對於藥品之管理，主管機關往往僅著重於新藥的核准，對於藥品上市後之監督即第四階段往往付之闕如，因此許多藥商利用上市後對於藥品之反應，往往變相做為另外新適應症的適用研究，對於主管機關而言，藥品標示外使用原則上是已核准藥品之運用，因此，若非有重大不良反應之回報，否則基本上是漠視。 藥害救濟基金會在西元1999年至西元2015年2月第1～217次審議會之統計資料顯示，其中有1030件申請案，審議會審定結果是不予救濟，進一步分析其不予救濟之理由，名列第二名的原因為「未依藥品許可證所載之適應症或效能而為藥品之使用」，占整體不予救濟給付案件的23%，突顯現行的藥害救濟制度下藥害政策與實際臨床用藥的落差。 本文認為醫療行為之目的，乃在救治病人生命及恢復病人之健康，其過程本就充滿不確定性與高度危險性，醫療行為之歸責，應以可合理期待之安全性為考量。然根據衛生署(民國102年7月改制成衛生福利部)於民國91年之函釋說明藥品標示外使用原則為「應據實告知病人」與「不得違反藥品使用當時，已知的、具公信力的醫學文獻」等。因此，雖藥品標示外使用為醫師治療方式之選項之一，但法令上對於藥品標示外使用，卻未有明確之規範，因此產生許多醫學倫理與法律責任之爭議。 本文主題內容鎖定在藥品標示外使用與醫療過失之探討，且從刑法理論觀點，探討藥品標示外使用之法律性質，其在我國刑法規範體系中之定位，並加以闡釋注意義務，告知後同意，醫療過失，醫師說明義務等概念，並以實際發生的實際案例為例，進行說明。 其中，藥品標示外使用是否成為醫師應說明義務之內容?又其說明義務之基礎如何架構，說明內容又為何? 除此之外，文中將分析醫師注意義務與說明義務在藥品標示外使用時所應該達成的程度為何，結合國內的實務現狀與看法提供立法意見。 / After marketing approval, the labels of on drug packages should outline the indications for use, dosage, administrative directions, and safety information. The use of drug could expand over time. Off-label use, which means prescribing an approved drug for a use that is not claimed in the product information, is common in medical practice, especially for some serious or rare diseases. Since there is no regulation for off-label use , a number of clinical , legal and ethical issues arise. According to Taiwan Drug Relief Foundation for Drug Hazards’ statistics regarding the rejected reasons by foundation from 1030 application cases 1999 to 2015. The 2nd reason for unapproved cases is off-label use which is around 23% of total unapproved cases. This shows current criteria for drug relief is quite not fit in real world practice. Medicine is intended to save patients’ lives and to help patients reach renewed health. During the process of treatment, the risk versus benefit profile beyond the original product approval should first be taken into consideration. In Taiwan, the department of health provides an guidance regarding off-label use, ex: The necessity of informed consent before prescribing off-label products. Do physicians need to follow the duty of informed consent whiling prescribing a drug which is off-label use? There should be a guidance to follow in this regard. This study has established the principles and flow chart of off-label use. We suggest that some amendments to the laws are necessary, including setting up the scope of the duty of disclosure.

Repair of DNA double-strand breaks is critical to the maintenance of genomic stability, and failure to repair these DNA lesions can cause loss of chromosome telomeric regions, complex translocations, or cell death. In humans this can lead to severe developmental abnormalities and cancer. A central pathway for double-strand break repair is homologous recombination (HR), a mechanism that operates during the S and G2 phases of the cell cycle and primarily utilizes the replicated sister chromatid as a template for repair. Most knowledge of HR is derived from work carried out in prokaryotic and eukaryotic model organisms. To probe the HR pathway in human cells, we performed a genome-wide siRNA-based screen; and through this screen, we uncovered cellular functions required for HR and identified proteins that localize to sites of DNA damage. Among positive regulators of HR, we identified networks of pre-mRNA-processing factors and canonical DNA damage response effectors. Within the former, we found RBMX, a heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with the spliceosome, binds RNA, and influences alternative splicing. We found that RBMX is required for cellular resistance to genotoxic stress, accumulates at sites of DNA damage in a poly(ADP-ribose) polymerase 1-dependent manner and through multiple domains, and promotes HR by facilitating proper BRCA2 expression. Screen data also revealed that the mammalian recombinase RAD51 is commonly off-targeted by siRNAs, presenting a cautionary note to those studying HR with RNAi and highlighting the vulnerability of RNAi screens to off-target effects in general. Candidate validation through secondary screening with independent reagents successfully circumvented the effects of off-targeting and set a new standard for reagent redundancy in RNAi screens.

