[Exploration of construction mode of real-world data system].

Real-world data study evidence, as an important part of evaluating the safety and effectiveness of drugs and devices, has attracted increasing attention from regulatory agencies and scholars both at home and abroad, and has become an essential source of evidence to support the development and review of drugs and devices. This paper systematically discusses the process and mode of real-world data system construction based on the preliminary practical study of real-world data according to the guidelines/technical specifications issued by regulatory agencies and academic research results. This study result provides not only reference for the generation of clinical evaluation evidence to meet the regulatory requirements for innovative drugs and devices, but also reference for researchers, sponsors and regulators to carry out real-world data studies successfully.

[Real-world data studies of medical products in the context of special healthcare policy: study designs and key considerations].

Boao Lecheng International Medical Tourism Pilot Area is the only administrative area in China where the pilot application of real-world data is performed. Based on the special healthcare policy in Boao Lecheng, conducting real-world data study to provide real-world evidence for the clinical evaluations and approvals of innovated medical products has become an important field that supports the reform of China's evaluation and approval system of medical products. Trustworthy real-world evidence needs to rely on both high-quality real-world data and reasonable and rigorous study designs. Based on the real-world data research guidelines and specifications issued by relevant academic research and regulatory authorities both at home and abroad, combined with the special policy environment of Boao Lecheng and previous practice experience, this paper summarizes the study designs of real world data in Boao Lecheng and discusses the key considerations of different study design in the context of special healthcare policies in Boao Lecheng in order to provide reference for the further study of real-world data.

[Surgical treatment of tricuspid valve disease due to permanent pacemaker lead].

Objective: To summarize the etiology and surgical treatment experience of tricuspid valve disease due to permanent pacemaker lead. Methods: The medical records of 22 patients who underwent tricuspid valve operation for tricuspid valve disease due to permanent cardiac pacemaker lead from January 2008 to December 2017 were retrospectively reviewed. There were 12 males and 10 females, with a mean age of (62.6±12.1) years old (45-82 years old). All patients underwent tricuspid valve surgery via open thoracotomy under general anesthesia, including 8 patients through median thoracotomy approach, 4 patients through right mini-thoracotomy approach, and 10 patients with endoscopy-assisted and totally endoscopic technique. Moreover, 8 patients underwent tricuspid valve replacement, and 14 patients received tricuspid valve repair. Results: During the operation, 10 cases of severe tricuspid regurgitation were detected due to valve and subvalvular structures dysfunction involved in the pacing electrode, 7 cases showed tricuspid annulus dilation, and pacing electrode-related infective endocarditis were involved in the tricuspid valve of 5 cases. Compared with conventional median thoracotomy surgery, the amount of postoperative drainage fluid and hospitalization time after minimally invasive surgery (including right mini-thoracotomy and endoscopic surgery) were significantly reduced [281(120, 489) ml vs 368(180, 560) ml, P=0.02; 9.2(4.8, 14.5) d vs 11.2(6.3, 16.9) d, P=0.03]. Postoperative echocardiographic data showed that the size of the right atrium and ventricle in these patients was significantly reduced compared with preoperative data, and their cardiac function were normal. There was no difference of pacing electrode parameters between pre-and postoperative period. All 22 patients were cured and discharged, with no valve-and pacemaker-related complications. Conclusions: Patients with tricuspid valve disease due to permanent cardiac pacemaker lead should actively undergo surgery including tricuspid replacement or repair according to different etiologies, which exhibit satisfactory outcomes. Minimally invasive endoscopic tricuspid surgery is a new technique for the treatment of isolated tricuspid valve disease, with less surgical trauma and faster recovery.

[Assessment of mortality burden and economic loss attributed to long-term PM(2.5) exposure in the Beijing-Tianjin-Hebei area].

