Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.

BACKGROUND AND OBJECTIVES: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models. METHODS: Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response. RESULTS: Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients. CONCLUSIONS: These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. TRIAL REGISTRY: ClinicalTrials.gov NCT00854152 and NCT00854126.

Global Burden of Alzheimer's Disease and Other Dementias Attributed to High Fasting Plasma Glucose from 1990 to 2019.

BACKGROUND: Burden of Alzheimer's disease (AD) and other dementias have grown rapidly over the decades, and high fasting plasma glucose (HFPG) was one of the well-established risk factors. It is urgently needed to estimate the global burden of AD and other dementias attributable to high fasting plasma glucose between regions, countries, age groups, and sexes to inform development of effective primary disease prevention strategies and intervention policies. METHODS: The burden of AD and other dementias attributable to HFPG was estimated based on a modeling strategy using the Global Burden of Disease Study 2019 dataset. The disease burden and time trend globally and by region, country, development level, age group, and sex were evaluated. RESULTS: The number of AD and other dementias-related deaths attributable to HFPG increased from 42,998.23 (95% uncertainty interval, UI: 4459.86-163,455.78, the year of 1990) to 159,244.53 deaths (95% UI 18,385.23-583,514.15, the year of 2019). The age-standardized death rate increased from 1.69 (95% UI 0.18-6.54) in 1990 to 2.24 (95% UI 0.26-8.24) in 2019. The burden was higher in more developed regions. The burden in women was double that in men, that HFPG-attributable AD and other dementias caused 99,812.79 deaths (95% UI 9005.67-387,160.60) in women and 59,431.74 deaths (95% UI 5439.02-214,819.23) in men, with age-standardized death rate of 2.27 (95% UI 0.20-8.79) per 100,000 population in women and 2.20 (95% UI 0.20-8.00) in men. CONCLUSION: Findings from the current study emphasizes the urgent requirement for targeted interventions in high-development regions, as well as the importance of proactive measures in middle-development countries in protection of AD and other dementias. The gender disparity necessitates the integration of gender-specific considerations in targeted approaches in prevention of AD and other dementias.

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor).

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size-time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.

[Analysis and prediction of disease burden of cirrhosis and other chronic liver diseases due to alcohol use in China from 1990 to 2030].

Objective: To comprehensively understand the disease burden of liver cirrhosis and other chronic liver diseases caused by alcohol use in China from 1990 to 2019, as well as to predict the trends in disease burden from 2020 to 2030. Methods: The analysis utilized data from the Global Burden of Disease study in 2019 (GBD2019). Key indicators such as incidence rate, mortality rate, disability-adjusted life years (DALY), years of life lost due to premature mortality, and years lived with disability were selected to describe the disease burden of alcohol-related liver cirrhosis and other chronic liver diseases in China from 1990 to 2019. The estimated annual percentage change (EAPC) was used to depict the temporal trends in disease burden. Furthermore, a Bayesian age-period-cohort (BAPC) model was constructed using R software to predict the age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of alcohol-related liver cirrhosis and other chronic liver diseases in China from 2020 to 2030. Results: From 1990 to 2019, the incidence of alcohol-related liver cirrhosis and other chronic liver diseases in China showed an upward trend, with an EAPC of 0.31% (95%CI: 0.10%-0.52%). However, the DALY declined, with an EAPC of -2.81% (95%CI: -2.92% - -2.70%). The ASMR showed a downward trend, with an EAPC of -2.55% (95%CI: -2.66% - -2.45%). The highest incidence of cirrhosis of liver caused by alcohol and other chronic liver diseases was reported in the age group of 35-49 years, while the ASMR increased gradually with age, with a significant rise after the age of 30. The age-standardized DALY rate peaked between the ages of 55 and 64. The disease burden indicators for males were consistently higher than those for females during the same period. According to the predictions of the BAPC model, from 2020 to 2030, the ASIR for cirrhosis of liver caused by alcohol and other chronic liver diseases in the entire population of China was projected to increase from 3.45/100 000 in 2020 to 3.78/100 000 in 2030, a growth of 9.57%. Conversely, the ASMR was expected to decrease from 1.45/100 000 in 2020 to 1.24/100 000 in 2030, a reduction of 14.48%. Conclusions: The disease burden of cirrhosis of liver caused by alcohol and other chronic liver diseases remained serious in China, especially in men and the middle-aged to elderly population. There is a pressing need to prioritize attention and resources towards these groups. Despite the projected decrease in ASMR, the ASIR continued to rise and is expected to persist in its upward trend until 2030.

