[Disease burden of colorectal cancer attributable to dietary risk factors from 1990 to 2019 in China].

Objective: To analyze the trend of mortality rate and disability-adjusted life year (DALY) of colorectal cancer attributable to dietary risk factors from 1990 to 2019 in China. Methods: Mortality rate and DALY rate of colorectal cancer attributable to dietary risk factors (diet high in processed meat, diet high in red meat, diet low in calcium, diet in low in fiber, diet low in milk, diet low in whole grains, dietary risks) were collected from the Global Burden of Disease study 2019 (GBD2019). Joinpoint regression model was selected to analyze the trend and an age-period-cohort model was used to estimate the effects of age, period and birth cohort. Results: Joinpoint regression analysis showed that the age-standardized mortality rate and age-standardized DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in milk, diet low in whole grains and dietary risks showed an upward trend (P<0.05) from 1990 to 2019, while those attributable to diet low in calcium and diet low in fiber showed a downward trend (P<0.05). The mortality rate and DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in milk, diet low in whole grains and dietary risks in age groups from 65 to 79 years showed a quicker upward trend than those in age groups from 25 to 64 years. The mortality rate and DALY rate attributable to diet low in calcium and diet low in fiber in age groups from 65 to 79 years showed a slower downward trend than those in age groups from 25 to 64 years. The mortality rate and DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in calcium, diet low in fiber, diet low in milk, diet low in whole grains, and dietary risks increased with age after adjusting for period effect and cohort effect (P<0.05). The mortality rate and DALY rate attributable to diet high in processed meat, diet high in red meat, diet low in calcium, diet low in milk, diet low in whole grains and dietary risks increased with period or cohort, while those attributable to diet low in fiber decreased with period or cohort. Period and cohort effect of dietary risk factors in this study were statistically significant (P<0.001). Conclusions: Disease burden of colorectal cancer attributable to dietary risk factors in China showed an upward trend in general. Elderly population is high at risk and more attention should be paid to science popularization and education on dietary risk factors in prevention and treatment of colorectal cancer.

Addressing health inequity during the COVID-19 pandemic through primary health care and public health collaboration: a multiple case study analysis in eight high-income countries.

BACKGROUND: The COVID-19 pandemic substantially magnified the inequity gaps among vulnerable populations. Both public health (PH) and primary health care (PHC) have been crucial in addressing the challenges posed by the pandemic, especially in the area of vulnerable populations. However, little is known about the intersection between PH and PHC as a strategy to mitigate the inequity gap. This study aims to assess the collaboration between PHC and PH with a focus on addressing the health needs of vulnerable populations during the COVID-19 pandemic across jurisdictions. METHODS: We analyzed and compared data from jurisdictional reports of COVID-19 pandemic responses in PHC and PH in Belgium, Canada (Ontario), Germany, Italy, Japan, the Netherlands, Norway, and Spain from 2020 to 2021. RESULTS: Four themes emerge from the analysis: (1) the majority of the countries implemented outreach strategies targeting vulnerable groups as a means to ensure continued access to PHC; (2) digital assessment in PHC was found to be present across all the countries; (3) PHC was insufficiently represented at the decision-making level; (4) there is a lack of clear communication channels between PH and PHC in all the countries. CONCLUSIONS: This study identified opportunities for collaboration between PHC and PH to reduce inequity gaps and to improve population health, focusing on vulnerable populations. The COVID-19 response in these eight countries has demonstrated the importance of an integrated PHC system. Consequently, the development of effective strategies for responding to and planning for pandemics should take into account the social determinants of health in order to mitigate the unequal impact of COVID-19. Careful, intentional coordination between PH and PHC should be established in normal times as a basis for effective response during future public health emergencies. The pandemic has provided significant insights on how to strengthen health systems and provide universal access to healthcare by fostering stronger connections between PH and PHC.

[Comparison of corneal power assessment methods after small incision lenticule extraction].

