Investigator-initiated clinical trials （IIT） are an important part of scientific and technological activities involving human study participants. Among them， high-quality IIT can be used to support the marketing and registration application of drugs， medical devices， and other products when conditions permit. Currently， there is a huge gap between IIT and industry-initiated clinical trials. The use of unlisted products in IIT has problems， such as lack of regulatory support， insufficient research funding support， the need to improve the ability of clinical research management departments， the weakness of professional clinical research teams， and the difficulty of ethics review to match the demands. The challenges could be addressed by improving regulations and conducting pilot trials on a small scale， guaranteeing adequate research funding， strengthening the construction of clinical research management systems， building professional clinical research teams， ensuring the quality of ethical reviews and strict follow-up reviews， shifting from ethical reviews to a system for protecting research participants， and reinforcing training for researchers. Ethics committees should strictly review key points， such as the risk-benefit ratio， informed consent， research funding， compensation for damages， qualifications and equipment of research team members， and management of conflict of interest.

PURPOSE: Septic shock is associated with high mortality and poor outcomes among sepsis patients with coagulopathy. Although traditional statistical methods or machine learning (ML) algorithms have been proposed to predict septic shock, these potential approaches have never been systematically compared. The present work aimed to develop and compare models to predict septic shock among patients with sepsis. METHODS: It is a retrospective cohort study based on 484 patients with sepsis who were admitted to our intensive care units between May 2018 and November 2022. Patients from the 908th Hospital of Chinese PLA Logistical Support Force and Nanchang Hongdu Hospital of Traditional Chinese Medicine were respectively allocated to training (n=311) and validation (n=173) sets. All clinical and laboratory data of sepsis patients characterized by comprehensive coagulation indexes were collected. We developed 5 models based on ML algorithms and 1 model based on a traditional statistical method to predict septic shock in the training cohort. The performance of all models was assessed using the area under the receiver operating characteristic curve and calibration plots. Decision curve analysis was used to evaluate the net benefit of the models. The validation set was applied to verify the predictive accuracy of the models. This study also used Shapley additive explanations method to assess variable importance and explain the prediction made by a ML algorithm. RESULTS: Among all patients, 37.2% experienced septic shock. The characteristic curves of the 6 models ranged from 0.833 to 0.962 and 0.630 to 0.744 in the training and validation sets, respectively. The model with the best prediction performance was based on the support vector machine (SVM) algorithm, which was constructed by age, tissue plasminogen activator-inhibitor complex, prothrombin time, international normalized ratio, white blood cells, and platelet counts. The SVM model showed good calibration and discrimination and a greater net benefit in decision curve analysis. CONCLUSION The SVM algorithm may be superior to other ML and traditional statistical algorithms for predicting septic shock. Physicians can better understand the reliability of the predictive model by Shapley additive explanations value analysis.
Humans ; Shock, Septic/blood* ; Machine Learning ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Sepsis/complications* ; ROC Curve ; Cohort Studies ; Adult ; Intensive Care Units ; Algorithms ; Blood Coagulation ; Critical Illness

OBJECTIVE: To screen the genetic risk factors related to severe hematology adverse effects (AEs) in patients with chronic myeloid leukemia (CML) treated with imatinib (IM), and explore the correlation of single nucleotide polymorphisms (SNPs) in IM drug metabolism and transport pathway gene polymorphism with the risk of severe hematology AEs. METHODS: 172 newly diagnosed Chinese Han patients in CML chronic phase (CML-CP) treated with IM were included and divided into severe hematology AEs group and non-severe hematology AEs group. The demographic characteristics and laboratory test results were compared between the two groups. 11 gene SNP sites in the included subjects were genotyped using SNaPshot multiplex SNPs technique. RESULTS: Compared with non-severe hematology AEs group, the severe hematology AEs group had higher white blood cell (WBC) and EOS% (both P < 0.05), but lower hemoglobin (Hb) and hematocrit (HCT) (both P < 0.01). For rs1045642 of ABCB1 gene, there were significant differences in the distribution of allele frequency and genotype frequency of this loci between severe hematology AEs group and non-severe hematology AEs group (both P < 0.05). Carriers of rs1045642 mutation allele A had an increased risk of severe hematology AEs (OR =2.09, 95% CI : 1.24-3.55, P =0.005). There was a significant difference in the distribution of NR1I2 gene rs3814055 genotype between severe hematology AEs group and non-severe hematology AEs group (P < 0.05). The additive model and recessive model of ABCB1 gene rs1045642 and the recessive model of NR1I2 gene rs3814055 were associated with the increased risk of severe hematology AEs (OR =2.14, 3.28, 5.54, all P < 0.05). CONCLUSION Peripheral blood WBC, EOS%, Hb and HCT in patients with newly diagnosed CML-CP are all related to the risk of severe hematology AEs. ABCB1 gene rs1045642 and NR1I2 gene rs3814055 related to the metabolism and transport pathway of IM are associated with severe hematology AEs after IM treatment in CML-CP patients, and they may be potential molecular markers to predict the risk of severe hematology AEs of CML patients treated by IM.
Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Polymorphism, Single Nucleotide ; Genotype ; ATP Binding Cassette Transporter, Subfamily B ; Gene Frequency ; Female ; Male ; Middle Aged ; Adult ; Asian People