Global trends in deaths and disability-adjusted life years of diabetes attributable to second-hand smoke and the association with smoke-free policies.

OBJECTIVES: The diabetic burden attributable to second-hand smoke (SHS) is a global public health challenge. We sought to explore the diabetic burden attributable to SHS by age, sex, and socioeconomic status during 1990-2019 and to evaluate the health benefit of smoke-free policies on this burden. STUDY DESIGN: Cross-sectional study. METHODS: The diabetic burden attributable to SHS was extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 dataset. Country-level smoke-free policies were obtained from the World Health Organization Global Health Observatory. The deaths or disability-adjusted life years (DALYs) were quantified, and the average annual percentage changes were calculated. Hierarchical linear mixed models were applied to evaluate the health effects. RESULTS: From 1990 to 2019, the absolute number of global deaths and DALYs of diabetes attributable to SHS has doubled, and the age-standardised rate has significantly increased. The disease burden was higher in females than in males and increased with increasing age. The SHS-related diabetic burden varied across regions and countries. Age-standardised death or DALY rates first increased and then decreased with increased Socio-demographic Index (SDI), peaking in the 0.60-0.70 range. In low to low-middle, and middle to high-middle SDI countries, SHS-related diabetic deaths and DALYs were significantly lower in countries with more than 3 smoke-free public places than in countries with 0-2 smoke-free public places. CONCLUSIONS: More attention should be paid to females and the elderly, who bear a heavy SHS-related diabetic burden. Banning smoking in public places was associated with reduced burden of SHS-attributable diabetes, especially in low to middle social development countries.

[Analysis of healthy life expectancy and related socioeconomic influencing factors among the middle-aged and elderly in China, the United States, and the European Union].

Objective: To calculate and compare the healthy life expectancy (HLE) of the middle-aged and elderly in China, the United States, and developing and developed countries in the European Union(EU) and analyze the impact of socioeconomic factors on HLE in different countries or regions. Methods: Four surveys from 2010 to 2019 were brought into the research. The data were collected from the China Health and Retirement Longitudinal Study, Health and Retirement Study, and the Survey of Health, Ageing and Retirement in Europe. Developed and developing countries in the EU were divided into two groups for calculation. Education level, total family wealth, and work retirement status were selected to measure socioeconomic status, and activities of daily living were used as health status indicators. We used the multi-state life cycle table method to calculate the transition probability between different health states and estimate life expectancy and HLE. Results: A total of 69 544 samples were included in the study. In terms of age, the middle-aged and elderly in the United States and developed countries of the EU have higher HLE in all age groups. In terms of gender, only Chinese women have lower HLE than men. Regarding socioeconomic factors, the middle-aged and elderly with higher education levels and total family wealth level have higher HLE. In China, working seniors have higher HLE, while for USA women and developed countries of the EU, retired or unemployed seniors have higher HLE. Conclusions: Demographic and socioeconomic factors impact HLE in different countries or regions. China should pay more attention to the health of women and the middle-aged and elderly retired with lower education and less total family wealth.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

PURPOSE: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy. PATIENTS AND METHODS: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design. RESULTS: For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) GMR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated. CONCLUSIONS: Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.

Global trends and regional differences in the burden of anxiety disorders and major depressive disorder attributed to bullying victimisation in 204 countries and territories, 1999-2019: an analysis of the Global Burden of Disease Study.

