经典名方三化汤基准样品量值传递研究

目的 阐明三化汤基准样品的关键质量属性,建立其特征图谱并测定紫花前胡苷、柚皮苷、新橙皮苷、5种游离蒽醌、和厚朴酚与厚朴酚等指标成分,探究三化汤饮片-基准样品量值传递规律,为评价三化汤制剂奠定物质基础。方法 通过文献考证,制备15批三化汤基准样品,采用UPLC建立特征图谱,计算其相似度并确定共有峰归属,结合指标成分及干膏转移率对基准样品进行量值传递分析。结果 建立的15批三化汤基准样品相似度均大于0.98,特征图谱相似度良好,共指认26个共有峰,其中5个来自厚朴,6个来自枳实,5个来自羌活,10个来自大黄;指标成分紫花前胡苷、柚皮苷、新橙皮苷、厚朴酚与和厚朴酚、游离总蒽醌从饮片到基准样品平均转移率分别为（28.08±5.28）%、（45.07±5.35）%、（41.03±4.91）%、（3.32±0.92）%、（16.54±3.57）%,全处方干膏转移率为64.43%～76.39%。结论 采用特征图谱结合多指标成分含量测定及出膏率等评价指标对经典名方三化汤基准样品进行了量值传递综合考察,为三化汤的质量控制和制剂开发提供了科学依据。     

经典名方清经散物质基准关键质量属性量值传递研究

目的 建立经典名方清经散物质基准,并对其关键质量属性量值传递进行研究。方法 制备15批清经散对应实物,建立物质基准高效液相色谱法（HPLC）特征图谱,进行特征峰归属分析;建立物质基准指标性成分含量测定方法,对指标成分从饮片到对应实物的转移率进行分析研究。结果 物质基准HPLC特征图谱共指认了6个特征峰,峰1、2（S）、3、5、9、11分别为芍药内酯苷、芍药苷、东莨菪内酯、毛蕊花糖苷、丹皮酚和盐酸小檗碱;共归属了12个特征峰,分别来自白芍（峰1）,白芍、牡丹皮（峰2、6）,地骨皮（峰3、8、10）,牡丹皮（峰4、9、12）,熟地黄（峰5）,青蒿（峰7）,盐黄柏（峰11）,芍药苷、东莨菪内酯、丹皮酚从饮片到对应实物的转移率分别为67.57%~79.69%、57.29%~77.57%、68.13%~73.11%。结论 采用HPLC特征图谱结合多指标性成分含量测定对清经散物质基准进行量值传递研究,该方法科学合理,可为清经散物质基准的建立及复方制剂的研究开发提供参考。     

Estimation of benchmark dose for pancreatic damage in cadmium-exposed smelters.

The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMDs in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 microg/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary beta2-microglobulin, urinary N-acetyl-beta-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 microg/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.     

An evaluation of HACCP implementation status in UK small and medium enterprises in food manufacturing

To reduce foodborne illnesses, hazard and risk-based quality management systems are essential. Small and medium sized companies (SMEs) tend to have a poor understanding of such systems and limited adoption of the Hazard Analysis Critical Control Point system (HACCP). The requirement for full HACCP implementation by 2006 will place an even greater burden on these businesses. The aim of this project is to assess the current levels of understanding of hazards and risks in SMEs in the manufacturing sector. A questionnaire survey was made of 850 SMEs, including microbusinesses. This determined the industry sector and processes carried out, whether the company operated hazard-based quality management and the knowledge of the technical manager regarding the associated hazards and risks. Follow-up visits to the manufacturing plant observed the processes and the operatives to determine their level of understanding. A benchmarking audit was carried out and each company was rated. The results show that the majority of respondents stated that they operated hazard analysis-based quality management. The ability of the respondents to correctly define a hazard or risk or identify different types of hazard was, however, poor. There was no correlation between business type and audit score. The microbusinesses did, however, perform significantly less well than the larger SMEs.     

Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients

No national benchmark figures exist for early mortality due to chemotherapy unlike for surgical interventions. Deaths within 30 days of chemotherapy during a 6-month period were identified from the Royal Marsden Hospital electronic patient records. Treatment intention--curative or palliative, cause of death and number of previous treatments--were documented. Between April 2005 and September 2005, 1976 patients received chemotherapy with 161 deaths within 30 days of chemotherapy (8.1%). Of these, 124 deaths (77.0%) were due to disease progression. Of the other 37 deaths, 12 (7.5%) were related to chemotherapy, six each for solid tumours and haematological malignancies, of which seven (4.3%) were due to neutropenic sepsis. For the remaining 25 deaths (15.5%) there was insufficient information. There were more deaths after third and subsequent lines of therapy than with first and secondlines of therapy. Only 12 of the 161 deaths occurred in patients who were receiving potentially curative chemotherapy to give a mortality rate in breast and gastrointestinal malignancy of 0.5 and 1.5%, respectively. It is possible to audit mortality within 30 days of chemotherapy and this should become a benchmark for standard practice nationally. Most deaths were due to disease progression in the palliative setting. We practice this form of audit each quarter and feed back to the treating teams so that deaths are discussed and practice monitored.     

