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ObjectiveTo analyze the exposure-response relationship of peripheral whole blood chromium level and lung function as well as genetic toxicity indicators in workers exposed to hexavalent chromium [Cr(Ⅵ)] compounds, and to propose a biological exposure limit of whole blood chromium for soluble Cr(Ⅵ) compounds-exposed workers. Methods A total of 515 workers from a dynamic occupational Cr(Ⅵ) compounds-exposed cohort in an enterprise from 2010 to 2017 were selected as the research subjects using a retrospective cohort study. A total of 918 followed-up results of research subjects and baseline data of a cohort were analyzed based on bibliometric analysis. The results include lung function tests, whole blood chromium level detected by inductively coupled plasma-mass spectrometry, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) detected by high performance liquid chromatography-tandem mass spectrometry, peripheral micronuclei frequency (MNF) detected by cytokinesis-block micronucleus assay, and mitochondrial DNA copy number (mtCN) detected by real-time fluorescence quantitative polymerase chain reaction. Results The results of bibliometric analysis showed that domestic and foreign studies on biological monitoring of Cr(Ⅵ) compounds increased year by year in the past 30 years, and whole blood chromium levels had a good correlation with the occupational Cr(Ⅵ) compounds exposure. The geometric mean of whole blood chromium levels in males and females among the occupational Cr(Ⅵ) compounds exposure cohort was 2.77 and 1.79 μg/L, respectively. A turning point appeared in 6.00 μg/L chromium in whole blood of the exposure-response curve of whole blood chromium levels with lung function indicators and genetic toxicity indicators. For each unit increase in the natural logarithm-transformed whole blood chromium level, the forced expiratory volume in one second (FEV1) decreased by 0.05 L, the FEV1/forced-vital-capacity decreased by 0.67%, the peak expiratory flow decreased by 0.15 L/s, the maximal mid-expiratory flow decreased by 0.09 L/s, the MNF increased by 0.149‰, the urinary 8-OHdG increased by 0.090 μg/g, and the mtCN increased by 0.013. When the whole blood chromium level was >6.00 μg/L, there was a significant increase in urinary 8-OHdG, MNF, and mtCN (all P<0.01). Conclusion The level of whole blood chromium can be used as a biomarker for occupational exposure to soluble Cr(Ⅵ) compounds. The preliminary biological exposure limit is set at 6.00 μg/L for whole blood chromium in workers exposed to soluble Cr(Ⅵ) compounds.
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Objective@#To explore the relationship between air pollutants and pediatric outpatient volumes in Baoshan District, Shanghai Municipality.@*Methods@#Data of meteorological factors, air pollutants and pediatric outpatient volumes in four general hospitals were collected in Baoshan District from 2015 to 2019, and a generalized additive model was used to fit the Poisson-like distribution. The exposure-response relationship between fine particulate matter (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and total pediatric outpatient volumes and pediatric respiratory outpatients.@*Results@#The median of the average daily temperature and relative humidity were 18.7 (interquartile range, 14.4) ℃ and 74.5% (interquartile range, 18.0%) in Baoshan District from 2015 to 2019, respectively. The median of the average daily concentrations of PM2.5, SO2, NO2 and O3 were 35.0 (interquartile range, 35.0), 11.0 (interquartile range, 7.0), 45.0 (interquartile range, 31.8) and 84.5 (interquartile range, 50.0) μg/m3, respectively. The median of the average daily total and respiratory pediatric outpatient volumes were 680 (interquartile range, 246) and 392 (interquartile range, 253). Spearman rank correlation analysis showed that temperature, relative humidity, PM2.5, SO2, NO2 and O3 were associated with total and respiratory pediatric outpatient volume (all P<0.05). Under the single pollutant model, the excess risk of total and respiratory pediatric outpatient volume due to PM2.5 (ER=0.318, 0.257), SO2 (ER=1.610, 2.546), and NO2 (ER=0.808, 0.839) reached the maximum effect on the same day, and the effect of O3 (ER=0.102, 0.222) reached its maximum at the first day of lag. Under the multi-pollutant model, after O3, SO2, NO2 and PM2.5 were introduced, a exposure-response relationship between air pollutants and total pediatric outpatient volumes was the largest on the sixth day after the lag (ER=0.419). There was no exposure-response relationship between air pollutants and respiratory pediatric outpatient volumes.@*Conclusion@#PM2.5, SO2, NO2 and O3 are associated with total and respiratory pediatric outpatient volumes, and the lag effects due to different air pollutants are different.
