chinese medicine (TCM) has made an important contribution to the prevention and control of the epidemic. This review aimed to evaluate the efficacy and explore the mechanisms of TCM for COVID-19. We systematically searched 7 databases from their inception up to July 21, 2021, to distinguish randomized controlled trials (RCTs), cohort studies (CSs), and case–control studies (CCSs) of TCM for COVID-19. Two reviewers independently completed the screening of literature, extraction of data, and quality assessment of included studies. Meta-analysis was performed using Review Manager 5.4 software. Eventually, 29 RCTs involving 3060 patients and 28 retrospective studies (RSs) involving 12,460 patients were included. The meta-analysis demonstrated that TCM could decrease the proportion of patients progressing to severe cases by 55% and the mortality rate of severe or critical patients by 49%. Moreover, TCM could relieve clinical symptoms, curtail the length of hospital stay, improve laboratory indicators, and so on. In addition, we consulted the literature and obtained 149 components of Chinese medicinal herbs that could stably bind to antiviral targets or anti-inflammatory or immune-regulating targets by the prediction of molecular docking. It suggested that the mechanisms involved anti-virus, anti-inflammation, and regulation of immunity. Our study made a systematic review on the efficacy of TCM for COVID-19 and discussed the possible mechanisms, which provided clinical reference and theoretical basis for further research on the mechanism of TCM for COVID-19.

In terms of treatment, a particularly targeted drug is needed to combat the COVID-19 pandemic. Although there are currently no specific drugs for COVID-19, traditional Chinese medicine(TCM) is clearly effective. It is recommended that through data analysis and mining of TCM cases (expert experience) and population evidence (RCT and cohort studies), core prescriptions for various efficacy can be obtained. Starting from a multidimensional model of regulating immunity, improving inflammation, and protecting multiple organs, this paper constructs a multidimensional model of targeted drug discovery, integrating molecular, cellular, and animal efficacy evaluation. Through functional activity testing, biophysical detection of compound binding to target proteins, multidimensional pharmacodynamic evaluation systems of cells (Vero E6, Vero, Vero81, Huh7, and caca2) and animals (mice infected with the new coronavirus, rhesus macaques, and hamsters), the effectiveness of effective preparations was evaluated, and various efficacy effects including lung moisturizing, dehumidification and detoxification were obtained. Using modern technology, it is now possible to understand how the immune system is controlled, how inflammation is reduced, and how various organs are protected. Complete early drug characterization and finally obtain effective targeted TCM. This article provides a demonstration resource for the development of new drugs specifically for TCM.

The Hippo signaling pathway is involved in cell growth, proliferation, and apoptosis, and it plays a key role in regulating organ size, tissue regeneration, and tumor development. The Hippo signaling pathway also participates in the occurrence and development of various human diseases. Recently, many studies have shown that the Hippo pathway is closely related to renal diseases, including renal cancer, cystic kidney disease, diabetic nephropathy, and renal fibrosis, and it promotes the transformation of acute kidney disease to chronic kidney disease (CKD). The present paper summarizes and analyzes the research status of the Hippo signaling pathway in different kidney diseases, and it also summarizes the expression of Hippo signaling pathway components in pathological tissues of kidney diseases. In addition, the present paper discusses the positive therapeutic significance of traditional Chinese medicine (TCM) in regulating the Hippo signaling pathway for treating kidney diseases. This article introduces new targets and ideas for drug development, clinical diagnosis, and treatment of kidney diseases.

IntroductionDiabetic kidney disease (DKD) is a severe and growing health problem, associated with a worse prognosis and higher overall mortality rates than non-diabetic renal disease. Chinese herbs possess promising clinical benefits in alleviating the progression of DKD due to their multi-target effect. This real-world retrospective cohort trial aimed to investigate the efficacy and safety of Naoxintong (NXT) capsules in the treatment of DKD. Our study is the first real-world study (RWS) of NXT in the treatment of DKD based on a large database, providing a basis for clinical application and promotion.MethodsThe data was collected from Tianjin Healthcare and Medical Big Data Platform. Patients with DKD were enrolled from January 1, 2011, to March 31, 2021. NXT administration was defined as the exposure. The primary outcome was the change in estimated glomerular filtration rate (eGFR). We employed the propensity score matching (PSM) method to deal with confounding factors.ResultsA total of 1,798 patients were enrolled after PSM, including 899 NXT users (exposed group) and 899 non-users (control group). The eGFR changes from baseline to the end of the study were significantly different in the exposed group compared to the control group (-1.46 ± 21.94 vs -5.82 ± 19.8 mL/(min·1.73m2), P< 0.01). Patients in the NXT group had a lower risk of composite renal outcome event (HR, 0.71; 95%CI, 0.55 to 0.92; P = 0.009) and deterioration of renal function (HR, 0.74; 95% CI, 0.56 to 0.99; P = 0.039).ConclusionNXT can significantly slow the decline of eGFR and reduce the risk of renal outcomes. However, large cohort studies and RCTs are needed to further confirm our results.

Diabetic kidney disease (DKD) is one of the major public health problems in society today. It is a renal complication caused by diabetes mellitus with predominantly microangiopathy and is a major cause of end-stage renal disease (ESRD). Autophagy is a metabolic pathway for the intracellular degradation of cytoplasmic products and damaged organelles and plays a vital role in maintaining homeostasis and function of the renal cells. The dysregulation of autophagy in the hyperglycaemic state of diabetes mellitus can lead to the progression of DKD, and the activation or restoration of autophagy through drugs is beneficial to the recovery of renal function. This review summarizes the physiological process of autophagy, illustrates the close link between DKD and autophagy, and discusses the effects of drugs on autophagy and the signaling pathways involved from the perspective of podocytes, renal tubular epithelial cells, and mesangial cells, in the hope that this will be useful for clinical treatment.

Background: Acute bronchitis (AB) is a common disease in pediatrics. Prolonged AB may develop into chronic bronchitis. Bronchitis caused by the influenza virus can lead to severe hypoxia or insufficient ventilation, causing great harm to patients and increasing the burden on children and society. Presently, there is no specific treatment for AB except symptomatic supportive treatment. It is urgent to find an effective treatment for AB. Jinzhen Oral Liquid (JZOL) has been found to have a broad spectrum of anti-inflammatory and antiviral effects in previous clinical and basic studies and has a good effect on AB in children. However, the large-sample, randomized, double-blind, head-to-head, evidence-based studies are lacking. The purpose of this protocol is to evaluate the efficacy, safety, and mechanism of JZOL in the treatment of AB in children.Methods: This is a randomized, double-blind, parallel-controlled multi-center clinical trial. The sample size is 500 participants in the intervention group and the control group respectively, with a total of 1000 participants. They will be recruited by 10 hospitals in China. The Intervention group takes JZOL and Ambroxol Hydrochloride and Clenbuterol Hydrochloride Oral Solution (AHCHOS) placebo, while the control group receives AHCHOS and JZOL placebo. The dosage of the two drugs varies according to age and weight. The medication lasts for 7 days. The disappearance time of cough is adopted as the primary outcome. Quality control will be carried out at every stage of data management and processing to ensure that all data are reliable and processed correctly. SAS is used for statistical analysis. Intention-to-treat analysis will be carried out in this trial. All statistical tests are conducted using a two-sided test, and p

