The development of medical research is completed by the cooperation of sponsors, investigators, subjects, and ethics committees. Clinically, it mainly includes clinical trials of medical devices, clinical medicine and new technology research. This paper analyzed the game and the relationship between rights, responsibilities and interests of relevant parties in medical research, combined with the relevant costs and sharing principles involved in medical research, and found that the use of the word "free" in the informed consent is easy to cause misunderstanding and the lack of relevant compensation costs in the informed consent, while the compensation and insurance costs had some problems, such as the imperfect subject compensation mechanism and the insufficient insurance purchase by the sponsor, which can not protect the basic rights and interests of the subjects. Therefore, in order to standardize the cost management of clinical medical research, it is necessary to standardize the process and content of informed consent, strengthen the supervision of medical research process, establish medical research damage compensation fund and research damage insurance system, so as to better protect the rights and interests of subjects.

Under the “patient-centered” drug regulation concept， the inclusion of patient dimensions in real-world evidence becomes increasingly important. Patient experience data can complement and interpret existing data， generate evidence directly from patients， and achieve patient participation in drug development. Data types include patient-reported outcomes and free-text data， which can be collected autonomously or obtained from databases. Application scenarios involve new drug registration， safety evaluation， and additional indications. In China， applying patient experience data to real-world study mainly faces the following challenges： lack of conditions， standards， and motivation to collect high-quality data， a single type of data， and the difficulty of balancing data security with freedom， etc. It is recommended to issue special guidelines， establish a measurement tool certification process， expand data collection channels， explore data source integration methods， optimize the informed consent mechanism， and establish an evidence synergy mechanism to promote the practical application of the “patient-centered” concept in real-world study of drugs.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.

With the continuous progress of medical technology, some violations of ethical principles often occur in science experimental research targeting humans. Taking the type of human experimental research as the starting point, through ethical analysis and evaluation of different types of human experimental research, this paper concluded that in human experimental research, it was necessary to adhere to humanitarian principles of human experimental research, fully respect the research participants’ right to informed consent, select research participants fairly, fully protect the research participants’ rights and interests, and supervise the whole research process. So as to better regulate the behavior of medical researchers in human experimental research and protect the rights and interests of research participants.

Objective:To determine the analytical performance of a candidate reference measurement procedure for 17α-hydroxyprogesterone in human serum by liquid chromatography-tandem mass spectrometry (LC-MS/MS).Methods:The serum spiked with a deuterium-labeled internal standard was extracted from serum from individual undergoing physical examination by liquid-liquid extraction with n-hexane/ethyl acetate (3∶2, v/v), separated by C18 reversed-phase chromatography and detected by positive electrospray ionization mass spectrometry. According to the Clinical and Laboratory Standards Institute (CLSI) C62-A documents, the analytical performance including linearity, limit of detection,limit of quantitation,relative matrix effect,precision and trueness,carry-over and specificity was evaluated.Results:The linear range of 17α-hydroxyprogesterone by LC-MS/MS was 0.21-119.67 μg/L. The limit of detection and limit of quantitation were 5.218 ng/L and 0.116 μg/L. The relative matrix effects were -0.02%, -0.40% and -0.90% for sera and solution mixtures in 3 different ratios (50∶50, 80:20 and 20∶80). The coefficients of variation ( CVs) of intra-assay were 1.73%-2.11%, 0.98%-1.71%, 0.47%-0.87% at 0.164 μg/L, 14.81 μg/L, 81.63 μg/L and the CVs of inter-assay were 1.82%, 1.03%, 0.80% at above three concentrations. The average recovery rates of 3 levels (0.5, 20 and 100 μg/L) were 100.4%, 101.7%, 102.8%, respectively. The measured values of GBW09829 of National Institute of Metrology were within the specified uncertainty range. Conclusion:The candidate reference measurement procedure for 17α-hydroxyprogesterone in human by LC-MS/MS is established with good accuracy and precision, which can be clinically used for measurement traceability.