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ObjectiveTo explore the association between air pollutants and hospital outpatient visits in a district of Shanghai. MethodsDaily meteorological data， environmental data， data of outpatient visits to two secondary hospitals and two tertiary hospitals in this district from January 1， 2015 to December 31， 2019 were collected. A Poisson regression generalized linear model was used to analyze the exposure-response relationship between the air pollutants and hospital outpatient visits in this area. ResultsDuring the study period， the total number of outpatient visits in the included hospitals was 17 802 634， with an average daily total of （9 750±4 191） outpatient visits，and an average daily of （761±341） respiratory outpatient visits. In the lag effect of single pollutant model， when the concentration of air pollutant increased by 10 μg·m-3， PM2.5， SO2， NO2 had the maximum lag effect on the number of outpatient visits in the department of internal medicine for respiratory diseases on lag day 4， day 5 and day 7， respectively. And the RR values and 95%CI were 1.002 0（1.001 3‒1.002 6）， 1.0154（1.012 3‒1.018 5）， and 1.006 1（1.005 3‒1.006 9）， respectively. ConclusionThere is a exposure-response relationship between air pollutants and the number of outpatient visits in each department of the hospitals， and different pollutants have different degrees of lag effects.
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Infliximab （IFX）， tumor necrosis factor-α inhibitor， is widely used in clinical practice for treating Crohn disease （CD）， but it is difficult to obtain the optimal therapeutic effect according to the conventional dose. It is recommended to perform therapeutic drug monitoring （TDM） for patients with poor therapeutic efficacy to guide clinical decisions. This paper reviews the pharmacokinetic characteristics of IFX， exposure-response relationship， the influencing factors of pharmacokinetic differences， and analytical methods in TDM. It is found that IFX doesn’t undergo liver or kidney metabolism， exhibits obvious exposure-response relationships in both the induction and maintenance phases of CD treatment； disease activity， albumin， antibodies to IFX （ATI） and other factors influence IFX’s exposure. It is recommended that trough concentration of IFX in the maintenance period should be kept above 3 μg/mL； the dose of IFX should be increased or medication interval should be shortened for patients with severe disease， low albumin levels and ATI formation， to promote therapeutic efficacy of IFX. It is suggested to use the same detection method for TDM of IFX in the same patient.
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Objective To construct an air health index (AHI) based on the exposure-response relationships of air pollution and ambient temperature with the years of life lost (YLL) in Tianjin. Methods The time series database of air pollution, meteorological factors, and non-accidental YLL from 2014-2019 in six urban areas of Tianjin were established. The data from 2014 to 2017 were used as the construction set to establish the exposure-response relationships of air pollution and ambient temperature with non-accidental YLL and establish the AHI model. The data from 2018 to 2019 were used as the validation set for verifying AHI. The generalized additive model (GAM) and weighted quantile sum (WQS) model were used to establish the exposure-response relationship between air pollution mixtures and non-accidental YLL. The distributed lag nonlinear model (DLNM) was fitted to assess the exposure-response relationship between ambient temperature and non-accidental YLL. Based on these obtained coefficients, the AHI and air quality health index (AQHI) were built. By comparing the associations between AHI, air quality health index (AQHI), and air quality index (AQI) with daily mortality and YLL and model goodness of fit to evaluate the validity of AHI. Results The formula for AHIt=EYLLt,air pollution+ambient temperature/475.11*10. The validation results showed that each IQR increase in AHI was associated with a higher increase in non-accidental mortality and YLL (10.61% and 353.37 person-year) compared with the corresponding values of AQHI and AQI. In addition, the model goodness of AHI was better than AQHI and AQI model. Conclusion Compared with AQHI and AQI, the AHI based on the integrating health effects of air pollution and ambient temperature has a better health risk prediction ability.
