Protocol development

All of the previously described planning is necessary to understand clearly the goals 

The most critical information in preparing a protocol that will ensure the success of 

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Further information and advice related to the use of the clinical trial design can be found in a variety of sources including textbooks, manuscripts, organizations and Internet sites. In addition to the chapter reference list which cites helpful sources of information related to clinical trial protocol development, design and analysis, the following sources are also recommended. 

The generic protocols developed for SDTF field studies with EPA input included the following recommendations for location of field collection stations ... 

Domino processes involving Homer-Wadsworth-Emmons (HWE) reactions constitute another important approach. Among others, HWE/Michael sequences have been employed by the group of Rapoport for the synthesis of all-cis-substituted pyrrolidines [143], and by Davis and coworkers to access new specific gly-coamidase inhibitors [144]. Likewise, arylnaphthalene lignans, namely justicidin B (2-281) and retrojusticidin B (2-282) [145], have been synthesized utilizing a domino HWE/aldol condensation protocol developed by Harrowven s group (Scheme 2.65) [146]. 

In another interesting turn of event, while we were attempting to add acetate anion in a 1,4-fashion into the enone system of 45, we isolated ene-dione 49b when using KOAc in the presence of 18-crown-6 (Scheme 8.11). While this was not what we had anticipated, it turned out to be a known protocol developed by Komblum and DeLaMare to ring-open endoperoxides through a deprotonation pathway [55]. It is noteworthy that ene-dione 49b did not equilibrate to the ene-trione 49b which could suffer from the aforementioned HDA pathway as we had also suffered from [47c],... 

Formalin-fixed and paraffin-processed sections from commercially prepared composite cell line block comprising the human breast carcinoma cell lines SK-BR-3, MDA-MB-453, MDA-MB-175, and MDA-MB-231, have been used consistently for the past 5 years for HER2 IffC EQA evaluation. More recently, the same composite cell line block reference material has been introduced for EQA evaluation of HER2 ISH testing of breast cancer. The principles and protocols developed and established for running of these two schemes have been recently described by Miller et al.13 and Bartlett et al.14... 

The protocol developed by Jacobsen and Katsuki for the salen-Mn catalyzed asymmetric epoxidation of unfunctionalized alkenes continues to dominate the field. The mechanism of the oxygen transfer has not yet been fully elucidated, although recent molecular orbital calculations based on density functional theory suggest a radical intermediate (2), whose stability and lifetime dictate the degree of cis/trans isomerization during the epoxidation <00AG(E)589>. 

In this Chapter further evidence is provided that precursors exist long before they escalate into an accident. It will be demonstrated that the existence of precursor information could have been used to foresee and even prevent recent accidents with hazardous substances. Moreover, a set of precursors retrieved from 17 recent accidents in the Dutch chemical process industry is used to validate the 7-stage protocol developed in the previous Chapter. In spite of the limited accident information it is shown that if a proper control action had been initiated, all of these 17 accidents could have been prevented. 

The protocol developed in Chapter 5, which was applied on accidents as shown in Chapter 6, is applied on three cases in the Dutch chemical process industry. First, the cases are selected according the criteria stated in Chapter 5. Secondly, the developed protocol of analysis is applied on these selected cases, to identify why and how it is still possible that accidents may occur despite precursors and several existing safety barriers. Thirdly, the results from the analysis are further elaborated on, indicating the problems in current safety management systems, allowing accidents to occur. 

The second glycolate chosen for thorough evaluation was EA 3443 (Fig. 15). It proved to have characteristics very similar to BZ with an almost identical onset time and duration ". It was at least 50% more potent, however, and had greater relative central potency. Our studies of EA 3443 were more systematic than those we had done with BZ. We had the advantage of more than a year of protocol development - a gradual process that became more sophisticated as experience with BZ increased. 

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