Objective In 2017,China launched a new round of medical reform(NMR)to address the inaccessibility of high-priced drugs for patients with serious diseases.This study explored the impact of the NMR on the accessibility ...Objective In 2017,China launched a new round of medical reform(NMR)to address the inaccessibility of high-priced drugs for patients with serious diseases.This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies(mAbs),and the effective promotion policies after the NMR.Methods We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province,China.By interviewing hospital pharmacy experts,we identified the potential value of the current NMR in improving the access to therapeutic mAbs.Results The average availability of 13 mAbs increased by 8.1%in the surveyed hospitals of Hubei province after the NMR.The median unit price of 10 mAbs dropped by 34.3%.The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident(56.2%reduction).The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs.However,the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs.Conclusion Not all current NMR policies play a positive role in promoting the accessibility of mAbs.To further improve the accessibility of mAbs in the future in China,it is therefore critical to increase the investment in independent research and development of high-quality mAbs,establish localized guidelines for the rational use of mAbs in clinical practice,and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.展开更多
The structural safety of high-speed trains is significantly endangered by increasing operating speeds.The objective of this research was to investigate the evolution of the flow field in trains passing through a tunne...The structural safety of high-speed trains is significantly endangered by increasing operating speeds.The objective of this research was to investigate the evolution of the flow field in trains passing through a tunnel while there is a strong crosswind at the tunnel entrance and exit.Moreover,the effect of aerodynamic pressure waves on structural strength was analyzed to evaluate the safety of the carbody.In this study,we selected the improved delayed detached-eddy simulation(IDDES)method as a turbulence model.The mechanism of interaction among the train,tunnel,and crosswind was evaluated through a complex computational fluid dynamics(CFD)model,simulating high-speed trains moving through tunnels at various crosswind speeds.Additionally,the dynamic stress response of the carbody was calculated using a sequential coupling approach,where integral aerodynamic forces were applied as substitutes for direct CFD pressure loads.We assessed the effect of aerodynamic loads on the dynamic stresses of the carbody at different crosswind velocities(0,10,15,and 20 m/s).The results indicate that crosswinds exert a substantial influence on the fluid structure surrounding the train.Consequently,the aerodynamic forces contribute significantly to potential damage to the carbody,posing increased safety risks for high-speed trains.展开更多
In the present study, we aimed to intensively study the chemical constituents, especially organic acids from a medicinal plant Portulaca oleracea L., and screen their anti-inflammatory and quinone reductase （QR, a ph...In the present study, we aimed to intensively study the chemical constituents, especially organic acids from a medicinal plant Portulaca oleracea L., and screen their anti-inflammatory and quinone reductase （QR, a phase II detoxyfication enzyme） inductive activity. A total of 20 compounds were isolated and identified based on spectroscopic methods, as succinic acid （1）, mono-methyl succinate （2）, L-malic acid （3）, L-l-methyl malate （4）, L-4-methyl malate （5）, L-dimethyl malate （6）, L-6-ethyl citrate （7）, L-1-methyl citrate （8）, L-1,5-dimethyl citrate （9）, 4-hydroxy-5-methylfuran-3-carboxylic acid （10）, 5-hydroxymethyl-furoic acid （11）, stearic acid （12）, L-pyroglutamic acid （13）, cyclo-（tyrosine-leucine） （14）, L-isoleucine （15）, （-）-dehydrovomifoliol （16）, （-）-epiloliolide （17）, 3,4-dihydroxyphenylethanol （18）, succinimide （19）, and uracil （20）. Among them, 14 compounds （2, 4-8, 10, 11, 13-18） were isolated from P. oleracea for the first time. Compotmd 18 （12.5 μM） exhibited potent anti-inflammatory effect in lipopolysaccharide （LPS）-induced macrophage cells （RAW264.7） by reducing NO production, and it also increased QR activity in Hepa lclc7 cells. Compound 16 （50 μM） showed weak QR inductive activity. None of other compounds showed anti-inflammatory or QR inductive activities.展开更多
Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY)...Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.展开更多