Objective: To compare the accuracy of different corneal curvature parameters in assessing the corneal refractive status and tracking corneal power changes after small incision lenticule extraction (SMILE). Methods: This prospective cross-sectional study tracked and recorded total corneal curvature parameters measured by different instruments before and three months after SMILE for myopia. These parameters, including total keratometry (TK) from the IOLMaster 700, total corneal refractive power (TCRP) from the Pentacam AXL, real keratometry (RK) from the CASIA 2, and corrected parameters calculated using the Haigis, Shammas, and Maloney methods, were compared with data obtained using the clinical history method (CHM). Surgically induced changes in TK, TCRP, and RK were analyzed and compared with those in spherical equivalent on the corneal plane (ΔSEco). Results: The study included 40 eyes (40 participants). After SMILE, the difference was smallest between TK [(0.08±0.38) D] and CHM values (P>0.05). However, TCRP, RK, KHaigis, KShammas, and KMaloney were significantly different from CHM data (P<0.05). The width of the 95% limits of agreement of TK (1.49 D) was narrowest, followed by that of RK (1.57 D). Pearson analysis showed that each parameter had a good correlation with CHM data. The differences between the changes in TK, TCRP and RK caused by surgery and ΔSEco were (0.03±0.39) D, (0.17±0.43) D, and (-0.19±0.46) D, respectively. The width of the 95% limits of agreement of ΔTK (1.54 D) was narrowest, and the correlation coefficient of ΔTK (0.951) was highest. Conclusion: The parameter TK of the IOLMaster 700 can provide accurate and objective corneal power evaluation after SMILE.

[Evaluation effect of COMPERA 2.0 risk assessment model on prognosis of Chinese patients with pulmonary arterial hypertension].

Objectives: To clarify the evaluation effect of COMPERA 2.0 risk assessment model on prognosis of pulmonary arterial hypertension (PAH) in China. Methods: Patients with newly diagnosed PAH admitted in Fuwai hospital between April 2019 and March 2022 were enrolled retrospectively and divided in low, intermediate-low, intermediate-high and high strata by scores of COMPERA 2.0 risk assessment model. All the patients were followed up by clinic or telephone. The primary endpoint was defined as a composite of all-cause mortality, exacerbated heart failure and aggravated symptoms. Kaplan-Meier analysis and log-rank trend test were used to determine the risk of endpoints among the 4 groups. Multivariate Cox proportional hazards regression were used to analyze the association between COMPERA 2.0 scores and prognosis in patients with PAH. Results: A total of 951 patients with PAH were enrolled in this study. The age [M (Q1, Q3)] of the patients was 35 (28, 47) years, of which 706 cases (74.2%) were females. A total of 328 cases (34.5%) were assigned in low strata, 264 cases (27.8%) in intermediate-low strata, 193 cases (20.3%) in intermediate-high strata, and 166 cases (17.5%) in high strata. During the duration [M (Q1, Q3)] of follow-up after discharge of 1.8 (1.0, 2.8) years, the primary endpoint was occurred in 12.8% (42/328), 21.2% (56/264), 28.5% (55/193) and 42.8% (71/166) of low, intermediate-low, intermediate-high and high strata, respectively. The rates of primary endpoint were significantly increased with strata rising (P<0.001). Multivariate Cox proportional hazards regression showed that COMPERA 2.0 risk scores were associated with the primary endpoints in PAH patients (HR=1.801, 95%CI: 1.254-2.588, P=0.001) after adjusting confounders. Conclusion: COMPERA 2.0 risk assessment model is a simple and effective tool for evaluating the prognosis of newly diagnosed PAH patients in China.

[Impact of systolic blood pressure on outcome of patients with nonvalvular atrial fibrillation].