Abstract The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), first broke out in Wuhan, China, in 2019. SARS-CoV-2 develops many types of mutations (such as B.1.1.7), making diagnosis and treatment challenging. Although we now have a preliminary understanding of COVID-19, including pathological changes, clinical manifestations, and treatment measures, we also face new difficulties. The biggest problem is that most COVID-19 patients might face sequelae (e.g., fatigue, sleep disturbance, pulmonary fibrosis) during the recovery phase. We aimed to test six Chinese patent medicines to treat three major abnormal symptoms in COVID-19 patients during the recovery phase, including cardiopulmonary function, sleep disturbance, and digestive function. We launched the “three syndromes and six Chinese patent medicines” randomized, double-blind, placebo-controlled, multicenter clinical trial on April 10, 2020. The results showed that Jinshuibao tablets and Shengmaiyin oral liquid significantly improved the cardiopulmonary function of recovering COVID-19 patients. Shumian capsules, but not Xiaoyao capsules, significantly improved patients’ sleep disorders. This might be because the indication of Xiaoyao capsules is liver qi stagnation rather than psychological or emotional problems. Xiangsha Liujun pills and Ludangshen oral liquid significantly improved digestive function. Our research provides a guideline for treating COVID-19 sequelae in patients during the recovery period based on high-quality evidence.

BackgroundDiabetic retinopathy (DR), one of the commonest microvascular complications in diabetic patients, is featured by a series of fundus lesions. Conventional Western medicine therapies for DR are always with modest treatment outcome. This paper is to assess the ocular fundus signs, vision and safety of Chinese patent medicines (CPMs) as an add-on treatment for DR.Method7 electronic databases were searched to determine eligible trials. Randomized controlled trials (RCTs) of non-proliferative diabetic retinopathy (NPDR) in which the intervention group received CPMs combined with calcium dobesilate (CD), and the control group received only CD were included for analysis. Two reviewers extracted the data independently. Results expressing as mean differences (MD) and relative risks (RR) were analyzed with a fixed-effects or random-effects models.Results19 RCTs involved 1568 participants with 1622 eyes met our inclusion criteria. The results suggested that compared with CD alone, CPMs plus CD for NPDR was superior at reducing the microaneurysm volume (MD -3.37; 95% confidence interval [CI], -3.59 to -3.14), microaneurysm counts (MD -2.29; 95%CI -2.97 to -1.61), hemorrhage area (MD -0.79; 95%CI -0.83 to -0.75), and macular thickness (MD -59.72; 95%CI -63.24 to -56.20). Participants in CPMs plus CD group also achieved a better vision. No obvious adverse events occurred.ConclusionCPMs as an add-on therapy for NPDR have additional benefits and be generally safe. This meta‐analysis demonstrated that CPMs combined with CD could improve retinal microaneurysm, hemorrhage, macular thickness, visual acuity, fasting blood glucose (FBG), and glycosylated hemoglobin (HbAlc) compared with CD alone. Further studies are needed to provide more conclusive evidence.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42021257999.

BackgroundDiabetic renal fibrosis (DRF) is an irreversible renal pathological change in the end-stage of diabetic kidney disease (DKD), which plays a significant role in the development and deterioration of the disease. However, data for bibliometric analysis of renal fibrosis in DKD is currently missing. This study aimed to provide a comprehensive and visualized view of DRF research and lay the foundation for further studies.Materials and MethodsFirstly, the data was collected from the Web of Science Core Collection (WoSCC) database. Secondly, the Web of Science analytic tool was performed to analyze publication years, authors, countries/regions, organizations, and citation frequency. Finally, CiteSpace was employed to construct a visualization bibliometric network to reveal the emerging trends and hotspots of DRF.ResultsA total of 3,821 publications from 1985 to 2020 were included in this study. The number of publications has maintained a growth trend since 2003. Cooper is the most prolific author in this field, and the American Journal of Physiology-Renal Physiology ranking as first place compared with other journals. In terms of the number of publications, China contributed the most to DRF. Monash University is the organization that published the most papers. The top 5 clusters of keyword co-appearance are “chronic kidney disease”, “primary biliary cirrhosis”, “receptor”, “TGF-beta”, “renal tubulointerstitium”. The top 5 clusters of reference co-citation are “microRNAs”, “bone morphogenetic protein”, “hypertrophy”, “glomerulosclerosis”, “diabetic kidney disease”. The strongest citation burst of keyword is “diabetic kidney disease” and the strongest burst of cited reference is “Meng, 2016”.ConclusionsThe present study analyzed the research hotspots, Frontiers, and development trend of DRF and have important implications for future research.

Background: Type 2 diabetes mellitus (T2DM) complicated with dyslipidaemia is associated with a high risk of cardiovascular diseases. The Jiangtang Tiaozhi (JTTZ) recipe is a Chinese herbal formula that has been used to regulate the blood glucose and lipid levels for many years. Interestingly, a previous study has demonstrated its efficacy; however, the associated mechanism remains unclear. We hypothesised that the therapeutic effect of the JTTZ on patients with T2DM may be mediated by the modulation of metabolites secreted by the gut microbiota. This study aims to examine this mechanism.Methods and analysis: This study is a randomised, positive drug parallel-controlled, open-label clinical trial in patients with T2DM and dyslipidaemia. A total of 96 patients will be recruited and randomly assigned to treatment with JTTZ or metformin for 12 weeks. The primary outcome will be the rates of effectively regulated blood glucose and lipid levels (measured with the levels of glycated haemoglobin, fasting plasma glucose, 2-h plasma glucose, triglyceride, and low-density lipoprotein cholesterol). The secondary outcomes will be the changes in body weight, body mass index, and waist circumference and Traditional Chinese Medicine symptom scores. In addition, 16S rRNA gene sequencing will be performed on the gut microbiota obtained from faeces, and metabolomics analysis will be performed based on blood and gut microbiota samples. Intention-to-treat, per-protocol analysis and safety analysis will be performed.Clinical trial registration number: https://clinicaltrials.gov/ct2/show/NCT04623567

Abstract Background Diabetic retinopathy (DR) is the leading cause of blindness in many countries. The current treatment for non-proliferative DR (NPDR) using Western medicine (WM) alone is insufficient. At present, the combination of NPDR treatment with traditional Chinese medicine (TCM) and WM is universally applied. We aimed to evaluate the effectiveness and safety of TCM as an add-on for NPDR using a systematic review and meta-analysis. Method Data from randomized controlled trials (RCTs) of TCM for NPDR treatment along with WM before July 6, 2019, were collected from the China National Knowledge Infrastructure, Wanfang Database, China Biomedical Database, Pubmed, Embase, and Cochrane Library. Relevant data were extracted by two reviewers. I 2 statistics was adopted to appraise heterogeneity. If I 2