The development of medical research is completed by the cooperation of sponsors, investigators, subjects, and ethics committees. Clinically, it mainly includes clinical trials of medical devices, clinical medicine and new technology research. This paper analyzed the game and the relationship between rights, responsibilities and interests of relevant parties in medical research, combined with the relevant costs and sharing principles involved in medical research, and found that the use of the word "free" in the informed consent is easy to cause misunderstanding and the lack of relevant compensation costs in the informed consent, while the compensation and insurance costs had some problems, such as the imperfect subject compensation mechanism and the insufficient insurance purchase by the sponsor, which can not protect the basic rights and interests of the subjects. Therefore, in order to standardize the cost management of clinical medical research, it is necessary to standardize the process and content of informed consent, strengthen the supervision of medical research process, establish medical research damage compensation fund and research damage insurance system, so as to better protect the rights and interests of subjects.

Objective:The aim of this study was to examine the change of serum bone-derived hormones osteocalcin and lipocalin 2 (LCN2) level in patients with active acromegaly, and to further investigate the potential role of osteocalcin and LCN2 in glucose metabolism.Methods:Fifty consecutive patients diagnosed as acromegaly in Nanjing Drum Tower Hospital from December 2016 to August 2018 were recruited. Of those, 41 patients after operations with complete follow-up data were also included. 30 sex, age, and body mass index matched healthy persons as normal controls. Serum osteocalcin and LCN2 levels were compared between controls and patients with acromegaly, as well as at pre- and post- operation periods. Univariate and multivariate linear regression analyses were used to investigate the correlation between bone-derived hormones and glucose metabolism indexes and to determine the independent associations between variables.Results:Compared with normal controls, serum osteocalcin increased [(55.45±34.02 vs 19.46±6.69)ng/ml, P<0.01] and LCN2 levels decreased [(34.15±9.95 vs 57.50±29.75)ng/ml, P<0.01] in patients with acromegaly. Homeostasis model assessment for insulin resistance (HOMA-IR) was also elevated ( P<0.01), but homeostasis model assessment for β cell function (HOMA-β) and area under curve of insulin during 0-120 min of the oral glucose tolerance test (AUC INS) changed non-significantly in acromegaly compared to normal controls ( P>0.05). After operation, with the decrease of serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1), serum osteocalcin level decreased [24.79(18.39, 32.59) vs 43.51(26.73, 65.66)ng/ml, P<0.01] and LCN2 level increased [(45.15±15.33 vs 37.03±9.73)ng/ml, P<0.05] significantly compare to pre-operation levels. In a multivariate linear stepwise regression analysis, lean mass was shown to be the only positive predictor for LCN2 ( β=0.44, P=0.015) and elevated serum IGF-1 was a positive predictor for osteocalcin ( β=0.512, P<0.01). In the multivariate models, low LCN2 ( β=-0.398, P=0.017) and elevated serum osteocalcin ( β=0.553, P=0.001) were predictors for AUC INS, osteocalcin was a positive predictor of HOMA- β ( β=0.519, P=0.004). GH ( β=0.294, P=0.029) and IGF-1( β = 0.428, P=0.002) were all identified as positive predictors of HOMA-IR during multivariate testing in acromegaly patients. Conclusions:Acromegaly patients had increased osteocalcin and decreased LCN2 serum levels, and corresponding alteration was detected with the correction of biochemical abnormalities. Serum osteocalcin and LCN2 were predictors of β-cell function in acromegaly patients. This study adds new evidence for the role of bone in regulating glucose metabolism in acromegaly.