Objective: To investigate the impact of different levels of systolic blood pressure on all-cause, cardiovascular and cerebrovascular mortality in patients with nonvalvular atrial fibrillation (AF). Methods: This is a prospective cohort study. Patients with AF or atrial flutter diagnosed by 12 lead electrocardiogram during physical examination of Kailuan Group employees from July 2006 to December 2017 or previously diagnosed with AF in an inpatient setting at a level 2A hospital or above were eligible for the study. Baseline clinical characteristics including age, gender, systolic blood pressure were collected. According to the level of systolic blood pressure, patients were divided into systolic blood pressure<120 mmHg (1 mmHg=0.133 kPa)group, 120 mmHg ≤ systolic blood pressure<140 mmHg group, and systolic blood pressure ≥140 mmHg group. The time of first diagnosis with AF was defined as the start of follow-up and the final follow-up ended at December 2018. Primary endpoint was all-cause death. Related information was obtained through the social security system or inpatient medical records. The cause of death was defined according to the International Classification of Diseases disease (ICD-10) codes by professional medical stuffs. Multifactorial Cox proportional risk model was used to analyze the relative risk ratios for the occurrence of death in different systolic blood pressure level groups. The relationship between systolic blood pressure levels and mortality in the patients with AF was analyzed by using natural spline function curves. Results: A total of 1 721 patients with AF were enrolled (average age=(67.0±9.0) years), patients were followed up for (6.3±3.8) years. 544 out of 1 721 patients with AF died during the follow-up period (31.61%). The cumulative incidence rate of all-cause mortality, cardiovascular and cerebrovascular death was 26.13%, 25.59%, 36.96% and 14.86%, 11.87%, 19.76% respectively in the systolic blood pressure<120 mmHg, 120 mmHg ≤ systolic blood pressure<140 mmHg and systolic blood pressure ≥140 mmHg groups. The cumulative incidence rate of all-cause, cardiovascular and cerebrovascular death was significantly higher in the group with systolic blood pressure ≥140 mmHg than in 120 mmHg ≤ systolic blood pressure<140 mmHg group (P<0.05). Compared with 120 mmHg ≤ systolic blood pressure<140 mmHg group, multivariable Cox proportional hazards regression models showed that the HRs (95%CI) for all-cause, cardiovascular and cerebrovascular death were 1.47 (1.20 to 1.79) and 1.69 (1.27 to 2.26) for the group with systolic blood pressure ≥ 140 mmHg (P<0.05). In contrast, the HRs (95%CI) for all-cause, cardiovascular and cerebrovascular death in the systolic blood pressure<120 mmHg group were 0.99 (0.73-1.35) and 1.24 (0.82-1.89), respectively, with no statistically significant differences between the two groups (P>0.05). The natural spline curve showed that there was a "U" relationship between systolic blood pressure levels and all cause death and cardiovascular and cerebrovascular death in this patient cohort. Systolic blood pressure greater than or less than 123 mmHg was associated with increased risk of death of AF patients in this cohort. Conclusion: Compared with systolic blood pressure<120 mmHg and systolic blood pressure≥140 mmHg group, the risk of all-cause and cardiovascular and cerebrovascular death is the lowest in AF patients with 120 mmHg ≤ systolic blood pressure<140 mmHg in this cohort.

[Assessment of corneal biomechanical changes after small incision lenticule extraction with Pentacam and Corvis ST].