Bisphenol A (BPA) is a kind of exogenous chemicals presenting in the human living environment widely which affects the action of endocrine hormones in the human body. Numerous studies have shown that BPA has reproductive toxicity in the spermatogenic function damage of the testes through a variety of mechanisms such as interfering with endocrine function, inducing oxidative stress, promoting spermatogonial cell apoptosis, destroying the integrity of the blood-testis barrier, and regulating epigenetic inheritance, thereby destroying male fertility. Relevant studies have shown that TCM can improve male fertility by reversing BPA-induced reproductive damage through multi-component, multi-target and multi-mechanisms. However, there is no systematic review on the mechanism of TCM to reduce the reproductive toxicity of BPA. Based on the existing studies, this article will systematically introduce the mechanisms of BPA-induced reproductive impairment in men and the progress of TCM interventions, with a view to providing reference targets and research directions for the development of new Chinese medicines.
Humans ; Benzhydryl Compounds/adverse effects* ; Male ; Phenols/adverse effects* ; Medicine, Chinese Traditional ; Infertility, Male/chemically induced* ; Testis/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Bisphenol A Compounds

Objective To investigate the therapeutic mechanism of Gandou Bushen Decoction(GDBSD)for improving reproductive disorders in male mouse models of Wilson disease(WD).Methods Sixty male homozygous TX mice were randomized equally into 4 groups and treated with daily gavage of saline(WD model group),penicillamine(0.09 g/kg),or GDBSD(0.2 mL/10 g),or with intraperitoneal injection of U0126(20 mg/kg)in addition to GDBSD gavage,with 15 male DL mice as control.After 4 weeks of treatment,copper content in testicular tissue of the mice was detected,and histopathology of the testes and epididymis was examined using HE staining and electron microscopy.TUNEL staining was used to identify apoptotic cells in the testes.The protein expressions of Bcl-2,Cytc,caspase-3,ERK,and p-ERK in the testicular tissue were evaluated with Western blotting,and BrdU-positive cells were detected with immunohistochemical labeling.Sperm density,viability,malformation rate and fertility levels of male mice were studied.Results Treatment with penicillamine and GDBSD obviously improved pathological changes of the testis,increased sperm density and motility,lowered sperm abnormality rate,fertility levels and increased testicular JOHNSEN score of TK mice,but the therapeutic effect of GDBSD was blocked by U0126.GDBSD treatment significantly lowered Cytc and caspase-3 expressions and increased Bcl-2 expression in the testicular tissue of TX mice(P<0.05),while U0126 treatment significantly lowered testicular Bcl-2 expression level.No significant differences were found in total protein expression levels of ERK1/2 among the 5 groups,but p-ERK protein expression was significantly reduced in WD and U0126 groups and increased in penicillamine and GDBSD groups.Conclusion GDBSD can improve spermatogenesis and enhance fertility of male TX mice with WD possibly by activating the ERK signaling pathway to enhance proliferation and reduce apoptosis of the spermatogenic cells.