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Objective:To systematically evaluate the intervention effect of exposure and response prevention (ERP) on obsessive compulsive disorder (OCD).Methods:PubMed, Web of Science Core Collection, EBSCO, Cochrane Library, Embase, Science Direct, Wanfang Data, China National Knowledge Infrastructure and VIP-CSTJ were used to collect randomized controlled studies related to ERP for OCD.Randomized controlled studies that met the criteria were included, with the score of Yale-Brown obsessive-compulsive scale as the primary outcome indicator and the scores of anxiety and depression scale as secondary outcome indicators, while the included literatures were evaluated for literature quality and data extraction.Review Manager 5.3 and Stata 16.0 softwares were used to conduct Meta-analysis on the extracted data.Results:Twenty-seven studies with a total of 1 239 patients were included, and 599 cases in the ERP group and 640 cases in the control group.Meta-analysis results showed that the efficacy of ERP group was significantly better than that of blank control group(MD=-6.55, 95% CI: -8.75--4.35, P<0.001) and significantly better than chlorpromazine control group treatment (MD=-5.88, 95% CI: -8.20--3.56, P<0.001) for improving patients' obsessive-compulsive symptoms, but not significantly different from CBT intervention (MD=0.21, 95% CI: -1.62-2.04, P=0.82), and the efficacy of ERP and CBT had no significant during the post-intervention follow-up period (MD=0.41, 95% CI: -2.45-3.27, P=0.78). For improving patients' depressed mood, ERP was effective in improving patients' depressed mood (SMD=-0.45, 95% CI: -0.74--0.17, P=0.002), but not significantly different from CBT (SMD=-0.05, 95% CI: -0.27-0.16, P=0.62). For improving anxiety, the efficacy of ERP group was not different from that of control group (SMD=-0.17, 95% CI: -0.56-0.23, P=0.41). Conclusion:ERP has good feasibility in improving obsessive-compulsive symptoms and depression in patients with OCD.However, long-term efficacy was not verified for improving anxiety and maintaining long-term efficacy during the follow-up period.
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Background Stroke has become a main cause of death in China. With global warming, the studies on temperature and stroke have attracted much attention. Objective To analyze he relationships between heatwave and the years of life lost (YLL) by different subtypes of stroke by controlling temporal and spatial effects with Bayesian spatio-temporal model, and to study the modifiers of the health effect of heatwave. Methods The daily information of stroke deaths, meteorological data, and air pollutant data in 40 districts and counties of Guangdong Province were collected during the warm seasons (from May to October) in the years from 2014 to 2017. The individual YLL was first calculated by matching age and gender according to the life table, and then the daily YLL rate (person-years/100 000 people) was obtained by summarizing the daily YLL and correcting it with the population of each district or county. Bayesian spatio-temporal model was used to fit a proposed exposure-response relationship between heatwave and the YLL rates of different subtypes of stroke. Finally, stratified analyses were conducted by age (<65 years, ≥65 years), gender (male, female), and region (Pearl River Delta and non-Pearl River Delta regions) to identify the major modifiers for the association between heatwave and stroke mortality. Results During the warm seasons from 2014 to 2017, a total of 23 heatwave events occurred in the 40 districts or counties of Guangdong Province, cumulatively lasting for 145 d. A total of 30 852 stroke deaths were recorded in the same time periods. The average daily YLL rate of total stroke was (2.39±3.63) person-years/100 000 people, and those for hemorrhagic stroke and ischemic stroke were (1.54±2.99) person-years/100 000 people and (0.84±1.85) person-years/100 000 people, respectively. Heatwave was associated with increased YLL rate of stroke in residents, and it had a greater impact on ischemic stroke with a lag effect. The largest cumulative effect of heatwave was at lag 0-1 day, which was associated with an increased YLL rate of total stroke and ischemic stroke by 0.17 (95%CI: 0.03-0.29) person-years/100 000 people and 0.13 (95%CI: 0.06-0.20) person-years/100 000 people, respectively. The results of stratified analyses showed that heatwave had a larger effect on ischemic stroke in residents of aged 65 years or older, male, and non-Pearl River Delta regions, and the rates of YLL increased by 1.11 (95%CI: 0.58-1.55), 0.13 (95%CI: 0.03-0.23), and 0.20 (95%CI: 0.07-0.32) person-years/100 000 people, respectively; Heatwave only had an effect on hemorrhagic stroke in residents aged 65 years or older with an increased YLL rate of 0.79 (95%CI: 0.26-1.31) person-years/100 000 people. Conclusion Heatwave could elevate the level of years of life lost associated with stroke in Guangdong residents, with greater impacts on ischemic stroke of the aged, men, and residents in non-Pearl River Delta regions, and on hemorrhagic stroke in the elderly.