AIM: This study aimed to analyse the temporal and spatial trends in the burden of anxiety disorders and major depressive disorder related to bullying victimisation on global, regional and country scales. METHODS: Data were from the 2019 Global Burden of Disease (GBD) Study. We assessed the global disability-adjusted life years (DALYs, per 100 000 population) of anxiety disorders and major depressive disorder attributable to bullying victimisation by age, sex and geographical location. The percentage changes in age-standardised rates of DALYs were used to quantify temporal trends, and the annual rate changes across 204 countries and territories were used to present spatial trends. Furthermore, we examined the relationship between the sociodemographic index (SDI) and the burden of anxiety disorders as well as major depressive disorder attributable to bullying victimisation and its spatial and temporal characteristics globally. RESULTS: From 1990 to 2019, the global DALY rates of anxiety disorders and major depressive disorder attributable to bullying victimisation increased by 23.31 and 26.60%, respectively, with 27.27 and 29.07% for females and 18.88 and 23.84% for males. Across the 21 GBD regions, the highest age-standardised rates of bullying victimisation-related DALYs for anxiety disorders were in North Africa and the Middle East and for major depressive disorder in High-income North America. From 1990 to 2019, the region with the largest percentage increase in the rates of DALYs was High-income North America (54.66% for anxiety disorders and 105.88% for major depressive disorder), whereas the region with the slowest growth rate or largest percentage decline was East Asia (1.71% for anxiety disorders and -25.37% for major depressive disorder). In terms of SDI, this study found overall upward trends of bullying-related mental disorders in areas regardless of the SDI levels, although there were temporary downward trends in some stages of certain areas. CONCLUSIONS: The number and rates of DALYs of anxiety disorders and major depressive disorder attributable to bullying victimisation increased from 1990 to 2019. Effective strategies to eliminate bullying victimisation in children and adolescents are needed to reduce the burden of anxiety disorders and major depressive disorder. Considering the large variations in the burden by SDI and geographic location, future protective actions should be developed based on the specific cultural contexts, development status and regional characteristics of each country.

Assessment of cytochrome P450 3A4-mediated drug-drug interactions for ipatasertib using a fit-for-purpose physiologically based pharmacokinetic model.

PURPOSE: Ipatasertib, a potent and highly selective small-molecule inhibitor of AKT, is currently under investigation for treatment of cancer. Ipatasertib is a substrate and a time-dependent inhibitor of CYP3A4. It exhibits non-linear pharmacokinetics at subclinical doses in the clinical dose escalation study. To assess the DDI risk of ipatasertib at the intended clinical dose of 400 mg with CYP3A4 inhibitors, inducers, and substrates, a fit-for-purpose physiologically based pharmacokinetic (PBPK) model of ipatasertib was developed. METHODS: The PBPK model was constructed in Simcyp using in silico, in vitro, and clinical data and was optimized and verified using clinical data. RESULTS: The PBPK model described non-linear pharmacokinetics of ipatasertib and captured the magnitude of the observed clinical DDIs. Following repeated doses of 400 mg ipatasertib once daily (QD), the PBPK model predicted a 3.3-fold increase of ipatasertib exposure with itraconazole; a 2-2.5-fold increase with moderate CYP3A4 inhibitors, erythromycin and diltiazem; and no change with a weak CYP3A4 inhibitor, fluvoxamine. Additionally, in the presence of strong or moderate CYP3A4 inducers, rifampicin and efavirenz, ipatasertib exposures were predicted to decrease by 86% and 74%, respectively. As a perpetrator, the model predicted that ipatasertib (400 mg) caused a 1.7-fold increase in midazolam exposure. CONCLUSION: This study demonstrates the value of using a fit-for-purpose PBPK model to assess the clinical DDIs for ipatasertib and to provide dosing strategies for the concurrent use of other CYP3A4 perpetrators or victims.

Multiscale Assessment of Agricultural Consumptive Water Use in California's Central Valley.

Spatial estimates of crop evapotranspiration with high accuracy from the field to watershed scale have become increasingly important for water management, particularly over irrigated agriculture in semiarid regions. Here, we provide a comprehensive assessment on patterns of annual agricultural water use over California's Central Valley, using 30-m daily evapotranspiration estimates based on Landsat satellite data. A semiempirical Priestley-Taylor approach was locally optimized and cross-validated with available field measurements for major crops including alfalfa, almond, citrus, corn, pasture, and rice. The evapotranspiration estimates explained >70% variance in daily measurements from independent sites with an RMSE of 0.88 mm day-1. When aggregated over the Valley, we estimated an average evapotranspiration of 820 ± 290 mm yr-1 in 2014. Agricultural water use varied significantly across and within crop types, with a coefficient of variation ranging from 8% for Rice (1,110 ± 85 mm yr-1) to 59% for Pistachio (592 ± 352 mm yr-1). Total water uses in 2016 increased by 9.6%, as compared to 2014, mostly because of land-use conversion from fallow/idle land to cropland. Analysis across 134 Groundwater Sustainability Agencies (GSAs) further showed a large variation of agricultural evapotranspiration among and within GSAs, especially for tree crops, e.g., almond evapotranspiration ranging from 339 ± 80 mm yr-1 in Tracy to 1,240 ± 136 mm yr-1 in Tri-County Water Authority. Continuous monitoring and assessment of the dynamics and spatial heterogeneity of agricultural evapotranspiration provide data-driven guidance for more effective land use and water planning across scales.