Abstract Background Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease and has become a heavy economic and social burden due to its high prevalence and morbidity. The most effective strategy is that patients with DKD should be diagnosed and treated early. Preliminary studies showed that the Chinese herbal Tangshen Formula (TSF) may delay the progression of DKD, reducing microalbuminuria and macroalbuminuria and improving renal function. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of TSF in patients with DKD. Methods/design This trial is a 13-center, randomized, double-blind, placebo-controlled study. A total of 632 participants will be randomized in a 1:1 ratio to an experiment group (TSF plus losartan) and a control group (placebo plus losartan). The trial cycle will last 24 weeks. The primary outcome will be the change in the urine microalbumin–creatinine ratio from baseline to week 24. The secondary outcome will be the change in the rate of progression to the clinical proteinuria period after intervention, the rate of urine microalbumin negative conversion, the rate of normal urinary microalbumin, the doubling rate of the baseline creatinine value and the glomerular filtration rate between the two groups. Safety in medication will also be evaluated. Discussion We hypothesize that patients with type 2 diabetes in the early stage of DKD will benefit from TSF. If successful, this study will provide evidence-based recommendations for clinicians. Trial registration ClinicalTrials.gov, NCT03009864. Registered January 2017.

Abstract Introduction Radix Salviae (Dan-shen in pinyin), a classic Chinese herb, has been extensively used to treat diabetic retinopathy in clinical practice in China for many years. However, the pharmacological mechanisms of Radix Salviae remain vague. The aim of this study was to decrypt the underlying mechanisms of Radix Salviae in the treatment of diabetic retinopathy using a systems pharmacology approach. Methods A network pharmacology-based strategy was proposed to elucidate the underlying multi-component, multi-target, and multi-pathway mode of action of Radix Salviae against diabetic retinopathy. First, we collected putative targets of Radix Salviae based on the Traditional Chinese Medicine System Pharmacology database and a network of the interactions among the putative targets of Radix Salviae and known therapeutic targets of diabetic retinopathy was built. Then, two topological parameters, “degree” and “closeness certainty” were calculated to identify the major targets in the network. Furthermore, the major hubs were imported to the Database for Annotation, Visualization and Integrated Discovery to perform a pathway enrichment analysis. Results A total of 130 nodes, including 18 putative targets of Radix Salviae, were observed to be major hubs in terms of topological importance. The results of pathway enrichment analysis indicated that putative targets of Radix Salviae mostly participated in various pathways associated with angiogenesis, protein metabolism, inflammatory response, apoptosis, and cell proliferation. The putative targets of Radix Salviae (vascular endothelial growth factor, matrix metalloproteinases, plasminogen, insulin-like growth factor-1, and cyclooxygenase-2) were recognized as active factors involved in the main biological functions of treatment, which implied that these were involved in the underlying mechanisms of Radix Salviae on diabetic retinopathy. Conclusions Radix Salviae could alleviate diabetic retinopathy via the molecular mechanisms predicted by network pharmacology. This research demonstrates that the network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine from a holistic perspective.

Traditional Chinese medicine (TCM) prescriptions lack standardization due to the complex composition of the prescribed herbs, the unclear mechanism of the formulas, and a lack of scientific data to support the dose-response relationship. Here, we proposed a new clinical strategy of dosage modification for TCM prescriptions to evaluate the clinical efficacy and guide the clinical medication. This study used two TCM prescriptions for the treatment of newly diagnosed type 2 diabetes mellitus (T2DM) to explore the key indications and the most appropriate critical values of dosage modification by analyzing two randomized controlled trials (RCTs). In this study, the indications refer to a change in the indicators from baseline at a certain time point (week 4, week 8, week 12), which could predict the change in outcome indicators, and the critical values refer to the change ranges closely related to the decrease in HbA1c at week 12. In Study 1, the correlation analysis between the change range of indicators at three time points (weeks 4, 8, and 12) from baseline and the decrease in HbA1c at week 12 from baseline (HbA1c 012) was carried out to screen the related indications. Next, we evaluate the related indications and the respective critical values to determine the key indicators, indications, and the most appropriate critical value. We conducted a correlation between the change range of key indicators (obtained from the result of Study 1) at three time points from baseline and HbA1c 012 to screen the key indications in the drug group, high-dose group, and low-dose group in Study 2. Key indications with critical values were determined to investigate the most appropriate critical value in the three groups separately. In Study 1, the key indicator was FBG, the key indication was FBG 04, and the most appropriate critical value was 0.5 mmol/L. In Study 2, the key indication was FBG 04 and the most appropriate critical value was 0.6 mmol/L in the drug group. In the high-dose group, the key indication was FBG 04, and the most appropriate critical value was 0.3 mmol/L. In the low-dose group, the key indication was FBG08, and the most appropriate critical value was 0.1 mmol/L. In addition, we summarized a verification strategy for dosage modification.

Gut microbiota forms a symbiotic relationship with the host and maintains the ecological balance of the internal and external environment of the human body. However, dysbiosis of the gut microbiota and immune deficiency, as well as environmental changes, can destroy the host-microbial balance, leading to the occurrence of a variety of diseases, such as polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), and obesity. Meanwhile, diseases can also affect gut microbiota, forming a vicious cycle. The role of the intestinal microbiota in different diseases have been proven by several studies; however, as a common target of PCOS and T2DM, there are few reports on the treatment of different diseases through the regulation of intestinal microbiota as the critical correlation. This review analyzed the common mechanisms of intestinal microbiota in PCOS and T2DM, including the dysbiosis of gut microbiota, endotoxemia, short-chain fatty acids, biotransformation of bile acids, and synthesis of amino acid in regulating insulin resistance, obesity, chronic inflammation, and mitochondrial dysfunction. The possible therapeutic effects of probiotics and/or prebiotics, fecal microbiota transplantation, bariatric surgery, dietary intervention, drug treatment, and other treatments targeted at regulating intestinal microbiota were also elucidated.

Food is people’s primal want. A reasonable diet and healthy food not only provide nutrients for human growth but also contribute to disease prevention and treatment, while following an unhealthy diet can lead to an increased risk of many diseases, especially metabolic disorders, such as diabetes. Nature is enriched with different food sources, and it seems that purely natural products are more in line with the current concept of health, which enhance the formation of the notion that “Food/Diet Supplements from Natural Sources as a Medicine.” As a delicious fruit, the medicinal values such as anticancer, antibacterial, antioxidation, and antiglycating properties of lychee have been found. Lychee (Litchi in Chinese) is a subtropical fruit plant belonging to the family Sapindaceae. It has been widely cultivated in warm climates worldwide, particularly in China, for thousands of years. In recent years, various phytochemical components such as quercetin, procyanidin A2, and (2R)-naringenin-7-O-(3-O-αL-rhamnopyranosyl-β-D-glucopyranoside) have been identified in a lychee seed, which may lend a lychee seed as a relatively safe and inexpensive adjuvant treatment for diabetes and diabetic complications. In fact, accumulating evidence has shown that lychee seed, lychee seed extracts, and related compounds have promising antihyperglycemic activities, including improving insulin resistance, anti-inflammatory effect, lipid regulation, neuroprotection, antineurotoxic effect, and renoprotection effect. In this review, we summarized publications on antiglycemic effects and mechanisms of lychee seed, lychee seed extracts, and related compounds, which included their efficacies as a cure for diabetes and diabetic complications in cells, animals, and humans, attempting to obtain a robust evidence basis for the clinical application and value of lychee seed.