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Background Adverse health effects associated with particulate matter have been demonstrated, but findings on seasonal variation in the health impacts are inconsistent. Objective To explore potential seasonal variation in particulate matter (PM2.5 and PM10) associated daily non-accidental mortality and corresponding years of life loss (YLL) in Tianjin. Methods The daily data of non-accidental deaths, air pollution, and meteorological factors in Tianjin from 2014 to 2019 were collected. A generalized additive model, with adjusting selected confounding factors such as temperature, relative humidity, long-term trends, day of the week, and holiday, was used to quantitatively evaluate the relationships of PM2.5 and PM10 with daily non-accidental deaths and YLL. Results The effects of PM2.5 and PM10 on daily non-accidental mortality and corresponding YLL were statistically significant in full year, spring, summer, and autumn (except for the effect of PM10 on non-accidental YLL in spring), but not statistically significant in winter. The non-accidental mortality and it's 95%CI increased by 0.28% (0.11%-0.44%) and 0.24% (0.11%-0.36%) in full year, 0.44% (0.11%-0.77%) and 0.17% (0.00%-0.33%) in spring, 1.32% (0.50%-2.16%) and 2.15% (1.54%-2.76%) in summer, and 0.68% (0.30%-1.06%) and 0.57% (0.28%-0.87%) in autumn for every 10 µg·m−3 increase in PM2.5 and PM10 concentrations, respectively; the corresponding YLL and it's 95%CI increased by 7.41 (2.42-13.07) and 5.75 (1.94-9.57), 13.11 (3.00-23.22) and 2.88 (−2.82-8.59), 34.66 (11.92-57.40) and 48.12 (31.48-64.75), and 16.13 (4.57-27.70) and 12.60 (3.56-21.65) person-years, respectively. When adopting the limits in the Global Air Quality Guidelines (2021) as the reference, excess deaths and YLL caused by PM2.5 and PM10 exposure were the greatest in summer. The excess deaths and it's 95%CI were 5.38 (5.08-5.69) and 8.62 (7.95-9.28), and the excess YLL and it's 95%CI were 112.23 (105.79-118.67) and 156.94 (44.99-168.89) person-years, respectively. Conclusion The effects of particulate matter on non-accidental mortality and corresponding YLL may vary seasonally in Tianjin with the greatest effects in summer, suggesting that the health protection related to particulate matter should be strengthened in summer.
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The antitumor drug has become one of the focused areas in new drug research and development. Their clinical research generally consumes a long period of time, with high cost and high risk. Model-informed drug development (MIDD) integrates and quantitatively analyzes physiological, pharmacological, and disease progression information through modeling and simulation, which can reduce the cost of drug development and improve the efficiency of clinical research. In this essay, Osimertinib and Pembrolizumab are given as examples to illustrate the specific application of MIDD in different phases of clinical research, aiming to provide references for the application of MIDD to guide the clinical research of antitumor drugs. .