Shaped charges are a well established type of projectile, subjected to a lot of research ever since emerging as a viable technology in the 1940s. The penetration achieved by shaped charges decreases with increased standoff distance. This is often attributed to the shaped charge jet losing its coherence. The Swedish Defence Research Agency however, noted no such loss of coherence in its experiments. An alternative explanation to the decrease of penetration was instead proposed. The object of this thesis was to investigate this proposed theory. To this end, the hydrocode Autodyn was used, modelling the impact of a high-velocity projectile into a generic target and analysing the resulting behaviour of the target. Several setups were used and several parameters were considered when evaluating the results. The conclusion of this thesis is that the alternative explanation offered is not supported by the observed behaviour of the target in the computer model.

No description available.

Proactive ergonomics is generally considered to be a more efficient and cost effective way of designing working environments than reactive ergonomics. It often requires preemptively selecting working postures and forces to reduce potential injury risk. One major issue with proactive ergonomic design is correctly identifying the true manual forces that will be required of a worker to complete defined tasks. Typically, these forces are represented as in direct opposition to the forces required by a particular task. However, this is likely an oversimplification as forces often act in different directions than the task-required direction to increase required force level, enhance balance and reduce joint moments, depending on specific experimental conditions. This study aims to quantify these off-axis forces as they change with different required on-axis force intensities. This thesis evaluated the effects of force intensity on the presence of off-axis forces across four conditions, which included free and constrained postures, and with and without off-axis force. Eighteen female subjects performed static, unilateral, manual pushing and pulling exertions while seated and were limited to force contributions from the right upper extremity. Hand forces and location of bony landmarks were collected from each subject and force intensity consisted of both maximal and submaximal levels (5% to 50% of the maximum producible on-axis force in increments of 5%). All principle direction forces were scaled to the on-axis force level and anatomically relevant joint moments scaled to the maximum capacity joint moment. The main objective of this study was to analyze off-axis force production as force intensity was increased under various constraint conditions. The highest maximum on-axis force was in the fully free condition (off-axis force allowed and posture unconstrained) and as conditions became more constrained for both pushing and pulling exertions, maximum on-axis force production decreased (p=<0.0001). For submaximal exertions in the free posture, participants used off-axis forces to target the shoulder flexion-extension moment by pushing increasingly upwards (p=0.0122) and to the left by 5.6% on-axis (p=0.0025), and by pulling 12.6% on-axis downward (p=<0.0001) and 4.7% on-axis rightward (p=0.0024) compared to when off-axis force was not allowed. When comparing the free to the constrained posture while allowing off-axis force, participants pushed downwards instead of upwards by a difference of 12.9% on-axis (p=0.0002) and pulled less downward (becoming slightly upward) by an increasing difference (p=0.0002) and from decreasing to increasing rightward (p=0.0006). These changes in off-axis force showed a unifying strategy of using less shoulder flexion-extension strength by targeting wrist and elbow moments for pushing and pulling exertions. When in the constrained posture allowing and not allowing off-axis force resulted in more internal elbow flexion (p=0.0003) moment during pushing, and less internal shoulder flexion (p=0.0092), more internal shoulder adduction (p=0.0252), more to less internal elbow supination (p=0.0415), and increasingly less internal wrist flexion (p=0.0296) moments during pulling, which verified previously observed strategies. Finally, for both maximal and submaximal exertions, pulling was more sensitive to changes in off-axis forces compared to pushing which was more sensitive to postural flexibility. In conclusion, the underlying principles as to how and why off-axis forces change provides valuable knowledge to ergonomists so that they can more accurately predict force production in workplace design, ultimately reducing the potential for injury.

Advancements in the biomedical field are driven by the design of novel materials with controlled physical and bio-interactive properties. To develop such materials, researchers rely on the use of highly efficient reactions for the assembly of advanced polymeric scaffolds that meet the demands of a functional biomaterial. In this thesis two main strategies for such materials have been explored; these include the use of off-stoichiometric thiol-ene networks and dendritic polymer scaffolds. In the first case, the highly efficient UV-induced thiol-ene coupling (TEC) reaction was used to create crosslinked polymeric networks with a predetermined and tunable excess of thiol or ene functionality. These materials rely on the use of readily available commercial monomers. By adopting standard molding techniques and simple TEC surface modifications, patterned surfaces with tunable hydrophobicity could be obtained. Moreover, these materials are shown to have great potential for rapid prototyping of microfluidic devices. In the second case, dendritic polymer scaffolds were evaluated for their ability to increase surface interactions and produce functional 3D networks. More specifically, a self-assembled dendritic monolayer approach was explored for producing highly functional dendronized surfaces with specific interactions towards pathogenic E. coli bacteria. Furthermore, a library of heterofunctional dendritic scaffolds, with a controllable and exact number of dual-purpose azide and ene functional groups, has been synthesized. These scaffolds were explored for the production of cell interactive hydrogels and primers for bone adhesive implants. Dendritic hydrogels decorated with a selection of bio-relevant moieties and with Young’s moduli in the same range as several body tissues could be produced by facile UV-induced TEC crosslinking. These gels showed low cytotoxic response and relatively rapid rates of degradation when cultured with normal human dermal fibroblast cells. When used as primers for bone adhesive patches, heterofunctional dendrimers with high azide-group content led to a significant increase in the adhesion between a UV-cured hydrophobic matrix and the wet bone surface (compared to patches without primers). / <p>QC 20140116</p>