Panax ginseng C.A.Mey. has been widely consumed as food/diet supplements from natural sources, and its therapeutic properties have also aroused widespread concern. Therapeutic properties of Panax ginseng C.A.Mey. such as anti-inflammatory, ameliorating chronic inflammation, enhancing the immunity, resisting the oxidation again, and regulating the glucose and lipid metabolism have been widely reported. Recent years, lots of interesting studies have reported the potential use of Panax ginseng C.A.Mey. in the management of DKD. DKD has become the leading cause of end-stage renal disease worldwide, which increases the risk of premature death and poses a serious financial burden. Although DKD is somehow controllable with different drugs such as Angiotensin-Converting Enzyme Inhibitors (ACEI), Angiotensin Receptor Blockers (ARB) and lowering-glucose agents, modern dietary changes associated with DKD have facilitated research to assess the preventive and therapeutic merits of diet supplements from natural sources as medicine including Panax ginseng C.A.Mey. Findings from many scientific evidences have suggested that Panax ginseng C.A.Mey. can relieve the pathological status in cellular and animal models of DKD. Moreover, a few studies showed that alleviation of clinical phenotype such as reducing albuminuria, serum creatinine and renal anemia in DKD patients after application or consumption of Panax ginseng C.A.Mey.. Therefore, this review aims to discuss the effectiveness of Panax ginseng C.A.Mey. as medicine for targeting pathological phenotypes in DKD from a pharmacological perspective. This review will provide new insights into the potential understanding use of Panax ginseng C.A.Mey. in the management of DKD in clinical settings.

Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

Background: Diabetic peripheral neuropathy (DPN) characterized by nerve damage is a common and disabling chronic microvascular complication in patients with type 2 diabetic mellitus (T2DM), affecting at least half of patients diagnosed with T2DM. Unfortunately, the current treatment for DPN is not ideal. Traditional Chinese medicine (TCM), with a unique theoretical system, has made outstanding contributions in the treatment of T2DM and related complications. Mudan granule, a Chinese patent medicine, has been previously validated that could ameliorate the symptoms, promote nerve tissue repair, increase nerve conduction velocity (NCV) in patients with DPN. However, the previous studies are of variable quality, which limits the clinical application of Mudan granule. Therefore, we designed a double-blind, randomized, placebo-controlled, parallel-arm, multi-center trial to estimate the safety and efficacy of Mudan granule in conjunction with methylcobalamin in individuals suffering from type 2 diabetic peripheral neuropathy.Methods: This work is conducted as a 14-center, double-blind, randomized, placebo-controlled, parallel-arm trial. In all, 402 subjects (aged 30–70 years) will be recruited and randomized in a 1:1 ratio to an intervention group (n = 201; Mudan granule + methylcobalamin) and a control group (n = 201; placebo + methylcobalamin). Treatment is administered in 24 weeks cycles without any treatment interruption between cycles. Michigan Diabetic Neuropathy Score (MDNS) as the primary outcome will be evaluated at baseline, 12 weeks during the intervention period, and after 24 weeks of the intervention. Adverse events and safety assessments will be also documented. The analysis of all data will be carried out based on a predefined statistical analysis plan.Discussion: The outcomes from this study will offer important evidence regarding the safety and efficacy that Mudan granule can be used as an alternative and complementary therapeutic intervention in patients with type 2 diabetic peripheral neuropathy.Clinical trial registration: Registered at https://clinicaltrials.gov/. Trial registration number: NCT04711980. Registered January 2021.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus causing serious human disease to spread across the world in the past 20 years, after SARS and Middle East respiratory syndrome. As of mid-September 2020, more than 200 countries and territories have reported 30 million cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, including 950,000 deaths. Supportive treatment remains the mainstay of therapy for COVID-19. The World Health Organization reported that four candidate drugs, including remdesivir, are ineffective or have little effect on COVID-19. According to China News, 90 % of Chinese patients with COVID-19 use traditional Chinese medicine (TCM), with an effectiveness rate of 80 %, and no deterioration in patient condition. We have compiled the direct evidence of TCM treatment for COVID-19 as of December 31, 2020. We describe the advantages of TCM in the treatment of COVID-19 based on clinical evidence and the required methods for its clinical use. TCM can inhibit virus replication and transcription, prevent the combination of SARS-CoV-2 and the host, and attenuate the cytokine storm and immune deficiency caused by the virus infection. The cooperation of many countries is required to establish international guidelines regarding the use of TCM in patients with severe COVID-19 from other regions and of different ethnicities. Studies on the psychological abnormalities in patients with COVID-19, and medical staff, is lacking; it is necessary to provide a complete chain of evidence to determine the efficacy of TCM in the related prevention, treatment, and recovery. This study aims to provide a reference for the rational use of TCM in the treatment of COVID-19.

Background: Coronavirus Disease 2019 (COVID-19) is still a relevant global problem. Although some patients have recovered from COVID-19, the sequalae to the SARS-CoV-2 infection may include pulmonary fibrosis, which may contribute to considerable economic burden and health-care challenges. Convalescent Chinese Prescription (CCP) has been widely used during the COVID-19 recovery period for patients who were at high risk of pulmonary fibrosis and is recommended by the Diagnosis and Treatment Protocol for COVID-19 (Trial Version sixth, seventh). However, its underlying mechanism is still unclear.Methods: In this study, an integrated pharmacology approach was implemented, which involved evaluation of absorption, distribution, metabolism and excretion of CCP, data mining of the disease targets, protein-protein interaction (PPI) network construction, and analysis, enrichment analysis, and molecular docking simulation, to predict the bioactive components, potential targets, and molecular mechanism of CCP for pulmonary fibrosis associated with SARS-CoV-2 infection.Results: The active compound of CCP and the candidate targets, including pulmonary fibrosis targets, were obtained through database mining. The Drug-Disease network was constructed. Sixty-five key targets were identified by topological analysis. The findings of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation suggested that the VEGF, Toll-like 4 receptor, MAPK signaling pathway, and TGF-β1 signaling pathways may be involved in pulmonary fibrosis. In the molecular docking analyses, VEGF, TNF-α, IL-6, MMP9 exhibited good binding activity. Findings from our study indicated that CCP could inhibit the expression of VEGF, TNF-α, IL-6, MMP9, TGF-β1 via the VEGF, Toll-like 4 receptor, MAPK, and TGF-β1 signaling pathways.Conclusion: Potential mechanisms involved in CCP treatment for COVID-19 pulmonary fibrosis associated with SARS-CoV-2 infection involves multiple components and multiple target points as well as multiple pathways. These findings may offer a profile for further investigations of the anti-fibrotic mechanism of CCP.