Objective To investigate the trends of major thyroid function indices in Chinese adolescent females at different ages and the differences from adult reference intervals.Methods A total of 791 female students from 4 junior high schools were enrolled in the study by selecting one junior high school in each of the following locations:Minhang District of Shanghai,Haimen City of Jiangsu Province,Yuhuan City of Zhejiang Province,and Deqing County of Zhejiang Province from Oct to Nov 2017 and from Jan to Mar 2019.The subjects were subjected to physical examination as well as thyroid hormone levels;and the Pubertal Developmental Events Self-Assessment Scale(PDS)was used to evaluate the staging of pubertal development.Follow-ups were conducted after 2 years,with the same survey content.Thyroid function levels were assessed in 5 age groups between 11 to 15 years old,95%CI were calculated,and mixed linear models were used to analyze the effects of age and pubertal developmental stage on hormone levels.Results The reference intervals for thyroid stimulating hormone(TSH),free triiodothyronine(FT3)and free thyroxine(FT4)in adolescent females differed significantly from those of adults,with misclassification rates ranging from 2.98%to 5.17%.Statistically significant differences were found for age,pubertal development staging,and the interaction of age and pubertal staging after correcting for BMI,waist circumference(all P<0.05).TSH levels were more affected by age before the completion of pubertal development,the level of the 12-year-old group was higher than that of the 11-year-old group(P=0.001 2)and the 13-year-old group(P<0.000 1);FT3 levels showed greater variability with age during late pubertal stage,with levels significantly higher at 13 years of age than at 11 and 12 years of age(P<0.0001),and gradually decreasing after 13 years of age(P<0.000 1).In contrast,FT4 levels were generally less affected by age between 11 and 15 years of age,with levels slightly higher at 13-15 years of age than at 11-12 years of age(P<0.000 1).Conclusion The levels of TSH,FT3,and FT4,as indicators of thyroid function in adolescent females,differ significantly from those of adults,and are differently affected by age and the stages of pubertal development;further refinement of the reference intervals for age-and pubertal-development-specific thyroid indicators is necessary.

Objective To construct trajectory models of care-seeking patterns for type 2 diabetes mellitus(T2DM)patients,analyze the influencing factors of different trajectories,and explore the fasting blood glucose control levels of T2DM patients with different trajectories.Methods A retrospective cohort study was carried out on 18088 T2DM patients who had health records and been involved in the diabetic management in Community Health Service Center of Minhang District,Shanghai from 2006 to 2009.Starting from Jan 1,2010,participants were followed up until Dec 31,2019,with complete follow-up information.Group-based trajectory modelling(GBTM)was employed to identify and construct the fluctuation trajectory of fasting blood glucose in the patients.Bayesian information criterion(BIC),average posterior probability(AvePP)and other evaluation indicators were used to select the optimum subgroup number model.Then the differences in demographic characteristics,health status,family history,fasting blood glucose,BMI,etc were compared among different categories.Multinational logistic regression model was constructed to explore the influencing factors of different fluctuation trajectories.Cox regression analysis was used to examine the relationship between the long-term trajectories of care-seeking patterns and fasting blood glucose control level.Results Using GBTM analysis,we constructed the optimal Model 4 to categorize 18088 T2DM patients with community health records into five distinct trajectory subgroups:continuous non-attendance group(22.29%),low-level increasing group(15.09%),high-level slowly decreasing group(14.18%),high-level rapidly decreasing group(14.90%),and continuous regular attendance group(33.54%).With the continuous regular attendance group serving as the reference,gender,age,place of residence,baseline comorbidity of hypertension,baseline fasting plasma glucose level,and BMI were found to influence the community attendance trajectories of T2DM patients(P<0.05).After adjusting for confounding factors,Cox regression analysis revealed that compared to the continuous non-attendance group,the low-level increasing group,high-level slowly decreasing group,and continuous regular attendance group had better glycemic control,with HRs of 0.37(95%CI:0.34-0.39),0.72(95%CI:0.67-0.78),and 0.78(95%CI:0.73-0.84),respectively.The glycemic control level in the high-level rapidly decreasing group was comparable,with an HR of 1.06(95%CI:0.99-1.12).Conclusion Based on the optimal model,the community medical treatment trajectories of T2DM patients showed different dynamic characteristics.Factors such as gender,residence,hypertension,and weight loss may influence these varying trajectories.Regular community visits and follow-up may help control blood glucose levels.