The aim of the present study was to measure the prevalence of multimorbidity in Bangladesh,India and China,and to assess the relationship between multimorbidity and patient's opinion regarding their involvement in...The aim of the present study was to measure the prevalence of multimorbidity in Bangladesh,India and China,and to assess the relationship between multimorbidity and patient's opinion regarding their involvement in healthcare decision-making and overall satisfaction of healthcare system.Cross-sectional data on 18696 men and women aged 18 and above were collected from the World Health Survey of World Health Organization(WHO).Outcome variables were subjective rating of(1)healthcare system's ability to involve patients in decision-making,and(2)satisfaction with the way healthcare system runs in the country.Self-reported chronic conditions were used to measure the prevalence of multimorbidity.Out of 9 chronic conditions,back pain,arthritis,and chronic cough appeared to be the most prevalent ones among majority of the participants.About one-third of the participants in China(30.7%)and two-thirds in Bangladesh(66.1%)and India(66.6%)reported having at least one chronic illness.Prevalence of multimorbidity was highest in India(34.3%)followed by Bangladesh(28.8%)and China(14.3%).In Bangladesh,India and China,respectively 70.5%,41.7%,61.3%women and 54.5%,42.8%and 58.8%men expressed dissatisfaction regarding the way healthcare system runs in their country.In Bangladesh and India,men who were living with multimorbidity were more likely to rate the patient-centeredness as"bad"than those who had no disease illness.This study suggests that the prevalence of multimorbidity was remarkably high especially in Bangladesh and India.Higher likelihood of dissatisfaction about healthcare system among multimorbid patients might be indicative of inadequacy in the provision of care in qualitative and quantitative terms.展开更多
HIV-1 reverse transcriptase(RT)is responsible for reverse transcription of viral single-stranded RNA to double-stranded DNA,which plays an important role in the replication cycle of HIV-1 and has been identified as a ...HIV-1 reverse transcriptase(RT)is responsible for reverse transcription of viral single-stranded RNA to double-stranded DNA,which plays an important role in the replication cycle of HIV-1 and has been identified as a key target for anti-HIV-1 drug discovery.Among HIV-1 RT inhibitors,allosteric inhibitors acting on non-catalytic sites have the advantages of high efficiency and low cytotoxicity,which are the focus of the research on anti-HIV-1 inhibitors.Great progress has been achieved in the structural biology of HIV-1 RT,which significantly facilitated the development of RT allosteric inhibitors.Herein,we provided a detailed review of the co-crystal structures of small molecule allosteric inhibitors in complex with RT reported in the last decade.Moreover,the strategies to discover novel and efficient inhibitors based on co-crystal structures have also been discussed,expecting to provide a reference for the development of the next-generation anti-HIV-1 drugs.展开更多
In China, the level of ambient fine particulate matter (PM_(2.5)) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM_(2.5) exposure have be...In China, the level of ambient fine particulate matter (PM_(2.5)) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM_(2.5) exposure have become a major public health issue. More than half of PM_(2.5)-related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM_(2.5) pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM_(2.5) on cardiopulmonary diseases in China, including studies relating to the effects of PM_(2.5) on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM_(2.5) across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM_(2.5) and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved;this may help us to take steps to reduce PM_(2.5) pollution and reduce the incidence of cardiopulmonary disease.展开更多
In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNI...In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.展开更多
基金supported by the grants from the National Natural Science Foundation of China(No.70903025,No.71373089).
文摘Objective In 2017,China launched a new round of medical reform(NMR)to address the inaccessibility of high-priced drugs for patients with serious diseases.This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies(mAbs),and the effective promotion policies after the NMR.Methods We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province,China.By interviewing hospital pharmacy experts,we identified the potential value of the current NMR in improving the access to therapeutic mAbs.Results The average availability of 13 mAbs increased by 8.1%in the surveyed hospitals of Hubei province after the NMR.The median unit price of 10 mAbs dropped by 34.3%.The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident(56.2%reduction).The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs.However,the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs.Conclusion Not all current NMR policies play a positive role in promoting the accessibility of mAbs.To further improve the accessibility of mAbs in the future in China,it is therefore critical to increase the investment in independent research and development of high-quality mAbs,establish localized guidelines for the rational use of mAbs in clinical practice,and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.
基金supported by the National Natural Science Foundation of China(No.52375160)the Natural Science Foundation of Hebei Province(No.2024105064),China.