Objective: To investigate the application value of Pentacam combined with Corvis ST in evaluation of the changes of corneal biomechanics after femtosecond laser small incision lenticule extraction (SMILE) in Chinese myopia with an irregular cornea. Methods: The clinical records for 104 eyes of 57 patients who received SMILE in the Refractive Center of Beijing Tongren Hospital during January 2018 and May 2018 were collected. According to the keratoconus severity index (KSI), they were divided into two groups: regular corneal group (KSI<15%) and irregular corneal group (KSI: 15% to 25%). In both groups, the anterior corneal surface radius curvature was>7.25 mm (K<46.50 diopters), the posterior corneal surface radius curvature was>5.90 mm, the thinnest pachymetry was>490 µm, and best corrected visual acuity was ≥1.0. The vision, refraction, and corneal biomechanics before and after SMILE were assessed. The Topographic and Biomechanics Index (TBI) was analyzed by Pentacam combined with Corvis ST. Results: Before SMILE, the Corvis Biomechanical Index (CBI), TBI, and Belin/Ambrósio Deviation Normalized Index (BADD) of the irregular corneal group were significantly higher (t=-2.17, -6.78, -4.37, P<0.05) than the regular corneal group, while the stiffness parameter (SPA1) was significantly lower (t=2.58, P=0.011) compared to the regular corneal group (P<0.05). In the irregular group, the TBI was (0.28±0.2); the maximum value was 0.03, and the minimum value was 0.43. The CBI was (0.09±0.21); the maximum value was 0.00, and the minimum value was 0.54. The BADD was (1.33±0.47); the maximum value was 0.42, and the minimum value was 2.26. In the regular group, the TBI was (0.05±0.08); the maximum value was 0.00, and the minimum value was 0.20. The CBI was (0.01±0.03); the maximum value was 0.00, and the minimum value was 0.17. The BADD was (0.92±0.46); the maximum value was 0.00, and the minimum value was 1.64. There was no significant difference between two groups in age (t=0.20, P=0.508), central corneal thickness (t=1.64, P=0.104), biomechanical corrected IOP (t=0.73, P=0.468), max inverse radius (t=-0.24, P=0.815), spherical equivalent (t=-0.97, P=0.335), and best corrected visual acuity (t=0.21, P=0.833). After SMILE, the deformation amplitude in the irregular group was significantly higher at 1 month and 3 months (t=-3.13, -3.09, P<0.05). The irregular group had a significantly higher deformation amplitude ratio at 1 week, 1 month, and 1 year (t=-2.72, -3.39, -2.51, P<0.05). The SPA1 in the irregular group was significantly lower than the regular group at 1 week, 1 month, and 3 months (t=2.11, 2.73, 3.70, P=0.335, 0.010,<0.001). The changes of deformation amplitude (t=0.50, -1.10, -0.73, 2.12, P>0.05), max inverse radius (t=-1.52, -1.41, 0.01, -0.79, P>0.05), and SPA1(t=0.89, 0.90, 1.12, 0.90, P>0.05) after SMILE were similar between the irregular and regular groups, except that at 1 month after SIMILE, the deformation amplitude ratio changed more significantly in the irregular group (t=-3.01, P=0.003). Conclusions: The changes of corneal biomechanics in the groups of regular cornea and irregular cornea were stable with no significant difference during 1 year of post-SMILE. The diagnosis based on the corneal topography and corneal biomechanics is of certain significance for the screening of early keratoconus before keratorefractive surgery. (Chin J Ophthalmol, 2020, 56:103-109).

A case study on the application of an expert-driven read-across approach in support of quantitative risk assessment of p,p'-dichlorodiphenyldichloroethane.

Deriving human health risk estimates for environmental chemicals has traditionally relied on in vivo toxicity databases to characterize potential adverse health effects and associated dose-response relationships. In the absence of in vivo toxicity information, new approach methods (NAMs) such as read-across have the potential to fill the required data gaps. This case study applied an expert-driven read-across approach to identify and evaluate analogues to fill non-cancer oral toxicity data gaps for p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), an organochlorine contaminant known to occur at contaminated sites in the U.S. The source analogue p,p'-dichlorodiphenyltrichloroethane (DDT) and its no-observed-adverse-effect level of 0.05 mg/kg-day were proposed for the derivation of screening-level health reference values for the target chemical, p,p'-DDD. Among the primary similarity contexts (structure, toxicokinetics, and toxicodynamics), toxicokinetic considerations were instrumental in separating p,p'-DDT as the best source analogue from other potential candidates (p,p'-DDE and methoxychlor). In vitro high-throughput screening (HTS) assays from ToxCast were used to evaluate similarity in bioactivity profiles and make inferences toward plausible mechanisms of toxicity to build confidence in the read-across approach. This work demonstrated the value of NAMs such as read-across and in vitro HTS in human health risk assessment of environmental contaminants with the potential to inform regulatory decision-making.

[Effectiveness of integrated early childhood development intervention on nurturing care for children aged 0-35 months in rural China].