Background: Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes mellitus (DM), which results in blindness among adults worldwide. Presently, the efficacy of drug treatments for diabetic retinopathy (DR) is not satisfactory, thus urgently necessitating effective drug treatment measures. TangWang prescription (TWP) has been found to have retinal protection effects in previous clinical and basic research. However, there is a lack of rigorous, randomized, and controlled studies. This study aims to evaluate the efficacy and safety of TWP in delaying the development of DR.Methods: This study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial, consisting of 384 participants to be randomized in a 1:1 ratio in the treatment and control groups. Furthermore, the treatment and control groups will be administered the TangWang prescription and the placebo, respectively, each at a dose of one bag twice a day. The study period will last for 48 weeks. The primary outcome measure will be the changes in the degree of retinal microvascular lesions before and after treatment. The secondary outcome will be changes in the degree of hemangioma, microvascular bleeding, microvascular leakage, macular edema, and vision. All statistical tests will be two-sided, and a p < 0.05 will be considered statistically significant.Discussion: We hypothesize that the patients with DR will benefit from TangWang prescription, and in addition to the central random system and platform of dynamic information collection, the patients’ conditions will be monitored, and the data collected for analysis. If successful, this study will provide evidence that the TWP formulation delays in the progression of DR.Trial registration: The design of this trial has been registered with the ClinicalTrials.gov (NCT03025399).

Traditional Chinese medicine (TCM) has played a significant role in the treatment of coronavirus disease 2019 (COVID-19) in Wuhan City. During the epidemic, Academician Tong Xiaolin suggested a close association of COVID-19 with cold-dampness, an etiological factor in TCM, by summarizing the characteristics of the COVID-19 patients in Wuhan. and the theory of Cold-dampness Plague was proposed. Based on the Cold-dampness Plague theory, a series of TCM drugs, such as Huoxiang Zhengqi Dropping Pills, Lianhua Qingwen Granules Hanshiyi Formula, and Tongzhi Granule were developed for the different stages, namely mild, moderate, severe, recovery, of the COVID-19. In addition, clinical evidences were obtained through randomized clinical trials or retrospective cohort studies. The Anti-SARS-CoV-2 mechanism of the TCM prescriptions were then summarized from the four aspects: targeting the ACE2 and 3CLPro, targeting cytokines, targeting acute immune responses to SARS-CoV-2, and targeting pulmonary fibrosis. Despite the clinical efficacy and therapeutic pharmacology speculation, more studies such as large-scale randomized clinical trials, cell and animal experiments are needed to further verify the theory of the Cold-dampness Plague in COVID-19 patients.

ObjectiveDuring the follow-up of patients recovered from coronavirus disease 2019 (COVID-19) in the quarantine and observation period, some of the cured patients showed positive results again. The recurrent positive RT-PCR test results drew widespread concern. We observed a certain number of cured COVID-19 patients with positive RT-PCR test results and try to analyze the factors that caused the phenomenon.MethodsWe conducted an observational study in COVID-19 patients discharged from 6 rehabilitation stations in Wuhan, China. All observed subjects met the criteria for hospital discharge and were in quarantine. Data regarding age, sex, body mass index (BMI), course of disease, comorbidity, smoking status and alcohol consumption, symptoms in and out of quarantine, and intervention were collected from the subjects’ medical records and descriptively analyzed. The main outcome of this study was the RT-PCR test result of the observed subjects at the end of quarantine (negative or positive). Logistic regression analysis was used to identify the influencing factors related to recurrent positive RT-PCR test results.ResultsIn this observational study, 420 observed subjects recovered from COVID-19 were included. The median age was 56 years, 63.6% of the subjects were above 50 years old, and 50.7% (213/420) were female. The most common comorbidities were hypertension [26.4% (111/420)], hyperlipidemia [10.7% (45/420)], and diabetes [10.5% (44/420)]. 54.8% (230/420) manifested one or more symptoms at the beginning of the observation period, the most common symptoms were cough [27.6% (116/420)], shortness of breath 23.8% (100/420)], and fatigue [16.2% (68/420)], with fever rare [2.6% (11/420)]. A total of 325 subjects were exposed to comprehensive intervention; 95 subjects were absence of intervention. The recurrence rate of positive RT-PCR test results with comprehensive intervention was 2.8% (9/325), and that with no intervention was 15.8% (15/95). The results of logistic regression analysis showed that after adjusted for factors such as age, sex, and comorbidity and found out that comprehensive intervention was correlated with the recurrent positive RT-PCR test results. There was appreciably less recurrence in the comprehensive intervention group.ConclusionsThe factors related to positive RT-PCR test results in observed subjects recovered from COVID-19 were age, comorbidity, and comprehensive intervention, among which comprehensive intervention might be a protective factor.Clinical Trial RegistrationChictr.org.cn, identifier ChiCTR2000030747.

Background: Metabolic syndrome (MS) is a powerful risk factor for cardiovascular and cerebrovascular diseases. Although lifestyle intervention reduces several of the symptoms of the syndrome and cardiovascular risks, the lifestyle intervention that yields the benefits is restrictive. Jinlida is a Chinese patent medicine that has shown activity in type 2 diabetes, which has been approved in China. Preclinical studies in Jinlida granules support an improved role of abnormal glucose and lipids metabolism as well as reducing weight. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for metabolic syndrome in patients with abnormal glucose metabolism.Methods: This study will enroll 880 subjects (aged 18–70 years) who have metabolic syndromes with abnormal glucose metabolism. All the participants in a double-blind, parallel, randomized, placebo-controlled trial, will receive Jinlida or placebo, orally, 9 g/time, three times daily for 2–4 years period on the basis of lifestyle intervention. The primary outcome measure (Incidence of type 2 diabetes) will be assessed during intervention cycles. Adverse events were monitored. All statistical tests will be performed using a two-sided test, and a p ≤ 0.05 (two-sided test) will be considered to be statistically significant results.Discussion: Results from this study will provide evidence on whether incorporating oral Jinlida granules treatment into lifestyle intervention can delay or inhibit the development of diabetes mellitus in metabolic syndrome subjects with abnormal glucose metabolism.Clinical trial registration: Registered at http://www.chictr.org.cn/enIndex.aspx. Trial registration number: ChiCTR1900023241.

Metabolic syndrome (MetS) is a multifarious metabolic disorder that could severely damage multiple organs. The emergence of MetS has markedly increased medical burden for patients. The treatment of MetS involves multitarget regulation, which is the advantage of traditional Chinese medicine (TCM). Many high-quality studies related to TCM for MetS have been conducted in recent years; however, no overall efficacy analysis has been reported. To evaluate the efficacy and safety of TCM against MetS, we reviewed randomized controlled trials of MetS published in the past decade and then selected and analyzed 16 high-quality articles from over 800 papers. The results showed that TCM might be beneficial in improving body weight as well as in regulating glucose and lipid metabolisms; thus, TCM might be an ideal alternative therapy for MetS management. Treatment safety was also estimated in our analysis. A more elaborately designed and long-term observation of TCM for MetS should be performed in the future.