文摘The structural safety of high-speed trains is significantly endangered by increasing operating speeds.The objective of this research was to investigate the evolution of the flow field in trains passing through a tunnel while there is a strong crosswind at the tunnel entrance and exit.Moreover,the effect of aerodynamic pressure waves on structural strength was analyzed to evaluate the safety of the carbody.In this study,we selected the improved delayed detached-eddy simulation(IDDES)method as a turbulence model.The mechanism of interaction among the train,tunnel,and crosswind was evaluated through a complex computational fluid dynamics(CFD)model,simulating high-speed trains moving through tunnels at various crosswind speeds.Additionally,the dynamic stress response of the carbody was calculated using a sequential coupling approach,where integral aerodynamic forces were applied as substitutes for direct CFD pressure loads.We assessed the effect of aerodynamic loads on the dynamic stresses of the carbody at different crosswind velocities(0,10,15,and 20 m/s).The results indicate that crosswinds exert a substantial influence on the fluid structure surrounding the train.Consequently,the aerodynamic forces contribute significantly to potential damage to the carbody,posing increased safety risks for high-speed trains.
基金National Natural Science Foundation of China(Grant No.81073005)Science and Technology Development Program of Shandong Province(Grant No.2014GSF119007)+2 种基金Major Project of Science and Technology of Shandong Province(Grant No.2015ZDJS04001)Young Scholars Program of Shandong University(Grant No.YSPSDU2015WLJH50)China-Australia Centre for Health Sciences Research(2015)
文摘In the present study, we aimed to intensively study the chemical constituents, especially organic acids from a medicinal plant Portulaca oleracea L., and screen their anti-inflammatory and quinone reductase （QR, a phase II detoxyfication enzyme） inductive activity. A total of 20 compounds were isolated and identified based on spectroscopic methods, as succinic acid （1）, mono-methyl succinate （2）, L-malic acid （3）, L-l-methyl malate （4）, L-4-methyl malate （5）, L-dimethyl malate （6）, L-6-ethyl citrate （7）, L-1-methyl citrate （8）, L-1,5-dimethyl citrate （9）, 4-hydroxy-5-methylfuran-3-carboxylic acid （10）, 5-hydroxymethyl-furoic acid （11）, stearic acid （12）, L-pyroglutamic acid （13）, cyclo-（tyrosine-leucine） （14）, L-isoleucine （15）, （-）-dehydrovomifoliol （16）, （-）-epiloliolide （17）, 3,4-dihydroxyphenylethanol （18）, succinimide （19）, and uracil （20）. Among them, 14 compounds （2, 4-8, 10, 11, 13-18） were isolated from P. oleracea for the first time. Compotmd 18 （12.5 μM） exhibited potent anti-inflammatory effect in lipopolysaccharide （LPS）-induced macrophage cells （RAW264.7） by reducing NO production, and it also increased QR activity in Hepa lclc7 cells. Compound 16 （50 μM） showed weak QR inductive activity. None of other compounds showed anti-inflammatory or QR inductive activities.
基金financial support from the National Natural Science Foundation of China (Nos. 81973181, 81903453)Shandong Provincial Natural Science Foundation (No. ZR2019BH011)+7 种基金Natural Science Foundation of Jiangsu Province (No. BK2019041035)China Postdoctoral Science Foundation (Nos. 2019T120596, 2018M640641)Science Foundation for Outstanding Young Scholars of Shandong Province (No. ZR2020JQ31)Science Foundation for Excellent Young Scholars of Shandong Province (No. ZR2020YQ61)National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2019ZX09301126)Shandong Provincial Key Research and Development Project (Nos. 2017CXGC1401, 2019JZZY021011)Foreign cultural and educational experts Project (No. GXL20200015001)the Taishan Scholar Program at Shandong Province and KU Leuven (No. GOA 10/014)。
文摘Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.