Comparing Diagnostic Properties of the FRAIL-NH Scale and 4 Frailty Screening Instruments among Chinese Institutionalized Older Adults.

OBJECTIVE: To examine the diagnostic test accuracy (DTA) of the FRAIL-NH and four frailty screening instruments among institutionalized older adults. DESIGN: Cross-sectional study. SETTING: Institutionalized setting, Jinan, China. PARTICIPANTS: A total of 305 older adults (mean age 79.3 ± 8.4 years, 57.0% female) were enrolled from nursing homes. MEASUREMENTS: Frailty was assessed by the FRAIL-NH, Physical Frailty Phenotype (PFP), FRAIL, Tilburg Frailty Indicator (TFI), and Groningen Frailty Indicator (GFI), respectively. The Comprehensive Geriatric Assessment (CGA) was used as a reference standard of frailty. The receiver operating characteristic (ROC) curve was plotted to examine the DTA of five frailty screening instruments against the CGA. The optimal cut-point was determined by the maximum value of the Youden index (YI, calculated as sensitivity + specificity - 1). RESULTS: The prevalence of frailty ranged from 25.9% (FRAIL) to 56.4% (GFI). Areas under the curve (AUCs) against the CGA ranged from 0.80 [95% confidence interval (CI) 0.74 - 0.85: FRAIL] to 0.83 (95% CI 0.78 - 0.88: PFP). At their original cut-points, all five frailty screening instruments presented low sensitivity (32.9% - 69.3%) and high specificity (80.0% - 93.8%), as well as high positive predictive values (90.7% - 94.9%) and low negative predictive values (33.2% - 48.1%). At their optimal cut-points, the sensitivity and specificity of the FRAIL-NH, PFP, and FRAIL tended to be balanced, and their correctly classified rates (76.1% - 81.3%) and kappa values (0.465 - 0.523) increased a lot. ROC contrasts showed that all five frailty screening instruments had similarly good diagnostic accuracy (χ2: 0.0003 - 1.38, P > .05). CONCLUSION: In the institutionalized setting, the specific FRAIL-NH, self-report FRAIL, TFI, and GFI as well as hybrid PFP, show similarly good diagnostic properties in identifying frailty against the CGA.

Analysis of Longitudinal-Ordered Categorical Data for Muscle Spasm Adverse Event of Vismodegib: Comparison Between Different Pharmacometric Models.

Longitudinal-ordered categorical data, common in clinical trials, can be effectively analyzed with nonlinear mixed effect models. In this article, we systematically evaluated the performance of three different models in longitudinal muscle spasm adverse event (AE) data obtained from a clinical trial for vismodegib: a proportional odds (PO) model, a discrete-time Markov model, and a continuous-time Markov model. All models developed based on weekly spaced data can reasonably capture the proportion of AE grade over time; however, the PO model overpredicted the transition frequency between grades and the cumulative probability of AEs. The influence of data frequency (daily, weekly, or unevenly spaced) was also investigated. The PO model performance reduced with increased data frequency, and the discrete-time Markov model failed to describe unevenly spaced data, but the continuous-time Markov model performed consistently well. Clinical trial simulations were conducted to illustrate the muscle spasm resolution time profile during the 8-week dose interruption period after 12 weeks of continuous treatment.

[Disease burden on falls among 0-19 years old population in China, in 1990 and 2017].

Objective: To analyze and compare the disease burden of falls in Chinese population aged 0-19, in 1990 and 2017. Methods: Indicators including number of deaths, mortality rates, years of life lost due to premature mortality (YLL), years lived with disability (YLD) and disability-adjusted of life years (DALY), on falls, were gathered from the Global Burden of Disease (GBD) 2017 and used to describe the disease burden and corresponding parameters on falls, between 1990 and 2017, in China. Results: In 2017, number of death, YLLs, YLDs, DALYs caused by falls were 5 321, 0.43 million person years, 0.14 million person years and 0.57 million person years respectively, among aged 0-19 group. Rates on standardized mortality, YLLs, YLDs and DALYs on falls were 1.76/100 000, 141.49/100 000, 46.99/100 000, and 188.48/100 000, respectively. The burden of falls decreased with the increase of age. Compared with 1990, disease burden of falls decreased in all age groups, both in male and female, with more seen in the lower age groups. Compared with 1990, the number of deaths, rates on YLLs, YLDs and DALYs caused by falls decreased by 65.08%, 46.63%, 47.38% and 36.33% respectively, in 2017. However, the YLDs rate increased by 73.31% between 1990 and 2017. The ratio of YLLs to DALYs decreased from 90.84% in 1990 to 75.07% in 2017, with a proportion as 17.36%. Conclusion: Compared with 1990, although the disease burden of falls among aged 0-19 group showed a decreasing trend, falls still caused serious disease burden for the aged 0-19 group. Research that targeting prevention on falls, should be continued.