Benchmarking ambulance call-to-needle times for thrombolysis after acute myocardial infarction in Australia: a pilot study

Background: Thrombolysis for patients with acute myocardial infarction (AMI) is of greatest benefit when treatment is commenced as soon as possible after symptom onset. The British Heart Foundation (BHF) recently set a benchmark recommending that eligible patients with AMI receive thrombolytic therapy less than 90 min after calling for medical assistance. Aims: The purpose of this study was to compare the performance of an urban emergency service to this benchmark. A secondary objective was to determine whether patients treated outside this time were at a greater risk of mortality. Methods: This study consisted of an explicit retrospective analysis of medical records for all patients who presented by ambulance to the Emergency Department (ED) of Western Hospital and received thrombolysis for AMI within 12 h of symptom onset. The study was conducted for the 18‐month period between 1 January 1999 and 30 June 2000. Information collected included times of: (i) symptom onset, (ii) call for ambulance, (iii) ambulance response, (iv) transport to hospital and (v) thrombolysis, as well as final diagnosis and in‐hospital mortality. For the purposes of this study, call‐to‐needle time (CTN) was defined as the time between calling the ambulance and commencement of thrombolytic therapy. Results: One hundred and twenty‐seven patients met the inclusion criteria. Median CTN was 81 min (range 42?279 min). Sixty‐four per cent of patients were treated within the 90‐min benchmark. The relative risk of mortality for patients treated outside the 90‐min benchmark was 2.6 (95% CI 0.98?6.72). Conclusion: This study showed that the BHF benchmark for CTN was not being met for over one‐third of patients in the study region, with potential impact on mortality after AMI. Further research is needed to establish: (i) whether there is relationship bet‐ween longer transportation times and mortality, (ii) whether the findings of this study may be applied to other regions and (iii) what strategies might be employed to reduce CTN. (Intern Med J 2002; 32: 138?142)     

Tri-Planar Geometric Dimensioning and Tolerancing Characteristics of SS 316L Laser Powder Bed Fusion Process Test Artifacts and Effect of Base Plate Removal

The precision of LPBF manufactured parts is quantified by characterizing the geometric tolerances based on the ISO 1101 standard. However, there are research gaps in the characterization of geometric tolerance of LPBF parts. A literature survey reveals three significant research gaps: (1) systematic design of benchmarks for geometric tolerance characterization with minimum experimentation; (2) holistic geometric tolerance characterization in different orientations and with varying feature sizes; and (3) a comparison of results, with and without the base plate. This research article focuses on addressing these issues by systematically designing a benchmark that can characterize geometric tolerances in three principal planar directions. The designed benchmark was simulated using the finite element method, manufactured using a commercial LPBF process using stainless steel (SS 316L) powder, and the geometric tolerances were characterized. The effect of base plate removal on the geometric tolerances was quantified. Simulation and experimental results were compared to understand tolerance variations using process variations such as base plate removal, orientation, and size. The tolerance zone variations not only validate the need for systematically designed benchmarks, but also for tri-planar characterization. Simulation and experimental result comparisons provide quantitative information about the applicability of numerical simulation for geometric tolerance prediction for the LPBF process.     

Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present analyses of 1‐ethyl‐1‐nitrosourea (ENU) and 1‐methyl‐1‐nitrosourea (MNU) dose–response data and additional approaches for the determination of genetic toxicity point‐of‐departure (PoD) metrics. We previously described methods to determine the no‐observed‐genotoxic‐effect‐level (NOGEL), the breakpoint‐dose (BPD; previously named Td), and the benchmark dose (BMD₁₀) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non‐linear slope‐transition‐dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL₁₀ and BMDL_1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL₁₀ values were often lower than the other PoDs, and the distribution of BMDL₁₀ values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609–623, 2014. © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.     

Development of an oral reference dose for the perfluorinated compound GenX

Ammonium 2,3,3,3‐tetrafluoro‐2‐(heptafluoropropoxy)‐propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long‐chain poly‐fluoroalkyl substances, which tend to have long clearance half‐lives and are environmentally persistent. Unlike poly‐fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non‐cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2‐year bioassay in rats (0.01–0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose‐response modeling described herein, should be informative for risk assessors and regulators interested in setting health‐protective drinking water guideline values for GenX.     

基准剂量在镉接触环境流行病学研究中的应用

[目的]通过环境流行病学研究，估测环境镉接触引起肾功能不全的基准剂量。[方法]镉污染区居住的居民为接触组，非污染区居民为对照组。尿镉(UCd)为接触生物标记物；β微球蛋白(UBM)、尿N-乙酰-β-D-氨基葡萄糖苷酶(UNAG)、尿视黄醇结合蛋白(URBP)和尿白蛋白(UALB)为效应生物标记物，并均用尿肌酐校正。[结果]长期接触镉可引起肾脏的损害。本次调查β2微球蛋白、视黄醇结合蛋白、尿NAG酶和尿白蛋白重污染区显著高于对照区，与尿镉的增长呈明显的剂量效应关系。计算得基准剂量(BMD)，推出基准剂量的95％低限水平(LBMD)。镉所引起的各肾脏损伤指标的LBMD值是不同的，大小依次为尿NAG同功酶B(NAG-B)、NAG、UBM和UALB。[结论]镉引起的肾小球损害晚于肾小管损害；而NAGB的基准剂量值最低，证明NAGB是监测肾小管损害的相对敏感的指标。