Objective: To accurately estimate the health burden and corresponding economic loss attributed to PM(2.5) pollution in the Beijing-Tianjin-Hebei (BTH) area in China in 2015. Method: By using satellite-retrieved PM(2.5) concentration data and population data provided by NASA (the spatial resolution was 1 km×1 km), this study estimated excess mortality attributed to long-term PM(2).5 exposure in BTH area in 2015 based on Global Exposure Mortality Model (GEMM). Besides, Value of Statistic Life (VSL) method was used to evaluate the corresponding health economic loss. Result: In BTH area, the population-weighted average PM(2.5) concentration during 2012-2014 was 46.25 µg/m(3), and 56.6% of total population lived in the area where annual average PM(2.5) concentration exceeded Grade Ⅱ of National Ambient Air Quality Standard in China (35 µg/m(3)); The PM(2.5)-related premature deaths amounted to 193.8 thousand (95%CI: 140.9 thousand-233.3 thousand), Beijing, Tianjin, Baoding, Shijiazhuang, and Handan were the top five cities with high incidences of PM(2.5)-related premature deaths; The corresponding health economic loss was about 35.934 billion (95%CI: 26.099 billion - 43.255 billion) RMB, accounting for 0.70% (95%CI: 0.51%-0.85%) of the area's GDP in 2015, Beijing, Tianjin, Baoding, Shijiazhuang, and Cangzhou were the top five cities with high health economic loss. Conclusions: PM(2.5) pollution has caused severe disease and economic burden in BTH area. Its spatial distribution suggested that it is particularly necessary to develop the air pollution prevention and control policies for key cities.

Expression and prognostic significance of melatonin receptor MT1 in patients with gastric adenocarcinoma.

Melatonin receptor type 1 (MTNR1A or MT1) is known to play an important role in cancer progression; however, its prognostic value for resected gastric adenocarcinoma (RGA) is unknown. In this study, we examined the potential of MT1 as a prognostic biomarker for RGA. The expression of the MT1 was evaluated in 67 patients with RGA by immunohistochemistry, and the relationship between MT1 levels and RGA prognosis was analyzed by Chi-square test, multivariate Cox regression, Kaplan-Meier method, and log-rank test. High MT1 expression was associated with a poor survival rate (29.0%, p=0.002) and the occurrence of metastasis (62.9%, p=0.004). Kaplan-Meier survival analysis and log rank tests revealed that patients with high expression of the MT1 had significantly shorter median overall survival compared to those with low expression (33.0 vs. 65.0 months, respectively; p=0.02). Multivariate Cox analysis indicated that the calculated death risk (hazard ratio [HR]) in patients with high expression levels of the MT1 increased to 2.68 (95% confidence interval [CI] 1.21-5.94, p=0.015), which was higher compared to those with low levels. HR of death was also high in patients with advanced T stage (2.51; 95 % CI 1.00-6.26, p=0.049) and metastasis (5.02; 95% CI 1.94-13.03, p=0.001). Our results showed that high MT1 expression in primary gastric adenocarcinoma tissues was associated with the occurrence of metastasis and poor prognosis. It may have prognostic significance as a potential biomarker in patients with RGA.

Epidemiological characteristics of malaria in Ningbo City, China 2000-2011.

The objective of this study was to explore the trend and the epidemiological characteristics of malaria in Ningbo from 2000 through 2011 and provide scientific evidence for the prevention and control. Using the retrospective study, data relating to malaria epidemics during 2000-2011 in Ningbo were collected through the questionnaires of the cases and other important surveillance data. Adult mosquitoes were collected using CDC light traps baited with CO2. Results showed that Plasmodium vivax was the main species, and Anopheles sinensis was the only vector species of malaria. The annual incidence rates (per 100000) ranged from 0.156 to 3.224, and about 95.41% of the cases were imported. The cases occurred mainly between May and November and the incidence showed two peaks, and the local transmission of malaria was determined by vector density. Considering the vast majority of these infections were imported vivax malaria cases from domestic endemic areas (particularly Anhui province), and may lead to limited local transmission, strengthening the routine monitoring of imported malaria, ensuring timely diagnosis, improving case detection rate, giving a standardized treatment to patients and intensifying public health education on malaria prevention are extremely important to malaria prevention and control activities.

Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic alpha1 and histaminergic H1 receptors in mice.

Epilepsy is characterized by neuronal hyperexcitability and hypersynchronization. Disruption of electroencephalographically (EEG) synchronized epileptiform discharges may be a possible therapy for epilepsy. In the present study, to clarify the role of EEG desynchronization on epilepsy, we investigated the effect of modafinil, a potent wake-promoting substance with EEG desynchronization activity, on epilepsy in mice and clarified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) kindling models. Modafinil given at 22.5, 45, and 90 mg/kg, i.p. significantly decreased the incidence of tonic hindleg extension in MES seizure models, and protected against PTZ-induced convulsive behaviors in a dose-dependent manner. In addition, modafinil at 180 mg/kg exerted an antiepileptic effect in the MES model; however, at the same dosage it increased the seizure stage in the PTZ-kindling model. The antiepileptic effect in both MES and PTZ models was antagonized by the adrenergic alpha(1) receptor antagonist terazosin, but not by the adrenergic alpha(2) receptor antagonist yohimbine or by dopaminergic receptor antagonists, SCH-23390 (for D(1) receptors) and haloperidol (for D(2) ones). Pyrilamine, a histaminergic H(1) receptor antagonist, counteracted the antiepileptic action of modafinil in the PTZ induced-kindling model, but not in the MES seizure model. Taken together, the present findings indicate that modafinil exerted its antiepileptic effect via adrenergic alpha(1) and histaminergic H(1) receptors, and might be of potential use in the treatment of epilepsy.