[Trends of injury mortality among children in different stages of the China Children's Development Outlines].

Objective: To describe the trends and potential reasons responsible for injury mortality among children under 18 years old in different stages of the China Children's Development Outlines (CCDO) for children from 1990 to 2017, in China. Methods: Data derived from the Global Burden of Disease 2017 (GBD2017) were used to analyze the change of injury mortality, among children under 18 years old, by sex and provinces. Results: Since 1990, the Chinese government had formulated and implemented three CCDOs on Children. Each CCDO proposed corresponding main targets and strategic measures based on the development of children under current situation, in each area, accordingly. The first two CCDOs failed to set clear targets for child injury prevention and control, but the third one did propose a quantifiable target. The injury mortality rate of children under 18 years old showed a declining trend in all periods of the three CCDOs, by 26.07%, 40.68% and 26.48%, respectively. Both boys and girls showed significant downward trend in these three stages. Mortality rate on child injury differed in these three stages in all the 31 provinces. Conclusion: Thanks to the contribution of CCDO in different stages that providing important policies and impetus for the prevention and control of child injury, the number of deaths caused by child injury kept reducing, from 1990 to 2017, in China.

[Application of three methods in occupational health risk assessment of automobile 4S shop].

Objective: To choose various occupational health risk assessment of the mature methods at home and abroad respectively occupational health risk assessment was carried out on the 4s stores, to explore different risk assessment methods on the 4 s shop the applicability of the occupational health risk assessment. Methods: Chemical was applied on the harmful factors of occupational health risk assessment technology guideline in the composite index method, quantitative cancer risk assessment method using the guidelines for the harmful factors of occupational health risk assessment of chemical technology of composite index method, quantitative cancer risk assessment method, international commission on mining and metals (ICMM) occupational health risk assessment quantitative method and the occupational-disease-inductive operation classification to evaluate chemical factors in 4S store, Combined with on-site occupational health investigation to compare with the result of risk assessment and analysis of international mining and metals (ICMM) committee occupational health risk assessment quantitative method and the occupational-disease-inductive operation classification of 4S store to evaluate chemical factors, combined with on-site occupational health investigation comparison and analysis the result of the risk assessment. Results: Except for 6 times, the results of ICMM matrix method and comprehensive index method were consistent, which were all higher than job classification. The other results were job classification of >of ICMM matrix method >comprehensive index method or job classification of >of ICMM matrix method. Conclusion: When the concentration of occupational-disease-inductive factors is lower than 1/2 limit, the risk assessment results tend to be ICMM quantitative >composite index method >operation classification. When the occupational-disease-inductive factors were involved with triphenyl, the quantitative non-carcinogenic risk assessment method was more likely to reach the conclusion that the occupational health risk was unacceptable.

Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting.

PURPOSE: To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. METHODS: ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. RESULTS: No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. CONCLUSION: Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.

Patterns of prescription opioid use before total hip and knee replacement among US Medicare enrollees.

