Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-κB transcription regulation and activating cAMP/CREB axis

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC50 value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Changes in the practice environment from the perspective of doctors in 136 tertiary public hospitals in China / 中华医院管理杂志

Objective:To understand the changes in the practice environment from the perspective of doctors in 136 tertiary public hospitals, and to provide evidence for formulating strategies and measures to improve the practice environment of doctors.Methods:The data was collected from five rounds of China Healthcare Improvement Evaluation Survey from December 2015 to March 2021. The sample size was 17 945, 19 774, 20 786, 23 289, and 22 836, with a total of 104 630. The self-designed questionnaire on four dimensions of doctor-patient relationship, workload, administrative logistics support and professional identity was performed.Results:From the 1st to the 5th survey, the approval ratio of " the administrative and logistics department of this hospital is highly efficient" showed the characteristics of " U-shaped distribution" , and the approval ratio of " approve or encourage children to continue to engage in medical work" increased from 13.38% to 23.91%.From the 2nd to the 5th survey, the percentage of doctors who experienced doctor-patient disputes dropped from 28.96% to 23.20%, and the percentage of doctors agreeing that the relationship between doctors and patients in this hospital was improving continued to increase from 33.20% to 60.45%.From the 3rd to the 5th survey, the proportion of doctors experiencing medical troubles dropped from 15.10% to 14.19%, and the recognition rate of " the cafeteria of this hospital provided medical staff with nutritious and delicious meals" increased from 36.25% to 47.52%, and the approval proportion of " my current work load is heavy" dropped from 61.55% to 45.24%. The results of the 5th survey showed that there were significant differences in the approval ratios of each dimension in different genders, job titles and hospital types( P<0.001). Conclusions:From the perspective of doctor-patient relationship, workload, administrative logistics support, and professional identity, the improvement of doctors′ practice environment is still insufficient. Hospital administrators should continue to focus on the improvement of the doctor-patient relationship, and take necessary measures to reduce doctors′ workload and improve doctors′ professional identity.

Current situation and trend of salary level and satisfaction rate of nurses in tertiary public hospitals in China / 中华医院管理杂志

Objective:To analyze the salary level, change trend and salary satisfaction of nurses in tertiary public hospitals in China.Methods:The data was derived from three round third-party evaluation of the China Healthcare Improvement Initiative at 136 tertiary public hospitals from December 2017 to January 2018, March 2019 and January to March 2021. The self-reported salary, expected salary and salary satisfaction rate of nurses were analyzed.Results:The sample sizes of the three evaluations were 27 575, 27 568 and 25 197, representing the salary situation in 2017, 2018 and 2020 respectively. In 2017, 2018 and 2020, the actual average annual salary of nurses was 81 600 yuan, 100 000 yuan and 110 000 yuan respectively, the expected average annual salary was 140 000 yuan, 160 000 yuan and 160 000 yuan respectively, and the ratio of expected salary to actual salary was 1.72, 1.60 and 1.45 respectively. In 2017, 2018 and 2020, the proportion of nurses satisfied with their current income was 34.0%, 33.7% and 43.6% respectively. In 2020, nurses in the eastern region, other specialized hospitals, senior professional titles and graduate degrees had highest annual salary.Conclusions:The salary level and satisfaction rate of nurses in tertiary public hospitals in China show a slow growth trend, and the gap between actual salary and expected salary is gradually narrowing.

Analysis on the current situation and trend of doctors′ salary and satisfaction rate in tertiary public hospitals in China / 中华医院管理杂志

Objective:To analyze the current level and dynamic change of the salary and income satisfaction rate of doctors in Chinese tertiary public hospitals in recent years.Methods:In January 2018, March 2019 and March 2021, the project team of " the third party evaluation of the China Healthcare Improvement Initiative" conducted a questionnaire survey among doctors of 136 tertiary public hospitals in 31 provinces. The first-line clinicians were investigated by stratified sampling method. The salary level and satisfaction of doctors were investigated by questionnaire. Chi square test was used for comparison between groups.Results:The sample size of the three surveys was 20 786, 23 289 and 22 836 respectively. The median value of doctors′ actual income after tax in 2017, 2018 and 2020 was 100 800 yuan, 120 000 yuan, 150 000 yuan respectively, and the median expected annual income after tax was 196 000 yuan, 250 000 yuan and 250 000 yuan. The proportion of doctors satisfied with the current income was 16.5%, 17.8% and 26.9% respectively. The salary and satisfaction rate of doctors had an upward trend, but the overall level was still low.Conclusions:In recent years, the salary of doctors in tertiary public hospitals in China has been improved to a certain extent, but on the whole, it is at a low level, and there is still much room for improvement. In the future, the government needs to improve the hospital salary system and increase the salary of doctors continuously, especially needs to pay attention to the doctors with high education level and intermediate titles.