The global greenhouse gas emitted from shipping activities is one of the factors contributing to global warming; thus, there is an urgent need to mitigate the adverse effect of climate change. One of the key strategies is to build a vibrant maritime industry with the use of innovation and digital technologies as well as intelligent systems. The digitization of the shipping industry not only provides a competitive edge to the shipping business model but also enhances ship operational and energy efficiency. This review paper focuses on the big data analytics and machine learning applied to harbour craft vessels with the aim to achieve fuel efficiency. The paper reviews the telemetry system requires for the digitalization of harbour craft vessels, its challenges in installation, the vessel monitoring and data transmission system. The commonly used methods for data cleaning are also presented. Last but not least, the paper considers two types of the machine learning systems, i.e., supervised and unsupervised machine learning systems. The multi-linear regression and hidden Markov model for supervised machine learning system and the artificial neural network, grey box model and long short-term memory model for unsupervised machine learning are discussed, and their pros and cons are presented.

Abstract Background Diabetic distal symmetric polyneuropathy (DSPN) is one of the most common microvascular complications of diabetes mellitus, and it has become a major public health problem worldwide because of its high and increasing prevalence, morbidity, and disability rate. The current medications for DSPN are not entirely satisfactory. Preliminary studies indicated that the Chinese herbal TangBi Formula may alleviate signs and symptoms and improve the velocity of nerve conduction in patients with DSPN. This study was designed to determine if Chinese herbal medicine used in combination with conventional treatment is more effective than conventional treatment alone. Methods/design We are conducting a multicenter, placebo-controlled, double-blind, randomized, controlled clinical trial as a means of assessing the therapeutic effects of traditional Chinese medicine (TCM) treatment. A total of 188 patients will be randomized in a 1:1 ratio to a treatment group (TangBi Formula plus mecobalamin) and a control group (placebo plus mecobalamin). The test period lasts 6 months, during which all of the patients will be given standard medical care as recommended by established guidelines. The primary outcome will be development of differences in changes in clinical symptoms and signs in patients and changes in Michigan Diabetic Neuropathy Score (MDNS) between the two groups before and after treatment. The secondary outcome will be changes in nerve conduction velocity and in single clinical signs and symptoms. Safety assessments and adverse events will also be evaluated. Discussion We postulate that patients with DSPN will benefit from therapy that includes TCM. If successful, this work will provide an evidence-based complementary therapeutic approach for treatment of DSPN. Trial registration ClinicalTrials.gov, NCT03010241 . Registered on 2 January 2017

As transcription factors derived from transposase, FAR-RED IMPAIRED RESPONSE1 (FAR1) and its homolog FHY3 play crucial roles in the regulation of light signaling and various stress responses by coordinating the expression of downstream target genes. Despite the extensive investigation of the FAR1/FHY3 family in Arabidopsis thaliana and other species, a comprehensive examination of these genes in maize has not been conducted thus far. In this study, we employed a genomic mining approach to identify 16 ZmFAR1 genes in the maize inbred line B73, which were further classified into five subgroups based on their phylogenetic relationships. The present study characterized the predicted polypeptide sequences, molecular weights, isoelectric points, chromosomal distribution, gene structure, conserved motifs, subcellular localizations, phylogenetic relationships, and cis-regulatory elements of all members belonging to the ZmFAR1 family. Furthermore, the tissue-specific expression of the 16 ZmFAR1 genes was analyzed using RNA-seq, and their expression patterns under far-red light conditions were validated in the ear and tassel through qRT-qPCR. The observed highly temporal and spatial expression patterns of these ZmFAR1 genes were likely associated with their specific functional capabilities under different light conditions. Further analysis revealed that six ZmFAR1 genes (ZmFAR1-1, ZmFAR1-10, ZmFAR1-11, ZmFAR1-12, ZmFAR1-14, and ZmFAR1-15) exhibited a response to simulated shading treatment and actively contributed to the development of maize ears. Through the integration of expression quantitative trait loci (eQTL) analyses and population genetics, we identified the presence of potential causal variations in ZmFAR1-14 and ZmFAR1-9, which play a crucial role in regulating the kernel row number and kernel volume weight, respectively. In summary, this study represents the initial identification and characterization of ZmFAR1 family members in maize, uncovering the functional variation in candidate regulatory genes associated with the improvement of significant agronomic traits during modern maize breeding.

Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.

Chondroitin sulfate (CS) has antioxidative, anti-inflammatory, anti-osteoarthritic and hypoglycemic effects. However, whether it has antidiabetic osteoporosis effects has not been reported. Therefore, in this study, we established a STZ-induced diabetic rat model; CS (500 mg kg−1 d−1) was orally administrated for eight weeks to study its preventive effects on diabetic osteoporosis. The results showed that eight weeks of CS treatment improved the symptoms of diabetes; the CS-treated group has increased body weight, decreased water or food intake, decreased blood glucose, increased bone-mineral density, repaired bone morphology and decreased femoral osteoclasts and tibia adipocytes numbers. After CS treatment, bone histomorphometric parameters returned to normal, the levels of serum inflammatory cytokines (IL-1β, IL-6 and TNF-α) decreased significantly, serum SOD, GPX and CAT activities increased and MDA level increased. In the CS-treated group, the levels of serum ALP, CTX-1, TRACP 5b, osteocalcin and RANKL decreased and the serum RUNX 2 and OPG levels increased. Bone immunohistochemistry results showed that CS can effectively increase the expression of OPG and RUNX2 and reduce the expression of RANKL in diabetic rats. All of these indicate that CS could prevent STZ induced diabetic osteoporosis—mainly through decreasing blood glucose, antioxidative stress, anti-inflammation and regulation of OPG/RANKL expression. CS can therefore effectively prevent bone loss caused by diabetes.

BackgroundIt remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM.Methods and findingsThis open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection.ConclusionsThe combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity.Trial registrationClinicalTrials.gov Identifier: NCT03493048.

BackgroundEvidence indicates that the addition of ezetimibe to statin therapy reduces cardiovascular events. However, the impact of ezetimibe–statin combination therapy on coronary plaque regression, plaque stabilization, and diameter stenosis remains a matter of controversy.MethodsWe performed electronic searches in PubMed, Web of Knowledge, and the Cochrane Central Register of Controlled Trials to identify eligible trials assessing the effects of ezetimibe–statin combination therapy versus statin monotherapy reporting at least one outcome among total atheroma volume (TAV), minimum fibrous cap thickness (FCT), lumen volume (LV), and lumen area (LA) derived from intravascular imaging modalities of intravascular ultrasound (IVUS) and optical coherence tomography (OCT). We used the random-effects model and performed trial sequential analysis (TSA) during this meta-analysis.ResultsEleven articles with a total of 926 individuals (460 in the dual-lipid-lowering therapy group and 466 in the statin monotherapy group) were included in the final meta-analysis. Compared to statin monotherapy, ezetimibe–statin combination therapy was associated with significantly decreased TAV [WMD = −3.17, 95% CI (−5.42 to −0.92), and p = 0.006], with no effect on the LV of the coronary artery [WMD = −0.52, 95% CI (−2.24 to 1.21), and p = 0.56], the LA of the coronary artery [WMD = 0.16, 95% CI (−0.10–0.42), and p = 0.22], or minimum FCT thickness [WMD = 19.11, 95%CI (−12.76–50.97)].ConclusionIn patients with coronary artery disease, ezetimibe–statin combination therapy resulted in a significant regression in TAV compared to statin monotherapy, whereas no overall improvements of minimum FCT or lumenal stenosis were observed.