Objective: To explore whether Integrated Early Childhood Development (IECD) program has effectively improved the nurturing care for children aged 0-35 months in rural China. Methods: IECD has been implemented by the government of China with support from the United Nations Children's Fund (UNICEF) in four poverty-stricken rural counties since 2014. The interventions targeting the five key components of nurturing care (i.e. child and caregiver health, child nutrition, early learning support, child protection and social security) were delivered through the IECD program to children aged 0 to 35 months and their caregivers. A population-based intervention trial was designed to evaluate intervention effectiveness with data collected in 2013 (baseline) and 2016 (mid-term). The changes of nurturing care in the intervention and control group were analyzed by using a difference-in-differences (DID) model. This approach provided adjustment for sociodemographic and other confounding factors. Results: The baseline and mid-term survey enrolled 1 468 and 1 384 children in the intervention group, and 1 485 and 1 361 in the control group. After two years of implementation, the prevalence of caregiver's depression in the intervention group showed a decrease of 9.1% (mid-term 34.8% (479/1 377) vs. baseline 43.9% (621/1 414)), whereas that in control group showed a decrease of 1.6% (mid-term 34.3% (464/1 353) vs. baseline 35.9% (509/1 419)). With the confounding adjusted in the difference-in-differences model, the decrease of the caregiver's depression prevalence in the intervention group was 7.0% greater than that in the control group (P=0.008). The qualified rate of minimum meal frequency in the intervention group showed an increase of 10.4% (mid-term 69.0% (532/771) vs. baseline 58.6% (481/821)), whereas the qualified rate in the intervention group showed an increase of 2.9% (mid-term 66.4% (469/706) vs. baseline 63.5% (508/800)). With the confounding adjusted in the difference-in-differences model, the increase of the qualified rate in the intervention group was 8.2% greater than that in the control group (P=0.021). The proportion of violent discipline by caregivers in the intervention group showed a decrease of 6.2% (mid-term 49.1% (478/973) vs. baseline 55.3% (554/1 001)), whereas the proportion in control group showed an increase of 4.5% (mid-term 58.4% (560/959) vs. baseline 53.9% (558/1 036)), and with the confounding adjusted in the difference-in-differences model, the difference in increase rate between two groups was 11.0% (P=0.001). The proportion of families with three or more children's books in the intervention group showed an increase of 12.7% (mid-term 42.7% (588/1 378) vs. baseline 30.0% (432/1 440)), whereas the proportion of the control group showed an increase of 4.2% (mid-term 25.7% (349/1 357) vs. baseline 21.5% (298/1 388)), and with the confounding adjusted in the difference-in-differences model, the difference in increase rate between two groups was 6.1% (P=0.007). Conclusions: The IECD intervention strategy implemented in rural China effectively improved the mental health of caregivers, optimizes families' child feeding and early stimulation behaviors, while reducing violent discipline and other risk factors. IECD provides better nurturing care for the early development of children aged 0-35 months in rural China.

[Health economic evaluation of bivalent human papilloma virus vaccine in China: based on the dynamic model].

Objective: This study aims to evaluate the prevention effect and cost-effectiveness of a prophylactic bivalent human papilloma virus (HPV) vaccine. Methods: A multiple health status dynamic model was developed, including natural history of diseases and prevention strategies. We built 19 prevention strategies including visual inspection with acetic acid/lugol's iodine (VIA/VILI) and/or 3 does prophylactic bivalent HPV vaccine administered to adolescent girls at the age of 15 years old every year under the assumption that vaccine coverage and screening coverage were 70%. The incremental cost-effectiveness ratio (ICER), optimal price of 3 does vaccine and cost-effectiveness frontier of these strategies were analyzed compared with no-intervention. The ICER threshold is 152 087 CNY. Results: Compared with no-intervention, Routine vaccination reduced the incidence of cervical cancer by 69.5%, superior to 5 strategies including VIA/VILI screening only. The range of effect was between 9.0% and 69.2%, and the effect of strategy increased significantly with the increase of screening frequency. Combination vaccination with screening at ages of 35 reduced the incidence of cervical cancer by 72.0%, and the effect increased with the increase of screening frequency. Combination vaccination with screening every 3 years between (35-64) years old reduced the incidence by 89.4%. Compared with no-intervention, the ICER of combination vaccination with screening twice between 35 years and 64 years was 121 292 CNY/life-year, which was cost-effective. The price of vaccine had a significant impact on the ICER of the strategy; when the vaccine price was less than 600 CNY, only routine vaccination or supplementary vaccination between 16-39 years old after routine vaccination was cost-effective; when the vaccine price was less than 1 200 CNY, supplementary vaccination between 16-19 years old plus VIA/VILI was cost-effective. Conclusion: Ther prevention strategy was cost-effective, which could effectively reduce the incidence of cervical cancer by implementation of HPV vaccination combined with VIA/VILI in suitable aging females.