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Humains , Antinéoplasiques/usage thérapeutique , Développement de médicament , Tumeurs du poumonRÉSUMÉ
The clinical trial of OBCA (OCALIVA) in the treatment of primary biliary cirrhosis (PBC) shows its efficacy. As it is difficult to conduct sufficient clinical studies in moderate and severe hepatic impairment population, the applicant and the FDA theorem have different opinions based on the same model, such as population PK, exposure-response and physiologically-based PK (PBPK). The applicant considers that the increase in the exposure of drug in liver tissue is limited, and there is no need for dose adjustment, that is, 5 mg, once a day. FDA believes that the influencing factors of the PBPK model have not been fully taken into account and the validation of the PBPK is not robust with a wide variability, and there is also a risk of high blood drug exposure in patients. It is recommended to significantly reduce the dose, that is, 5 mg, once a week, no more than 10 mg, per week at least 3 days interval, and accordingly written into the medication instructions. After approval many patients with hepatic impairment did not take medicine according to the instructions, therefore overdosed, resulting in death. The results fully prove that the original considerations and decisions of FDA have been verified, and the experience and lessons of this example once again suggest that modeling and simulation need bold assumptions and careful verification.
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Nivolumab is a humanized monoclonal antibody that blocks the programmed death 1 (PD-1) receptor. The initially recommended dose was 3 mg/kg every 2 weeks (Q2W) when nivolumab was firstly approved by the US FDA in 2014. A flat dose of 240 mg Q2W was approved in 2016, and subsequently 480 mg Q4W in 2018. Model-informed drug development (MIDD) approach was applied for the analyses of drug exposure, safety and efficacy based on the data from existed clinical studies, and the model-informed analyses became the key evidences supporting approval of new dosage regimens. Relevant studies and regulatory considerations related to the nivolumab dose selection and subsequent modification were reviewed in this paper. The application of MIDD approach in dose optimization is additionally discussed.
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Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.
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The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. Seven escalating doses of virtual drugs with equal potency and efficacy but with five different Hill coefficients were used in simulations of single and multiple dose scenarios with dense sampling design. A total of 70 scenarios with 100 subjects were simulated and estimated 100 times applying 1-compartment PK model and sigmoid E(max) model. The bias and precision of the parameter estimates in each scenario were assessed using relative bias and relative root mean square error. For the single dose scenarios, most PD parameters of sigmoid E(max) model were accurately and precisely estimated when the C(max) was more than 85% of EC₅₀, except for typical value and inter-individual variability of EC₅₀ which were poorly estimated at low Hill coefficients. For the multiple dose studies, the parameter estimation performance was not good. This simulation study demonstrated the effect of the relative range of sampled concentrations to EC₅₀ and sigmoidicity on the parameter estimation performance using dense sampling design.
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Biais (épidémiologie) , Étude clinique , Côlon sigmoïdeRÉSUMÉ
Druggability is crucial in pharmaceutical drug development as the source of drug research. Druggability research will face greater challenges because Chinese materia medica (CMM) is the multicomponent drug. In this paper, ideas and methods of study on CMM druggability were mainly proposed in combination with the chemical material basis of muticomponents of CMM.
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ObjectiveTo research the intestinal absorption characteristics in rats of multiple constituents,when Wuwei-Jiangya recipe was used in rats and showed reducing blood pressure effects.Methods ① After extracting Wuwei-Jiangya recipe,we fed it to rats once daily,until the blood pressure reduced; ②Establish Wuwei-Jiangya recipe and intestinal absorption of multiple constituents fingerprint by using reverted gut sac method and RP-HPLC fmgerprint.ResultsAfter one week's administration,there was the hypotensive effects and multiple constituents can be absorbed by intestine.ConclusionWhen the drug works,reverted gut sac method for studying intestinal absorption constituents can be used for locking the exposure constituents.
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The character of exposure-response relationship between particulate matter and population mortality has been one of the critical and difficult problems in air pollution epidemiological study. The character of exposure-response relationship included the shape of the exposure-response relationship and the existence of the threshold concentration. In this paper, the recent relevant researches on the character of exposure-response relationship between particulate matter and population mortality were reviewed. The threshold concentration of particulate matter for mortality was not found and the shape of the exposure-response curve need to be further studied. Now, in China, we are facing a good opportunity for researching the exposure-response relationship between particulate matter and population mortality.
