The treatment effect of the Shanxi Comprehensive Reform Area policy on PM2.5 concentrations: A study based on a quasi-experiment.

Based on panel data on 248 prefecture-level cities in China from 2003 to 2018, this study first estimates the treatment effect of the Shanxi Comprehensive Reform Area policy on PM2.5 concentrations using a PSM-DID method within the counterfactual framework. The average treatment effect shows that contrary to the naive before-after analysis, on average, the Shanxi Comprehensive Reform Area policy significantly increased the PM2.5 concentrations of prefecture-level cities in Shanxi Province by 0.211% annually, and the place-based placebo test shows that the treatment effect obtained above is robust. Second, the dynamic treatment effects show a continuous decrease in incremental effects during 2011-2018, gradually decreasing from a significant positive increment during 2011-2015 to a zero or even a negative increment during 2016-2018, indicating that the Shanxi Comprehensive Reform Area policy gradually increased in environmental friendliness. Third, the mediating effects estimated by the causal steps procedure show that the Shanxi Comprehensive Reform Area policy influenced PM2.5 concentrations by increasing the intensity of resource exploitation and decreasing the intensity of environmental regulations, but the capacity of scientific and technological innovations had no mediating effect on the relationship between the policy and PM2.5 concentrations. Therefore, the government should further reduce the intensity of resource exploitation, strengthen the intensity of environmental regulations, and promote environmentally focused scientific and technological innovations to reduce PM2.5 concentrations in Shanxi Province.

ECG Signal Classification Based on Fusion of Hybrid CNN and Wavelet Features by D-S Evidence Theory.

At present, cardiovascular disease is regarded as one of the dangerous diseases that threaten human life. The morbidity and lethality caused by cardiovascular disease are constantly increasing every year. In this paper, we propose a two-stream style operation to handle the electrocardiogram (ECG) classification: one for time-domain features and another for frequency-domain features. For the time-domain features, convolutional neural networks (CNN) are constructed for feature learning and classification of ECG signals. For the frequency-domain features, support vector regression (SVR) machines are designed to perform the regression prediction on each signal. Finally, the D-S evidence theory is adopted to perform the decision fusion strategy on the time-domain and frequency-domain classification results. We confirm a recognition performance of 99.64% from the experiment result for the D-S evidence theory recognition system upon the MIT-BIH arrhythmia database. The analysis of various methods of ECG classification shows that the model delivers superior performance promotion across all these scenarios.

The economic and environmental effects of the Beijing-Tianjin-Hebei Collaborative Development Strategy- taking Hebei Province as an example.

In 2014, the Beijing-Tianjin-Hebei Collaborative Development Strategy (hereinafter the Jing-Jin-Ji Strategy) was formally proposed as a major national strategy, providing an unprecedented opportunity for the overall development of Hebei. This article evaluates the treatment effects of the Jing-Jin-Ji Strategy on Hebei's economy and environment. Employing a panel data program evaluation method developed by Hsiao et al. (2012), we construct hypothetical counterfactuals for the GDP growth rate, the percentage of tertiary industry in GDP, and the geographic mean PM2.5 concentrations for Hebei in the absence of the Jing-Jin-Ji Strategy using the outcomes of selected untreated provinces. The results show that the Jing-Jin-Ji Strategy increased the percentage of tertiary industry in GDP by an average of 2.53 percentage points per year between 2014 and 2018 and decreased the geographic mean PM2.5 concentrations by an average of 11.1 percentage points per year between 2014 and 2017. However, it does not appear to have had significant effects on Hebei's GDP growth rate. The leave-one-out method demonstrates the robustness of the above results. This article suggests that Hebei should speed up its economic growth and bridge the gap with Beijing and Tianjin while ensuring the quality of its economic development and a sound ecological environment.

Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

Clinical efficacy of administering oxaliplatin combined with S-1 in the treatment of advanced triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is not amenable to current targeted therapies and carries a poor prognosis; however, a specific systemic regimen cannot yet be recommended. The optimal duration of oxaliplatin (OXA) and S-1 combinatorial chemotherapy in patients with advanced breast cancer is not currently known and is likely to be patient-specific based on efficacy and toxicity. In the present study, 52 patients with advanced TNBC received OXA and S-1 chemotherapy. The efficacy and toxicity were observed. The results showed that the median number of regimens was 4 (range 2-6). The therapeutic efficacy was evaluated in all patients. The complete response, partial response, overall response and disease control rates were 3.8, 30.8, 34.6 and 69.2%, respectively. Four patients were lost to follow-up, and the median follow-up time was 13.7 months. The median progression-free survival time was 6.7 months [95% confidence interval (CI), 4.5-9.0] and the median overall survival (OS) time was 13.3 months (95% CI, 9.1-17.5). From the subgroup analysis, it was found that the median OS time of patients with stage IV disease and ≥2 metastases was significantly shorter than that of patients with stage IIIC disease and only 1 metastasis [11.3 vs. 22.7 months, P=0.010 (stage IV vs. stage IIC); 11.3 vs. 15.7 months, P=0.048 (≥2 vs. 1 metastasis)]. The main grade 3/4 toxic effects were neutropenia (11.5%), nausea (7.7%) and nerve toxicity (3.8%). The other toxic effects were mainly of grades 1-2 and included diarrhea, liver dysfunction, stomatitis, anemia and hand-foot syndrome. In conclusion, OXA combined with S-1 is an effective and tolerable regimen for the treatment of patients with advanced TNBC.

Clinical study on fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain.

OBJECTIVE: To observe treatment effects and safety of fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. METHODS: Patients confirmed pathologically with cancer and complicated with moderate to severe pain, were divided into control and experimental groups. Oxycodone prolonged-release tablets, with or without fluvoxamine, were administrated to all study patients until pain relief. Degree of pain relief, dose of oxycodone prolonged-release tablets, side effects and quality of life were compared before and after treatment. RESULTS: In total, 120 patients were recruited. No statistically significant difference was detected regarding age, gender, types of cancer, KPS between two groups of patients (P> 0.05). Baseline pain score of patients with moderate pain in treatment and control group was 4.9±0.8 and 5.1±0.8, respectively; and decreased to 1.8±1.1 and 1.2±1.1 after treatment, respectively. Pain intensity was significantly reduced in the treatment group (P =0.028). Average daily consumption of oxycodone prolonged- release tablets was (54.0±19.6) mg and (44.7± 18.7) mg respectively, which is lower in treatment grpup than in control group, but the difference was not statistically significant (P=0.065). Baseline pain score of patients with severe pain in treatment and control groups were 8.3±1.1 and 8.3±1.1, respectively; and pain intensity after treatment decreased to 2.9±1.0 and 2.3±1.0. Pain intensity was significantly reduced in the treatment group, with statistical significance (P =0.026). Average daily consumption of oxycodone prolonged-release tablets was (132.0±42.2) mg and (110.7±33.9) mg, respectively, which is lower in treatment group than in control group, and the difference was statistically significant (P=0.035). In terms of quality of life, patients in treatment group had better performance status, daily activity, mood, and sleep than that in control group (P < 0.05). Patients in two groups had similar side effects, eg., constipation, nausea/vomiting, lethargy, dizziness, itchy skin, dysuria, and ataxia. Lower incidence of nausea/vomiting, lethargy, was obtained from patients in treatment than in control group, while significant low constipation was observed in treatment than in control group (35.0% vs 49.2%, P=0.026). CONCLUSION: Fluvoxamine combined with oxycodone prolonged-release tablets could be more effective in treating patients with cancer pain, and could reduce the dosage of oxycodone prolonged-release tablets and thus be associated with lower side effects, and improved quality of life.

Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.

Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.