[Assessment of undiagnosed critical congenital heart disease before discharge from the maternity hospital].

Objective: Undiagnosed critical congenital heart disease (CCHD) was assessed before discharge from maternity hospital.Basic information was provided for screening CCHD in the early neonatal stage.Chi-squared test was used for comparison of categorical variables(detection rate of different types of CCHD). Method: A retrospective cohort study was conducted in neonates with CCHD who were admitted to Children's Hospital of Fudan University between 1 January 2012 and 31 December 2015. For comparing with the previously reported undiagnosed rate of CCHD at discharge, CCHD was defined as all duct dependent congenital heart disease (DDCHD) and any cyanotic CHD that required early surgery. Result: A total of 1 036 infants with CCHD were included. The prenatal detection rate of CCHD was 14.04%(122/869). As a whole, 52.51% (544/1 036) of CCHD cases were undiagnosed at discharge, and 14.09%(146/1 036)were still missed after 6-week examination. The diagnoses most likely to be unrecognized at discharge included critical coarctation of the aorta (COA) (75.00%), total anomalous pulmonary venous connection (61.54%), pulmonary atresia (PA) with ventricle septal defect (VSD) (61.45%), single ventricle (SV) (60.10%) and critical aortic stenosis (52.94%). Among newborns diagnosed prior to discharge, 54.88% (270/492) due to symptom or prenatal ultrasonographic diagnosis, 45.12% (222/492) due to abnormal findings in routine examination. Among asymptomatic CCHD cases without prenatal diagnosis, 71.02% (544/766) were undiagnosed and the most common delayed diagnosis was SV (82.78%), interrupted aortic arch (81.82%), transposition of the great arteries with intact ventricular septum (79.63%), PA/VSD (79.07%), and critical COA (78.57%). Newborns with DDC were more likely to develop symptoms within the first few days after birth, in comparison with non-DDC cases. However, their detection rates were close to each other. Conclusion: The rate of misdiagnosis of CCHD before discharge from maternity hospitals is high in China, indicates the importance of implementation of CCHD screening in Chinese maternity hospitals, so as to give timely diagnosis and proper treatment.

Editor's Highlight: Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment.

The rate of new chemical development in commerce combined with a paucity of toxicity data for legacy chemicals presents a unique challenge for human health risk assessment. There is a clear need to develop new technologies and incorporate novel data streams to more efficiently inform derivation of toxicity values. One avenue of exploitation lies in the field of transcriptomics and the application of gene expression analysis to characterize biological responses to chemical exposures. In this context, gene set enrichment analysis (GSEA) was employed to evaluate tissue-specific, dose-response gene expression data generated following exposure to multiple chemicals for various durations. Patterns of transcriptional enrichment were evident across time and with increasing dose, and coordinated enrichment plausibly linked to the etiology of the biological responses was observed. GSEA was able to capture both transient and sustained transcriptional enrichment events facilitating differentiation between adaptive versus longer term molecular responses. When combined with benchmark dose (BMD) modeling of gene expression data from key drivers of biological enrichment, GSEA facilitated characterization of dose ranges required for enrichment of biologically relevant molecular signaling pathways, and promoted comparison of the activation dose ranges required for individual pathways. Median transcriptional BMD values were calculated for the most sensitive enriched pathway as well as the overall median BMD value for key gene members of significantly enriched pathways, and both were observed to be good estimates of the most sensitive apical endpoint BMD value. Together, these efforts support the application of GSEA to qualitative and quantitative human health risk assessment.

Cost-effectiveness of the Health X Project for tuberculosis control in China.