Objective To investigate the effects of electromagnetic pulse (EMP) on reproductive function of male adult mice.Methods A total of 48 healthy adult male BALB/c mice (8 weeks old) were randomly divided into sham group and EMP group with 24 animals in each group.The mice were wholebody exposed or sham exposed to EMP at 720 kV/m for 100 pulses with 1 Hz repetition rate and 40 ns pulse width.At 1,7,14 and 35 d after EMP exposure,the mice were anesthetized and the sperms were collected from the bilateral epididymal tail.After that,the sperm quality including the number of sperms,the ratio of abnormalities and the survival rate was evaluated.In addition,the morphology of testis was observed by HE staining and the diameter of seminiferous tubules was measured by Image J 1.43 u software.The protein level of stem cell factor (SCF) and glial-derived neurotrophic factor (GDNF) in testis tissue were detected by ELISA and Western blot.Results The sperm quality and the morphology of testis did not change obviously at different times after exposing mice to EMP at 720 kV/m for 100 pulses,compared with sham group (P＞0.05).The diameters of seminiferous tubules at 1,7,14 and 35 d after exposure were (196.85+ 16.65),(196.79+ 14.33),(196.35±22.71) and (198.60±25.88) μm in exposed mice,respectively,while (204.31±27.13),(197.07± 18.11),(194.37±21.45) and (200.59± 19.36) Iμm in sham exposed mice,respectively.There was no significant difference between two groups (P＞0.05).Additionally,the levels of SCF and GDNF in testis tissue between EMP group and sham group had no statistically significant difference (P＞0.05).Conclusion Under this exposure condition,EMP couldn't affect the reproductive function of male adult mice.

Objective To investigate the frequencies of the impaired glucose tolerance and diabetes mellitus in a large cohort of active acromegaly and to identify risk factors associated with the presence of diabetes at diagnosis in these patients.Methods This study included 88 patients with newly diagnosed acromegaly.Patients were further divided into normal glucose tolerance (NGT),impaired glucose regulation (IGR),and diabetes (DM) groups according to oral glucose tolerance test or previous history.Insulin sensitivity and β cell function were also evaluated by homeostasis model assessment (HOMA).Logistic regression analysis was used to explore the independent risk factors for diabetes in patients with acromegaly.Results Impaired glucose regulation was found in 25 (28.4％),and DM in 37(42.0％) acromegaly patients.Compared to NGT and IGR patients,higher proportion of DM patients had family history of diabetes (P＜0.05).Compared to NGT group,higher post-OGTT growth hormone (GH) levels were detected in IGR and DM groups.Insulin-like growth factor 1 (IGF-1) levels were higher in IGR group while lower in DM group (P＜0.01).Homeostasis model assessment for β cell function (HOMA-β) was slightly higher in IGR group,but significantly lower in DM group (P ＜ 0.01).Homeostasis model assessment for insulin resistance (HOMA-IR) was slightly higher in IGR and DM groups but without significant difference among 3 groups.In multivariate analyses,family history of diabetes(OR=12.710,95％ CI 1.176-137.30,P=0.036),age(OR=1.106,95％ CI 1.018-1.202,P=0.017),and GH levels(OR=1.075,95％ CI 1.007-1.147,P=0.030) were independent risk factors of diabetes in acromegaly patients.Conclusion Impaired glucose metabolism is present in nearly 70％ of patients at diagnosis of acromegaly,and is associated with age,family history of diabetes,and higher GH levels,but not with IGF-1 levels.

A 23-year-old male patient presented with repeated painful erosion on the soles of both feet for 10 years, and with walking difficulties for half a month. Skin examination showed thick dark-brown finger and toe nails with distal protuberance, and hard keratinous materials under the nails. Obvious hyperkeratosis and maceration occurred on the soles of both feet, which appeared milky-white in color; diffuse papulovesicles were observed on the soles and lateral margins of both feet with scattered erosions. Vesicles were observed on the wrist and forehead. Follicular papules and fine scales were scattered on the extensor aspect of the forearm and elbow, and diffuse white patches were observed on the surface of the tongue. The above clinical manifestations were consistent with pachyonychia congenita. Peripheral blood samples were obtained from the patient, his parents and grandmother, and subjected to whole-exome sequencing. Sequencing showed two mutations in both the patient and his father, including base deletions at position 516-518 (c.516-518 del CAA) in exon 1 of the KRT6A gene, which caused pachyonychia congenita-K6a, and a base substitution at position 3 970 (c.3970 C>T) in exon 27 of the PLEC gene, which may cause epidermolysis bullosa simplex Ogna. The same mutation in the PLEC gene was found in the patient′s grandmother. The patient was diagnosed with pachyonychia congenita complicated by suspected epidermolysis bullosa simplex Ogna. After 9-month treatment with acitretin, the nails became lighter in color, plantar skin lesions were obviously relieved, and scattered millet-like vesicles in the wrist completely subsided. The patient was followed up at present.