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor

Survey on the self-rated health of doctors and nurses at China′s 144 tertiary public hospitals / 中华医院管理杂志

Objective@#To establish comprehensive understanding of the self-rated health of the Chinese doctors and nurses and probe into their influencing factors.@*Methods@#Data were drawn from a hospital performance survey, which was conducted by the Peking Union School of Public Health from March 18th to April 9th, 2019, among the 144 tertiary public hospitals in 31 provinces, autonomous regions, and municipalities. The survey included a cell-phone based questionnaire filled out by the sampled doctors and nurses, in which they were asked to rate their health using a 5-level Likert scale(from " very poor" to " very good" ). Mann-Whitney U test was used to analyze the differences in self-rated health between doctors and nurses. Chi-square test and two-class multivariate logistic regression were performed to analyze factors affecting self-rated health of the providers.@*Results@#Among the 144 sample hospitals, the proportion of doctors, who rated their health as " healthy" , was 20.30%(4 979/24 529), that of nurses was 28.92%(8 361/28 910). It was worse than that in some developed countries and lower than the general population in China. Multi-variate analysis showed that adequate sleeping time, satisfaction with the work and with the doctor-patient relationship, were positively associated with the level of self-rated health of the sampled doctors and nurses(P<0.05). It was also found that the longer the average weekly working time, the higher the recognition of " the work load is too heavy" , the lower the proportion of doctors and nurses who rated their health as " healthy" (P<0.05).@*Conclusions@#Sleep time, job satisfaction, workload and doctor-patient relationship are important factors affecting self-rated health of the Chinese doctors and nurses.

Major findings from the 4th Evaluation of the National Healthcare Improvement Initiative / 中华医院管理杂志

Objective@#To carry out the 4th round of third-party evaluation on the implementation and effect of the 1st year of the 2nd Phase National Healthcare Improvement Initiative(abbreviated as Initiative)since 2015.@*Methods@#The 4th round of the evaluation survey adopted the same methods, organization and execution, and technical roadmap as the former three rounds of evaluations.@*Results@#The 4th round of evaluation was carried out from 18 March to 9 April, 2019 at 185 public hospitals in 31 provinces(autonomous regions, municipalities directly under the Central Government)and Xinjiang Production and Construction Corps.Facility survey, health professional survey and patient survey were conducted at each of the sample health facilities. A total of 120 782 valid questionnaires were collected from 144 non-psychiatric health facilities, 16 246 valid questionnaires were obtained from 41 psychiatric health facilities, and 252 cases of outstanding departments/hospitals in healthcare improvement were also collected. The average overall scoring of the 12 dimensions to assess Initiative implementation at 144 non-psychiatric health facilities was 84.4%. The overall outpatient satisfaction scoring was 91.1%, 96.7%for the inpatients. The overall inpatient satisfaction(family members inclusive) at 41 psychiatric health facilities was 93%. Areas remaining to be improved include day-surgery, telemedicine and medical social work. Compared with technical services, non-technical care should be further strengthened. The compensation, workload and work environment of the healthcare providers are still to be improved.@*Conclusions@#The implementation of the Initiative by health facilities has been greatly improved. The percentage of health facilities and patients who had positive perceptions of improved doctor-patient relationship has been increasing. Patient care experiences at public hospitals have been generally improved, and the implementation of promoting traditional Chinese Medicine practices also made progress. However, work satisfaction of healthcare providers was found to be rather low, compared to the high level of patient satisfaction.