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La medición del impacto de los contaminantes atmosféricos sobre la salud se realiza a través de funciones exposición-respuestas (FERs), las que permiten estimar la proporción de sujetos afectados en la población. El presente trabajo tiene como objetivos definir criterios metodológicos para la determinación de FERs, resumir el análisis de la aptitud de los estudios epidemiológicos nacionales con este propósito y proponer una serie de FERs basadas en evidencias nacionales y extranjeras para su empleo en evaluaciones de impacto. Se exponen los criterios metodológicos con vista a la formulación de FERs para contaminantes del aire a partir de estudios epidemiológicos mediante la determinación de la pendiente concentración-respuesta, y se asume que las FERs constituyen funciones lineales, sin umbral; se expone la metodología adoptada para evaluar la aptitud de estudios para el establecimiento de FERs. Los resultados muestran que numerosos estudios epidemiológicos nacionales han reportado asociaciones entre contaminantes del aire y morbilidad respiratoria aguda y crónica, aunque solo en tres de ellos han sido expuestas las FERs. Los principales problemas y limitaciones identificados incluyen: predominio de estudios descriptivos, inadecuada evaluación de la exposición por dificultades en el monitoreo de contaminantes o estimadas mediante modelos de dispersión de precisión incierta y evaluación estadística con débil componente epidemiológico (análisis principalmente bivariado, sin control de posibles factores de confusión). Se propone una selección de FERs para mortalidad y morbilidad, dirigida a su empleo preliminar en evaluaciones de impacto en salud, previa fundamentación de su aptitud.
The measurement of the impact of air pollutants on health is carried out through exposure-response functions (ERFs), which allow to estimate the proportion of affected subjects in the population. The aim of the present paper is to define the methodological criteria for the determination of ERFs, to summarize the analysis of the aptitude of national epidemiological studies with this purpose and to propose a series of ERFs based on national and international evidences for their use in impact evaluations. The methodological criteria are explained in order to formulate FERs for air pollutants, starting from epidemiological studies by the determination of the concentration-response slope. It is assumed that FERs are lineal functions without threshold. The methodology adopted to evaluate the aptitude of of the studies for the establishment of FERs is exposed. The results show that several national epidemiological studies have reported associations between air pollutants and acute and chronic respiratory morbidity, eventhough only in three of them ERFs have been exposed. The main problems and limitations identified include: predominance of descriptive studies, inadequate evaluation of the exposure due to difficulties in the monitoring of pollutants, or estimates by dispersion models of uncertain accuracy and statistical evaluation with a weak epidemiological component (a mainly bivariate anlysis without control of possible confounding factors). A selection of ERFs is proposed for mortality and morbidity for its preliminary use in health impact evaluations, previous foundation of its aptitude.
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Objective To do the epidemiological analysis based on the data of air fine particulate matter PM2.5 and daily mortality and to estimate the exposure-response relationship. Methods Based on the online search of relevant studies with the same endpoint meta-analysis was used to do the comprehensive assessment to determine the exposure-response relationship. Results The exposure-response relationship between short-term exposure to ambient PM2.5 and the increased percentage of daily mortality was found as the concentration of air fine particulate increased a certain degree(100 ?g/m3) the daily mortality of residents increased by 12.06%(95%CI 8.31%-15.82%). Conclusion The exposure-response relationship recommended in the present paper can be applied to the health risk assessment of air fine particulate matter in various cities of China.
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Objective To analyze the epidemiological data on air particulate matter and adverse health outcomes in China, and to estimate the exposure_response relationships. Methods An electronic search of relevant literature was conducted to determine the exposure_response relationship for each health outcome associated with exposure to air particulate matter, and the approach of Meta_analysis was used when there were several studies describing the same health endpoint. Results For each health outcome from morbidity to mortality changes, the relative risks were estimated when the concentration of air particulate matter increased some certain units. Conclusion The exposure_response relationships described here might be further applied to health risk assessment of air particulate matter in China.