BackgroundExtensive spinal epidural abscess (SEA) is an exceptional and threatening condition that requires prompt recognition and proper management to avoid potentially disastrous complications. We aimed to find key elements of early diagnosis and rational treatments for extensive SEA.Case presentationA 70-year-old man complained of intense pain in the cervical-thoracic-lumbar spine that radiated to the lower extremity. Laboratory test results revealed a marked increase in all indicators of infection. The spinal magnetic resonance imaging (MRI) revealed a ventral SEA extending from C2 to L4. Owing to the patient's critical condition, laminectomy, drainage, and systemic antibiotic therapy were administered. And the multidrug-resistant Staphylococcus epidermidis was detected in the purulent material from this abscess.ResultsPostoperative MRI revealed diminished epidural abscess, and the clinical symptoms were dramatically and gradually relieved after two rounds of surgery and systemic antibiotic therapy involving the combination of ceftriaxone, linezolid, and rifampicin.ConclusionsA comprehensive emergency assessment based on neck or back pain, neurological dysfunctions, signs of systemic infection, and MRI are important for early diagnosis of extensive SEA. Further, the combination of laminectomy, drainage, and systemic antibiotic therapy may be a rational treatment choice for patients with SEA, especially for extensive abscess or progressive neurological dysfunction.

Objective To study the promoting effect of Shenmai injection on myocardial angiogenesis in myocardial infarction(MI) rats. Methods Forty-one MI model rats were divided into model group, low and high-dose groups, with 10 rats each, and 11 rats in the positive group. Low and high-dose groups were treated with 1, 2 mol/kg of Shenmai injection injected intraperitoneally, positive group was treated with 2 mg/kg enalapril. HE staining was used to observe the pathological changes of myocardial tissue in each group. Immunohistochemical staining was used to observe the capillary density in the infarct area. Western blot was used to detect the relative expression of PI3K, AKT, p-AKT and VEGF protein. Results The pathological changes of the low and high-dose groups and the positive group were reduced. Compared with the sham operation group, the capillary density and arteriole density, the expression of PI3K and VEGF protein, and p-AKT/AKT in the model group were increased (P＜0.05). Compared with the model group, the capillary density and arteriole density, the expression of PI3K and VEGF protein, and p-AKT/AKT in the low and high-dose groups and the positive group were increased (P＜0.05). Conclusions Shenmai injection may promote myocardial angiogenesis in MI rats in a dose-dependent manner. It is speculated that the mechanism of this drug is related to the activation of PI3K/AKT signaling pathway.

Background: Vasospastic angina (VSA) is characterized by chest pain at rest with transient ischemic electrocardiographic changes in the ST segment, and a prompt response to nitrates. Vasospastic angina is among the most frequent of the coronary artery diseases in Asia, and coronary computed tomography angiography (CCTA) may become available as a non-invasive diagnosis method. Methods: We prospectively enrolled 100 patients with suspected vasospastic angina at two centers from 2018 to 2020. All patients underwent baseline CCTA without a vasodilator in the early morning followed by catheterized coronary angiography and spasm testing. CCTA with intravenous infusion of nitrate (IV) was repeated within 2 weeks of baseline CCTA. Vasospastic angina as detected by CCTA was defined as significant stenosis (≥50%) with negative remodeling without definite plaques or diffuse small diameter (n = 36; probable positive, n = 18; positive, n = 31). The diagnostic accuracy in terms of CCTA per patient had a sensitivity of 55% (95% CI, 40–69), specificity of 89% (95% CI, 74–97), positive predictive value (PPV) of 87% (95% CI, 72–95), and negative predictive value (NPV) of 59% (95% CI, 51–67). Conclusions: Dual-acquisition CCTA can support the non-invasive detection of vasospastic angina with relatively good specificity and PPV. CCTA was helpful for non-invasive screening of variant angina.

Abstract The anticoagulant application is an effective treatment modality for cardiovascular diseases such as coronary heart disease, unstable angina pectoris, and myocardial infarction. In this study, the antithrombotic effect of recombinant neorudin (EPR‐hirudin, EH) was evaluated using a canine model of coronary artery thrombosis. A canine model with platelet thrombosis in the left circumferent branch of the coronary artery was designed using Folt's method, and the anti‐thrombus activity of EH was investigated. Femoral administration of EH intravenously had a significant dose‐dependent inhibitory effect on canine coronary artery thrombosis and the effective rates were 66.7% (p

Objectives To determine whether the rates of postoperative complications, rate of readmission, cumulative transfusion volume, and length of stay (LOS) differ between simultaneous total hip arthroplasty (THA) and staged bilateral THA and to assess whether the length of the interval between staged procedures influences surgery outcome. Methods This was a retrospective cohort study comparing the rate of postoperative complications, readmission, cumulative transfusion volume, and LOS between simultaneous THA and staged bilateral THA in our hospital's registration database. The inclusion criteria is listed as follows: patients who underwent bilateral primary THA between January 2011 and January 2015 with minimum 3‐month follow‐up; simultaneous bilateral THA; staged bilateral THA; postoperative complications, readmission, cumulative transfusion volume, length of stay of the patients and the influence of the interval between stages of bilateral THA on the outcome above; and retrospective cohort study. Finally, a total of 1145 patients, including simultaneous bilateral THA in 863 patients (1726 hips) and staged bilateral THA in 282 patients (564 hips), were eligible for the present study. The patients were divided into three groups according to the interval time (≤30 days, 30–90 days, >90 days) between the two stages of bilateral THA and we compared postoperative complications, readmission rates, cumulative transfusion volume, and LOS for the three groups. All patients’ medical records and outpatient notes were reviewed to extract preoperative data, perioperative complications, readmission, cumulative transfusion, and LOS. Preoperative information included patients’ age, sex, diagnosis, body mass index, and American Society of Anesthesiologists (ASA) classification. Perioperative complications were sorted into two groups: (i) medical complications included cardiovascular, pulmonary, neurological, digestive, and urologic system complications, along with other miscellaneous issues; and (ii) surgical complications included dislocation, superficial wound infection, hematoma, deep periprosthetic joint infection, and nerve palsy. Patients who failed to come back to visit our hospital in the postoperative 3 months were followed up by telephone, at which point we inquired about any postoperative complications and readmission. Results Simultaneous THA was performed more often in younger men, and patients in the simultaneous group had fewer major medical complications (excluding venous thromboembolism), fewer surgical complications, and shorter hospital stays; however, patients in the simultaneous group were likelier to have a higher transfusion rate than patients in the staged group. Among patients in the staged group, there were no differences for differing time intervals, except that patients with a between‐stage interval of ≤30 days required more blood transfusions. Conclusion With careful patient assessment and selection, simultaneous bilateral THA is a safe procedure, and has lower rates of surgical and major medical complications than staged bilateral THA.