Survey on the self-rated health of doctors and nurses at China′s 144 tertiary public hospitals / 中华医院管理杂志

Objective To establish comprehensive understanding of the self-rated health of the Chinese doctors and nurses and probe into their influencing factors. Methods Data were drawn from a hospital performance survey, which was conducted by the Peking Union School of Public Health from March 18th to April 9th, 2019, among the 144 tertiary public hospitals in 31 provinces, autonomous regions, and municipalities. The survey included a cell-phone based questionnaire filled out by the sampled doctors and nurses, in which they were asked to rate their health using a 5-level Likert scale(from " very poor" to " very good" ). Mann-Whitney U test was used to analyze the differences in self-rated health between doctors and nurses. Chi-square test and two-class multivariate logistic regression were performed to analyze factors affecting self-rated health of the providers. Results Among the 144 sample hospitals, the proportion of doctors, who rated their health as " healthy" , was 20.30% (4 979/24 529), that of nurses was 28.92% (8 361/28 910). It was worse than that in some developed countries and lower than the general population in China. Multi-variate analysis showed that adequate sleeping time, satisfaction with the work and with the doctor-patient relationship, were positively associated with the level of self-rated health of the sampled doctors and nurses(P<0.05). It was also found that the longer the average weekly working time, the higher the recognition of " the work load is too heavy" , the lower the proportion of doctors and nurses who rated their health as " healthy" (P <0.05). Conclusions Sleep time, job satisfaction, workload and doctor-patient relationship are important factors affecting self-rated health of the Chinese doctors and nurses.

Major findings from the 4th Evaluation of the National Healthcare Improvement Initiative / 中华医院管理杂志

Objective To carry out the 4th round of third-party evaluation on the implementation and effect of the 1st year of the 2nd Phase National Healthcare Improvement Initiative ( abbreviated as Initiative) since 2015. Methods The 4th round of the evaluation survey adopted the same methods, organization and execution, and technical roadmap as the former three rounds of evaluations.Results The 4th round of evaluation was carried out from 18 March to 9 April, 2019 at 185 public hospitals in 31 provinces ( autonomous regions, municipalities directly under the Central Government ) and Xinjiang Production and Construction Corps. Facility survey, health professional survey and patient survey were conducted at each of the sample health facilities. A total of 120 782 valid questionnaires were collected from 144 non-psychiatric health facilities, 16 246 valid questionnaires were obtained from 41 psychiatric health facilities, and 252 cases of outstanding departments/hospitals in healthcare improvement were also collected. The average overall scoring of the 12 dimensions to assess Initiative implementation at 144 non-psychiatric health facilities was 84.4%. The overall outpatient satisfaction scoring was 91.1% , 96.7% for the inpatients. The overall inpatient satisfaction(family members inclusive) at 41 psychiatric health facilities was 93%. Areas remaining to be improved include day-surgery, telemedicine and medical social work. Compared with technical services, non-technical care should be further strengthened. The compensation, workload and work environment of the healthcare providers are still to be improved. Conclusions The implementation of the Initiative by health facilities has been greatly improved. The percentage of health facilities and patients who had positive perceptions of improved doctor-patient relationship has been increasing. Patient care experiences at public hospitals have been generally improved, and the implementation of promoting traditional Chinese Medicine practices also made progress. However, work satisfaction of healthcare providers was found to be rather low, compared to the high level of patient satisfaction.

Outcomes analysis of the 3rd round evaluation for China′ s tertiary hospitals in Healthcare Improvement Initiative / 中华医院管理杂志

Objective To assess the implementation of Healthcare Improvement Initiative ( the Initiative)by 136 tertiary hospitals nationwide in 2017, and provide reference for improving relevant policies. Methods Hospital questionnaires 1 and 2 were designed, and data were collected by self-report and expert scoring.Descriptive statistics, Mann-Whitney U test, Kruskal-Wallis H(K), and Spearman rank correlation were used for statistical analysis.Results The median score of the first 11 dimensions of these hospitals was 91.89% , and that of the first 12 dimensions of 30 women and children hospitals was 90.54%.The total score rate of the top 11 hospitals in the eastern region was higher than that of both the central region and western region(P<0.001).The total score rate of the first 12 dimensions of women and children′s hospitals in the eastern region was higher than that in the central and western regions(P=0.032).The total score rate of the first 11 dimensions of the national level hospitals was higher than that of the local hospitals ( P =0.004).The correlation coefficient between the total number of patients and the total score of the first 11 dimensions and the first 12 dimensions was 0.578 and 0.413, respectively.Conclusions Implementation of the Initiative is satisfactory in general. There are however still rooms of improvement for hospitals in the central and western regions, and local level hospitals as well. General hospitals are better than TCm and specialist hospitals.The larger the scale, the better the performance in service improvement.

Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPAR agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound , the most effective one, gave the IC of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure-activity relationships and provide evidence for further structural modifications.