BACKGROUND: Between 2002 and 2008, China's National Tuberculosis Control Programme created the Health X Project, financed in part by a World Bank loan, with additional funding from the UK Department for International Development. OBJECTIVES: To assess the cost-effectiveness of the Project and its impact from a financial point of view on tuberculosis (TB) control in China. METHODS: A decision-analytic model was used to evaluate the cost-effectiveness of the Project. Sensitivity analysis was used to assess the impact of different scenarios and assumptions on results. The primary outcome of the study was cost per disability-adjusted life-year (DALY) saved and incremental DALYs saved. RESULTS: In comparison with alternative scenario 1, the Project detected 1.6 million additional cases, 44 000 deaths were prevented and a total of 18.4 million DALYs saved. The Project strategies cost approximately Chinese yuan (CNY) 953 per DALY saved (vs. CNY1140 in the control areas), and saved an estimated CNY17.5 billion in comparison with the unchanged alternative scenario (scenario 1) or CNY10.8 billion with the control scenario (scenario 2). CONCLUSION: The Project strategies were affordable and of comparable cost-effectiveness to those of other developing countries. The results also provide strong support for the existing policy of scaling up DOTS in China.

Assessment of genotoxic effects of flumorph by the comet assay in mice organs.

The present study investigated the genotoxic effects of flumorph in various organs (brain, liver, spleen, kidney and sperm) of mice. The DNA damage, measured as comet tail length (µm), was determined using the alkaline comet assay. The comet assay is a sensitive assay for the detection of genotoxicity caused by flumorph using mice as a model. Statistically significant increases in comet assay for both dose-dependent and duration-dependent DNA damage were observed in all the organs assessed. The organs exhibited the maximum DNA damage in 96 h at 54 mg/kg body weight. Brain showed maximum DNA damage followed by spleen > kidney > liver > sperm. Our data demonstrated that flumorph had induced systemic genotoxicity in mammals as it caused DNA damage in all tested vital organs, especially in brain and spleen.

Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework.

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency.

Temporal concordance between apical and transcriptional points of departure for chemical risk assessment.

The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development is overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days and 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points of departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with eight additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two, suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment.

Application of computational toxicological approaches in human health risk assessment. I. A tiered surrogate approach.

Hazard identification and dose-response assessment for chemicals of concern found in various environmental media are typically based on epidemiological and/or animal toxicity data. However, human health risk assessments are often requested for many compounds found at contaminated sites throughout the US that have limited or no available toxicity information from either humans or animals. To address this issue, recent efforts have focused on expanding the use of structure-activity relationships (SAR) approaches to identify appropriate surrogates and/or predict toxicological phenotype(s) and associated adverse effect levels. A tiered surrogate approach (i.e., decision tree) based on three main types of surrogates (structural, metabolic, and toxicity-like) has been developed. To select the final surrogate chemical and its surrogate toxicity value(s), a weight-of-evidence approach based on the proposed decision tree is applied. In addition, a case study with actual toxicity data serves as the evaluation to support our tiered surrogate approach. Future work will include case studies demonstrating the utility of the surrogate approach under different scenarios for data-poor chemicals. In conclusion, our surrogate approach provides a reasonable starting point for identifying potential toxic effects, target organs, and/or modes-of-action, and for selecting surrogate chemicals from which to derive either reference or risk values.

SU-E-T-491: A FLUKA Monte Carlo Computational Model of a Scanning Proton Beam Therapy Nozzle at IU Proton Therapy Center.

PURPOSE: Charged particle therapy, especially proton therapy is a growing treatment modality worldwide. Monte Carlo (MC) simulation of the interactions of proton beam with equipment, devices and patient is a highly efficient tool that can substitute measurements for complex and unrealistic experiments. The purpose of this study is to design a MC model of a treatment nozzle to characterize the proton scanning beam and commissioning the model for the Indiana University Health Proton Therapy Center (IUHPTC. METHODS: The general purpose Monte Carlo code FLUKA was used for simulation of the proton beam passage through the elements of the treatment nozzle design. The geometry of the nozzle was extracted from the design blueprints. The initial parameters for beam simulation were determined from calculations of beam optics design to derive a semi-empirical model to describe the initial parameters of the beam entering the nozzle. The lateral fluence and energy distribution of the beam entering the nozzle is defined as a function of the requested range. The uniform scanning model at the IUHPTC is implemented. The results of simulation with the beam and nozzle model are compared and verified with measurements. RESULTS: The lateral particle distribution and energy spectra of the proton beam entering the nozzle were compared with measurements in the interval of energies from 70 MeV to 204.8 MeV. The accuracy of the description of the proton beam by MC simulation is better than 2% compared with measurements, providing confidence for complex simulation in phantom and patient dosimetry with the MC simulated nozzle and the uniform scanning proton beam. CONCLUSIONS: The treatment nozzle and beam model was accurately implemented in the FLUKA Monte Carlo code and suitable for the research purpose to simulate the scanning beam at IUHPTC.