Objective To investigate the outcomes of total knee arthroplasty (TKA) in patients with a prior femoral or tibial fracture, and identify the risk factors for surgical site complications and reoperations. Methods Seventy‐one TKAs performed in 71 patients with a prior tibial or femoral fracture between January 2005 and December 2016 were reviewed retrospectively. Forty males (40 knees) and 31 females (31 knees) were included. The mean age at the time of TKA was 59.2 (range, 29–83) years. Outcomes were assessed using the Knee Society score before surgery and at the final follow‐up visit. The patients' satisfaction rates were evaluated. Complications and reoperations were recorded by clinical and radiographic assessment. Logistic regression analysis was used to identify the risk factors for surgical site complications and reoperations. Results The median follow‐up period was 4.7 (range, 3.2–7.1) years. The median knee range of motion increased from 90° preoperatively to 110° at the latest follow‐up. The Knee Society knee score and function score improved from 35 (30, 40) and 40 (30, 50) to 90 (82, 93) and 90 (65, 100), respectively. The degree of overall satisfaction after TKA surgery was very satisfied in 41 patients, satisfied in 20 patients, neutral in four patients, dissatisfied in four patients, and very dissatisfied in two patients. The overall satisfaction (very satisfied and satisfied) rate was 85.9% (61 knees). Twelve knees (16.9%) had 19 surgical site complications. Six knees (8.3%) underwent reoperations, including one revision due to periprosthetic joint infection, one debridement and implant retention for superficial infection, two debridements for delayed wound healing, one open reduction and internal fixation for supracondylar fracture, and one re‐fixation and bone grafting for hardware failure after a combined femoral shaft osteotomy and TKA. Preoperative patella baja was diagnosed in 12 knees, and was identified as a risk factor for surgical site complications and reoperations. Conclusions TKA for post‐fracture osteoarthritis significantly relieved pain and improved function, but the incidence of surgical site complications and reoperations was high. Preoperative patella baja was a risk factor for surgical site complications and reoperations.

Objectives This study was performed to investigate the effects of aging on nasality and the influence of age-related changes in nasal cavity volume and nasal patency on nasality. Methods A total of 180 healthy Korean-speaking adult volunteers, who had no nasal or voice-related complaints, were enrolled in this study. Nasometry, acoustic rhinometry, and rhinomanometry were performed to obtain the nasalance score, nasal cavity volume, and nasal resistance, respectively. Changes in these parameters with age were analyzed. Results Nasal cavity volume increased significantly, and nasal resistance decreased significantly, with age. The nasalance scores for the nasal passage and oronasal passage decreased significantly with age, while there were no age-related changes in nasalance scores for the oral passage. Conclusion Nasalance scores for the passages containing nasal consonants decreased with age although significant increases were observed in nasal cavity volume and nasal patency with age. Therefore, the age-related decreases in nasalance scores may result from factors other than changes in the nasal cavity.

Background: East Asian patients receiving treatment with the potent P2Y12 inhibitors prasugrel or ticagrelor experience more potent platelet inhibition than with clopidogrel. Methods: This study investigated differences in OPR rates with reduced doses of prasugrel (n = 38) or ticagrelor (n = 40) for maintenance therapy in 118 Korean ACS patients who had undergone PCI, in comparison to conventional-dose clopidogrel (n = 40). We assessed drug responses at one- and three-months post-PCI with VerifyNow and multiple electrode aggregometry assays. Results: At the one-month period, patients receiving standard-dose prasugrel or ticagrelor had lower platelet reactivity as determined by the three assays than those receiving the conventional dose of clopidogrel (VN: p = 0.000; MEA: p = 0.000; LTA: p = 0.000). At the 3-month point, platelet reactivity was lower in those receiving reduced-dose prasugrel or ticagrelor than the clopidogrel-treated patients (VN: p = 0.000; MEA: p = 0.012; LTA: p = 0.002). Prasugrel resulted in significantly lower platelet inhibition than ticagrelor as determined by VN and LTA (VN: p = 0.000; LTA: p = 0.003). At three months, there was a significant overall difference in OPR among the three groups when measured by VN (p < 0.001), but not when measured by MEA (p = 0.596). OPR in the reduced-dose prasugrel group was not significantly different to the clopidogrel group at three months (VN: p = 0.180; MEA: p = 0.711). OPR in the reduced-dose ticagrelor group was similar to clopidogrel as determined by MEA at three months, but was different when assessed by VN (VN: p = 0.000; MEA: p = 0.540). Compared to standard-dose, the reduced-dose prasugrel OPR rate was significantly increased (VN: p = 0.008; MEA: p = 0.020). Conclusions: OPR values for reduced-dose prasugrel and conventional-dose clopidogrel at three months were similar but higher than for reduced-dose ticagrelor as determined by VN, but no differences were noted by MEA. The MEA assay might have less sensitivity and consistency than the VN assay. Further studies are needed to explore this discrepancy.

Objective: This study aimed to evaluate the reliability and validity of the Chinese version of the Fear of Hypoglycemia scale with 15 items (FH-15). Methods: After obtaining the original author's authorization, the English version of the FH-15 scale was translated, back translated, and culturally debugged to obtain the Chinese version of FH-15. A convenient sampling method was used to extract patients with type 2 diabetes from four tertiary hospitals in Tianjin. A total of 408 patients with type 2 diabetes were investigated in the hospital to test the reliability and validity of Chinese version FH-15 scale. Results: The content validity index of the scale was 0.92, and the content validity index of each item was 0.8–1.0. The exploratory factor analysis extracted three common factors (fear, avoidance, and interference), which contained 15 items, and the cumulative variance contribution rate was 71.245%. The confirmatory factor analysis results showed that the model fit was better at 1.981 χ2/df, GFI = 0.901, CGI = 0.962, TLI = 0.952, and RMSEA = 0.070. The cut-off value for the total hypoglycemia fear scale was 30.5. The Cronbach's α coefficient of the three dimensions of the scale was 0.918, the Cronbach's α coefficient of each dimension is 0.876–0.916, the test–retest reliability was 0.903, and the test–retest reliability of each factor was 0.733–0.930. Conclusion: The Chinese version of the FH-15 scale can be considered reliable and valid. The item expression is concise, clear, and easy to understand. It is suitable for clinical practice as an initial screening tool to identify and evaluate the severity of fear of hypoglycemia in patients with type 2 diabetes. Keywords: Diabetes mellitus, Type 2, Fear, Hypoglycemia, Reliability, Validity