OBJECTIVE: To examine patterns of prescription opioid use before total joint replacement (TJR) and factors associated with continuous use of opioids before TJR. DESIGN: We conducted an observational cohort study among Medicare enrollees aged ≥65 years who underwent TJR between 2010 and 2014. Preoperative opioid use was defined as having any opioid prescription in the 12-month period before TJR. Patients who had an opioid prescription every month for a 12-month period were defined as continuous users. We examined patients' demographics, pain-related conditions, medication use, other comorbidities, healthcare utilization and their association with use of opioids before TJR. RESULTS: A total of 473,781 patients underwent TJR:,155,516 THR and 318,265 TKR. Among the total cohort, 60.2% patients had any use of opioids and of those, 12.4% used opioids at least once a month continuously over the 12-month baseline period. Correlates of continuous opioid use included African American race (OR = 2.14, 95% confidence intervals (CI) = 2.01-2.28, compared to White patients), history of drug abuse (OR = 5.18, 95% CI = 3.95-6.79) and back pain (OR = 2.32, 95% CI = 2.24-2.39). CONCLUSIONS: In this large cohort of patients undergoing TJR, over 60% ever used opioids and 12.4% of them continuously used opioids in the 12-month prior to surgery. Utilization of opioids became more frequent and high-dosed near the surgery. History of drug abuse, back pain, and African American race were strongly associated with continuous use of opioids preoperatively. Further research is needed to determine short-term and long-term risks of preoperative use of opioids in TJR patients and to optimize pre- and post-TJR pain management of patients with arthritis.

[Disease burden of animal injury in China, 1990-2016].

Objective: To analyze the disease burden of animal injury in China between 1990 and 2016. Methods: Data obtained from the Global Burden of Disease 2016 were used to analyze the age and gender specific disease burden of animal injury in China, using the incidence and disability adjusted of life years (DALYs) rate. Relative and annual changes were evaluated. Results: In 2016, the age-standardized incidence and DALYs rate of animal injury in China showed as 245.05 per 100 000 people and 12.73 per 100 000. The age-standardized incidence of non-venomous animal injury was significantly higher than that of venomous animal injury, but the differences in age-standardized incidence and DALYs rate between venomous animal injury and non-venomous animal injury were not significant. Between 1990 and 2016, there was a significantly decreasing trend in the age-standardized incidence and DALYs rate of animal injury, and obvious decline could be seen in the incidence of non-venomous animal injury, compared with venomous animal injury. The incidence and DALYs rate of animal injury declined in both males and females and in different age groups. The obvious decline of incidence and DALYs rate could be found in children aged 5-14 years and aged <5 years. Conclusions: Between 1990 and 2016, there was a significant alleviation of the disease burden of animal injury in China. Young children were most prone to animal injury, resulting in serious disability and death, indicating more attention should be paid to this population at high risk and in animal injury prevention and control programs.

Policy implications of regional variations in eye disease detection and treatment on Prince Edward Island: a repeated cross-sectional analysis, 2010-2012.

BACKGROUND: In Canada, government insurance covers eye care services provided by ophthalmologists and other physicians. However, government coverage for services provided by optometrists, non-medical school trained primary eye care providers, varies regionally. Little is known about the impact of a funding model in which ophthalmologist services are government-insured but services provided by optometrists are not, on eye care utilization and eye disease detection and treatment. We aimed to address this question by examining geographic variations in eye care service utilization on Prince Edward Island (PEI). METHODS: PEI physician-billing data from 2010 to 2012 was analyzed across five distinct geographic regions (Charlottetown, Summerside, Prince, Queens & Kings and Stratford). The residential location of patients and practice locations of eye care providers were identified using the first three digits of their respective postal code. Age-standardized rates were computed for comparisons across different regions. RESULTS: There were six ophthalmologists practicing on PEI, five with offices in Charlottetown. Twenty optometrists practiced on the island with offices across the province. Stratford is closest and Prince farthest from Charlottetown. Age-standardized utilization rates of ophthalmologists per 100 populations were 10.44 in Charlottetown and 10.90 in Stratford, which was significantly higher than in other regions (7.74-8.92; p < 0.05). The disparities were most pronounced amongst the elderly. The prevalence of glaucoma visits was higher in Charlottetown (6.10%) and Stratford (6.38%) and lower in other regions. A similar pattern was observed for the prevalence of cataract visits. While the prevalence of diabetes visits was higher in Prince and Summerside, the utilization of ophthalmologists by people with diabetes was almost twice as high in Charlottetown (6.49%) than in Prince (3.88%). CONCLUSIONS: The observed discrepancies in vision care utilization across geographic regions were likely attributed to barriers in accessing government-insured, geographically concentrated ophthalmologists, as opposed to a reflection of the true differences in eye disease occurrence. The lower prevalence of glaucoma visits in regions farther away from ophthalmologist offices may result in delayed detection and blindness in this population. Encouraging ophthalmologists to work in other areas of the province and/or to publicly fund services provided by optometrists may mitigate the observed disparities. TRIAL REGISTRATION: Not applicable.