This paper mainly focuses on one of the new specifications of Phillips curve family, the threshold Phillips curve. By estimating the threshold model using G7 plus Australia countries quarterly data, the threshold effect is confirmed only by U.S. and Canadian Phillips curves. No strong evidence for the threshold effect was found among other countries. Moreover, the estimation results for both standard and threshold Phillips curve model indicate weak trade-o relations between inflation and unemployment. Policy makers should review Phillips curve as a forecasting tool with extra caution. Future studies can focus on specific country's threshold effect testing with detailed explanation.

Long-term mine plans are based on forecast future metal prices. By the time the development is put in place, the forecasts may have been proved wrong and the production plan might not meet the company's financial objectives. At that point, the common reaction to this situation is to create a new revised long-term plan and spend more capital, only to find out at a later time that the metal prices have changed again. This results in an inefficient use of capital with low returns to the investors. The objective of this thesis is to develop a methodology to determine the cut-off grade and production rate of a narrow-vein underground mine such that the long-term strategic plan is robust. As a requirement to do so, it is necessary to have a good understanding of the resources, revenues, capital and operating costs as a function of the design parameters. Also, the operational limits of the mine must be determined so that the solution is practical. Afterwards, annual metal prices are randomly generated with a Monte Carlo process on stochastic metal price models, and the combination of production rate and cut-off grade yielding the highest net present value is identified and recorded. This process is repeated many times, and the probabilities of the solutions occurring at any given design combination are calculated. The results are plotted on a bubble graph, where the size of a bubble is directly proportional to the probability a solution occurs at that point. Finally, the combination with the largest bubble is the solution, as this point has the highest probability of yielding the highest net present value in most circumstances. The model was first tested on an actual gold-copper orebody where very detailed resource and cost information was available. The methodology was applied with success and the solution reflected the important impact of the copper milling and roasting process on revenues. Other tests were then done on a hypothetical gold orebody and the results showed a great degree of sensitivity to the average grade of the deposit. / Thesis (Ph.D, Mining Engineering) -- Queen's University, 2008-04-25 12:42:24.623

A novel interpretation of leaf mass variation in plants has been recently proposed based on its relationship with variation in leafing intensity – number of leaves produced per unit remaining above-ground dry mass. It is now widely established that between species variation in these two traits is strongly, negatively (and isometrically) correlated for woody and herbaceous species. Possible fitness advantages of higher leafing intensity (requiring smaller leaf size) can be interpreted in terms of the greater concentration of axillary meristems (larger ‘bud bank’), which may provide greater potential deployment flexibility for growth or reproduction. However, no research to date has addressed how these two traits are related at different scales, specifically at the between-individual (within-species) level, or between sexes in dioecious species. For the majority of 24 herbaceous angiosperms studied here, between-individual (within species) co-variation in leaf size and leafing intensity displayed as an isometric trade-off. For the few species with allometric trade-offs, plants with smaller body size produced disproportionately more leaves, indicating a possible mechanism for promoting reproductive economy when plant size is suppressed (e.g. by competition). For two out of three woody dioecious species, and two out of three herbaceous dioecious species, males tended to produce more, smaller leaves than females, possibly promoting pollen dispersal through a more broadly-spaced floral display (developing from more numerous axillary meristems). In contrast, the larger (but fewer) leaves in females may serve to maximize local photosynthetic resources available for axillary fruit and seed maturation. Males and females did not differ in branching rates associated with differences in leafing intensities, but in one herbaceous species, higher leafing intensity in males was associated with higher flower production than in females. In the larger 24-species data set, there was no evidence that species with higher leafing intensity (providing more axillary meristems) was associated with either a greater magnitude or a greater flexibility in branching or flowering intensity. Additional studies are required to explore the possibility that large ‘bud banks’ of axillary meristems (conferred by high leafing intensity) may promote effective mechanisms for tolerating environmental variability, responding to damage (e.g. from herbivory), and/or maximizing reproductive economy. / Thesis (Master, Biology) -- Queen's University, 2009-10-27 21:20:03.509

No description available.