[Studies on mutation of isoniazid resistant genes in M. tuberculosis].

OBJECTIVE: To understand mutation of isoniazid-resistant genes in M. tuberculosis clinical isolates, and to develop the method for rapid detection of drug resistance. METHOD: Analyzing the katG genes in 30 M. tuberculosis clinical isolates with PCR-SSCP(single stranded conformation polymorphism) and PCR-DS (direct sequencing) techinques. RESULTS: With the reference of M. tuberculosis strain H37 Rv was used as control, all isoniazid-sensitive isolates and 4 isoniazid-resistant isolates displayed ab normal PCR-SSCP and PCR-DS patterns. But of 12 isoniazid-resistant isolates, 4(33.4%) isolates displayed abnormal katG PCR-SSCP pattern, 8 (46.7%) isolates displayed abnormal katG PCR-SSCP pattern, 5(41.7%) isolates were missense mutation at codon 94, 3(25%) isolates were cosense mutation at codon 96. CONCLUSIONS: Resistance to isoniazid in most M. tuberculosis isolates is due to the mutations on katG genes. PCR-SSCP techniques could be used as a method for rapid detection of isoniazid-resistance in M. tuberculosis.

Effects of toquipidine on ionic channels of cultured embryonic Xenopus laevis myoblasts and neurons.

AIM: To study the effects of toquipidine (1-p-methyl-phenyl-2-(alpha-piperidinoacetyl)-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride, Toq), a new anti-arrhythmic agent first synthesized in China, on ionic channels. METHODS: Ionic channel currents were recorded by whole-cell patch clamp technique in cultured embryonic Xenopus laevis myoblasts and neurons. RESULTS: Toq (0.1, 1, 10, and 100 mumol L-1) caused a concentration-dependent inhibition of the Na+ currents with IC50 7.2 mumol L-1 (5.3-9.8 mumol L-1). Toq (10 mumol L-1) also suppressed the high-voltage-activated Ca2+ currents in neurons. But the steady-state outward K+ currents in myoblasts were activated by Toq (10 mumol L-1). CONCLUSION: Toq blocked the Na+ and Ca2+ channels and opened the steady-state outward K+ channels.

Effects of nimodipine, felodipine, and verapamil on isolated human arteries.

AIM: To evaluate whether there might be some difference in the action modes of nimodipine (Nim) and felodipine (Fel). METHODS: Compare the inhibitory effects of Nim and Fel with that of verapamil (Ver) as a representative of phenylalklamine on norepinephrine (NE)- and CaCl2-evoked contractions of human arteries. RESULTS: In Ca(2+)-free and high K+ depolarized solution, inhibitory effects of Nim, Fel, and Ver were more potent on CaCl2-induced contractions on isolated human arteries than those on NE-induced contractions. In CaCl2-induced contraction, the pD2 values for Nim, Fel, and Ver were 7.5, 7.42, 6.35 on uterine arteries; 7.38, 7.65, 7.20 on mesenteric arteries and 7.87, 9.10, 7.32 on renal arteries, respectively. Ver inhibited 2 components of NE-evoked contraction, while Nim and Fel only inhibited extracellular Ca(2+)-dependent contractions. CONCLUSION: The result indicates that Fel has a selective action on human renal arteries.

Study on the mechanism of interferon action (XI)--Effect of pppA2'p5'A on the level of cAMP and cGMP in macrophages.

In this paper, the increase of cellular cAMP and cGMP levels in macrophages induced by ppA2'p5' A2'p5'A (briefly 2'-5'P3A3) is first reported. The optimal concentration of 2'-5' P3A3 for the elevation of cellular cGMP to the highest level is 10(-7)-10(-6) mol/L, while that for cAMP is 10(-7) mol/L. The time for cGMP to reach its peak value is 15 min and that for cAMP is 2 h, when the cells are treated with 2'-5' P3A3 at 10(-7) mol/L, which is the optimal concentration for developing biological effect of macrophages (phagocytosis). These results suggest that cGMP and cAMP may be related to, or may be the mediators for, 2'-5'P3A3 action.