Compliance with the CURB-65 score and the consequences of non-implementation.

BACKGROUND: The CURB-65 (confusion, urea >7 mmol/l, respiratory rate ≥ 30 breaths/min, low blood pressure and age ≥ 65 years) score is a simple, well-validated tool for the assessment of severity in community-acquired pneumonia (CAP). It is unknown whether it is used routinely in China. OBJECTIVE: To determine the frequency of use of the CURB-65 score in routine hospital practice and the consequences of non-implementation. METHODS: A retrospective analysis of medical records from 1230 in-patients with CAP in a Chinese medical college-affiliated hospital. RESULTS: No CAP patient underwent the CURB-65 test at admission. Based on the British Thoracic Society guidelines, the 716 (58.2%) in-patients with a CURB65 score of 0 and the 402 (32.7%) in-patients with CURB-65 score of 1 should have received ambulatory treatment, whereas the 14 (1.2%) patients with CURB65 scores of ≥ 3 should have been admitted to the critical care unit. The maximum excess total annual costs for managing CAP patients with CURB-65 scores of 0 and 1 were estimated at respectively US$94 383.12 and US$66 313.92 in the hospital. CONCLUSIONS: The CURB-65 scoring tool in patients with CAP was not applied in routine hospital practice, resulting in inappropriate hospitalisation and excess costs.

Application of transcriptional benchmark dose values in quantitative cancer and noncancer risk assessment.

The traditional approach for estimating noncancer and cancer reference values in quantitative chemical risk assessment is time and resource intensive. The extent and nature of the studies required under the traditional approach has limited the number of chemicals with published risk assessments. In this study, female mice were exposed for 13 weeks to multiple concentrations of five chemicals that were positive in a 2-year cancer bioassay. Traditional histological and organ weight changes were evaluated, and gene expression microarray analysis was performed on the target tissues. The histological, organ weight changes, and the original tumor incidences in the original cancer bioassay were analyzed using standard benchmark dose (BMD) methods to identify noncancer and cancer points of departure, respectively. The dose-related changes in gene expression were also analyzed using a BMD approach and the responses grouped based on cellular biological processes. A comparison of the transcriptional BMD values with those for the traditional noncancer and cancer apical endpoints showed a high degree of correlation for specific cellular biological processes. For chemicals with human exposure data, the transcriptional BMD values were also used to calculate a margin of exposure. The margins of exposure ranged from 1900 to 54,000. Both the correlation between the BMD values for the transcriptional and apical endpoints and the margin of exposure analysis suggest that transcriptional BMD values may be used as potential points of departure for noncancer and cancer risk assessment.

Assessment of transvaginal sonography combined with endometrial cytology as a mass screening method for endometrial cancer in Beijing.

This was a two-phase, large sample-group study assessing the effectiveness of combined transvaginal sonography (TVS) and endometrial cytology in endometrial cancer screening. In phase one, 3308 women without known cancer were enrolled and TVS was performed on those with symptoms or endometrial cancer risk factors. Endometrial cytology was carried out on post-menopausal women with endometrial thickness >or= 5 mm and on pre-menopausal women with endometrial thickness >or= 10 mm. Dilation and curettage (D & C) was performed if cytological findings were inconclusive, or indicated cancer or pre-cancer. The mass screening safety interval is at least 2 years and phase two was carried out 2 years after phase one, using the same procedures, on the 3305 women who were originally found to be cancer free. Combined TVS and endometrial cytology resulted in 100% sensitivity and 99.0% specificity, reducing unnecessary D & C by 91.7% and screening costs by 20.1%. Combined TVS examination and endometrial cytology decreased potentially harmful examinations, patient suffering and medical costs, and is worth considering for broad implementation.