Objective To investigate the therapeutic mechanism of Gandou Bushen Decoction(GDBSD)for improving reproductive disorders in male mouse models of Wilson disease(WD).Methods Sixty male homozygous TX mice were randomized equally into 4 groups and treated with daily gavage of saline(WD model group),penicillamine(0.09 g/kg),or GDBSD(0.2 mL/10 g),or with intraperitoneal injection of U0126(20 mg/kg)in addition to GDBSD gavage,with 15 male DL mice as control.After 4 weeks of treatment,copper content in testicular tissue of the mice was detected,and histopathology of the testes and epididymis was examined using HE staining and electron microscopy.TUNEL staining was used to identify apoptotic cells in the testes.The protein expressions of Bcl-2,Cytc,caspase-3,ERK,and p-ERK in the testicular tissue were evaluated with Western blotting,and BrdU-positive cells were detected with immunohistochemical labeling.Sperm density,viability,malformation rate and fertility levels of male mice were studied.Results Treatment with penicillamine and GDBSD obviously improved pathological changes of the testis,increased sperm density and motility,lowered sperm abnormality rate,fertility levels and increased testicular JOHNSEN score of TK mice,but the therapeutic effect of GDBSD was blocked by U0126.GDBSD treatment significantly lowered Cytc and caspase-3 expressions and increased Bcl-2 expression in the testicular tissue of TX mice(P<0.05),while U0126 treatment significantly lowered testicular Bcl-2 expression level.No significant differences were found in total protein expression levels of ERK1/2 among the 5 groups,but p-ERK protein expression was significantly reduced in WD and U0126 groups and increased in penicillamine and GDBSD groups.Conclusion GDBSD can improve spermatogenesis and enhance fertility of male TX mice with WD possibly by activating the ERK signaling pathway to enhance proliferation and reduce apoptosis of the spermatogenic cells.

Objective This study aimed to investigate the protective effect and mechanism of carvacrol hydrogel on the alveolar bone in rats with periodontitis.Methods A thermosensitive hydrogel supported by carvacrol was pre-pared using poloxamer and hydroxypropyl methyl cellulose as matrix.SD rats were randomly divided into blank group,periodontitis group,blank hydrogel group,and low-,medium-,and high-dose hydrogel groups.The periodonti-tis symptoms and the CT structure of the alveolar bone were observed.The changes in liver,spleen,kidney,and peri-odontal tissues were observed.The related indexes of bone metabolism in serum were detected.The expression of os-teoprotegerin(OPG)and nuclear transcription factor-κB(NF-κB)pathway proteins was determined by Western blot.The levels of inflammatory factors were assessed by quantitative reverse transcription polymerase chain reaction(qRT-PCR).Results Carvacrol hydrogel had good slow release,biocompatibility,and cell adhesion.The periodontitis of rats in the carvacrol hydrogel group was significantly alleviated,the expression of OPG protein in gingival tissue was significantly increased(P<0.01),and the levels of receptor activator of NF-κB ligand(RANKL),receptor activator of NF-κB(RANK),NF-κB protein,and inflammatory factors were significantly decreased(P<0.01).Conclusion Car-vacrol hydrogel can regulate the OPG and NF-κB pathways,reduce alveolar bone absorption,and improve periodontal inflammation.

Psoriasis is a refractory disease mainly co-acted by immune,genetic and environment.Tumor necrosis factor α (TNF-α)-related biologics have brought the landmark advances in the treatment of psoriasis;however,the anti-TNF-α therapy has the adverse response,its limitation may be related to the different bio-logical functions exerted by activation of TNF-α different receptors.Tumor necrosis factor receptor 2 (TNFR2) is one of the key receptors for TNF-α,and after binding to TNF-α,it can activate multiple signaling pathways such as NF-κB,PI3K/Akt,MAPK,STAT3,etc.,which are involved in the regulation of inflamma-tion,epidermal homeostasis,cellular apoptosis,cellular proliferation,cellular autophagy and other biological processes.It is suggested that TNFR2 is closely related to the occurrence and development of psoriasis.Previ-ous studies have often overlooked the role of TNFR2 in anti-TNF-α therapies;therefore,this article reviews the structure and signaling pathways of TNFR2,research advances in the disease,and its relationship with psoriasis to provide new references for exploring the pathogenesis and treatment of psoriasis.