文摘The aim of the present study was to measure the prevalence of multimorbidity in Bangladesh,India and China,and to assess the relationship between multimorbidity and patient's opinion regarding their involvement in healthcare decision-making and overall satisfaction of healthcare system.Cross-sectional data on 18696 men and women aged 18 and above were collected from the World Health Survey of World Health Organization(WHO).Outcome variables were subjective rating of(1)healthcare system's ability to involve patients in decision-making,and(2)satisfaction with the way healthcare system runs in the country.Self-reported chronic conditions were used to measure the prevalence of multimorbidity.Out of 9 chronic conditions,back pain,arthritis,and chronic cough appeared to be the most prevalent ones among majority of the participants.About one-third of the participants in China(30.7%)and two-thirds in Bangladesh(66.1%)and India(66.6%)reported having at least one chronic illness.Prevalence of multimorbidity was highest in India(34.3%)followed by Bangladesh(28.8%)and China(14.3%).In Bangladesh,India and China,respectively 70.5%,41.7%,61.3%women and 54.5%,42.8%and 58.8%men expressed dissatisfaction regarding the way healthcare system runs in their country.In Bangladesh and India,men who were living with multimorbidity were more likely to rate the patient-centeredness as"bad"than those who had no disease illness.This study suggests that the prevalence of multimorbidity was remarkably high especially in Bangladesh and India.Higher likelihood of dissatisfaction about healthcare system among multimorbid patients might be indicative of inadequacy in the provision of care in qualitative and quantitative terms.
基金support from the National Natural Science Foundation of China(NSFC No.82273773)Shandong Laboratory Program(SYS202205,China)+1 种基金Major Basic Project of Natural Science in Shandong Province(ZR2021ZD17,China)Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province.
文摘HIV-1 reverse transcriptase(RT)is responsible for reverse transcription of viral single-stranded RNA to double-stranded DNA,which plays an important role in the replication cycle of HIV-1 and has been identified as a key target for anti-HIV-1 drug discovery.Among HIV-1 RT inhibitors,allosteric inhibitors acting on non-catalytic sites have the advantages of high efficiency and low cytotoxicity,which are the focus of the research on anti-HIV-1 inhibitors.Great progress has been achieved in the structural biology of HIV-1 RT,which significantly facilitated the development of RT allosteric inhibitors.Herein,we provided a detailed review of the co-crystal structures of small molecule allosteric inhibitors in complex with RT reported in the last decade.Moreover,the strategies to discover novel and efficient inhibitors based on co-crystal structures have also been discussed,expecting to provide a reference for the development of the next-generation anti-HIV-1 drugs.
基金supported by grants from the National Key Research and Development Program of China(No.2016YFC0206500)the National Research Program for Key Issues in Air Pollution Control of China(No.DQGG0401).
文摘In China, the level of ambient fine particulate matter (PM_(2.5)) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM_(2.5) exposure have become a major public health issue. More than half of PM_(2.5)-related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM_(2.5) pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM_(2.5) on cardiopulmonary diseases in China, including studies relating to the effects of PM_(2.5) on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM_(2.5) across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM_(2.5) and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved;this may help us to take steps to reduce PM_(2.5) pollution and reduce the incidence of cardiopulmonary disease.
基金financial support from the Key Project of NSFC for International Cooperation(No.81420108027,China)the National Natural Science Foundation of China(NSFC Nos.81273354,81573347,81903453)+6 种基金Young Scholars Program of Shandong University(YSPSDU No.2016WLJH32,China)Shandong Provincial Natural Science Foundation(ZR2019BH011,China)China Postdoctoral Science Foundation(2018M640641,2019T120596)Key research and development project of Shandong Province(No.2017CXGC1401,China)KU Leuven(GOA 10/014,Belgium)the Spanish Government(MINECO Project SAF2017-881074-R,AEI/FEDER,UE)Generalitat de Catalunya(2017SGR1746,Spain)for the financial support
文摘In this report,a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket(NNIBP)by incorporating an aromatic moiety to the left wing of the lead K-5 a2.The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase(RT).Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors(NNRTI)-resistant mutations.Especially,compound 26 exhibited the most potent activity against wild-type and a panel of single mutations(L1001,K103 N,Y181 C,Y188 L and E138 K)with an EC50 ranging from 6.02 to 23.9 nmol/L,which were comparable to those of etravirine(ETR).Moreover,the RT inhibition activity,preliminary structure-activity relationship and molecular docking were also investigated.Furthermore,26 exhibited favorable pharmacokinetics(PK)profiles and with a bioavailability of 33.8%.Taken together,the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.
