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Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI-1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte co-culture (MPCC) model HepatoPac® . Differences across hepatocellular health (cellular adenosine triphosphate/glutathione content), function (urea production/albumin secretion) and taurocholic acid transport (biliary clearance/excretion index) were compared using amiodarone and ciclosporin A as positive controls. Ambrisentan had the weakest potency in all six endpoints, while sitaxsentan, bosentan and CI-1034 had more potent effects on hepatobiliary transport than health/function endpoints. Normalization to clinical Cmax gave the following relative rank order of safety based on margins for each endpoint: ambrisentan ≥ CI-1034 ~ bosentan > sitaxsentan. These data suggested impaired hepatobiliary disposition might contribute to a more prominent role in liver injury associated within sensitive human populations exposed to these compounds than direct hepatocellular toxicity. Rat, dog and monkey MPCCs also showed greater sensitivity potential to disrupted hepatobiliary disposition compared with hepatocellular health/functional endpoints. Drug metabolism competency was exhibited across all species. In vivo, rats and dogs appear more resistant to transaminase elevations and/or histological evidence of liver injury caused by these mechanisms even at exceedingly high systemic exposures relative to sensitive humans. Rats and dogs are resistant to hepatobiliary toxicants due to physiological differences in bile composition/handling. Although traditional animal testing provides adequate safety coverage for advancement of novel pharmaceuticals into clinical trials, supplemental assays employing human MPCCs may strengthen weight-of-evidence predictions for sensitive human populations. Proving the predictive value of this single impact assessment model in advance of clinical trial information for human liver injury risk is needed across more pharmaceuticals.

Introduction Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process. The aim of this study was to examine the correlation between in vitro/ex vivo assays that are routinely used to measure Nav1.5 activity and determine the translatability of the individual assays to QRS prolongation in the clinic. Methods A set of clinical compounds with known Nav1.5 activity was profiled in several in vitro/ex vivo assays (binding, membrane potential, patch clamp and the Langendorff isolated heart). Clinical data comprising compound exposure levels and changes in QRS interval were obtained from the literature. Sensitivity/specificity analysis was performed with respect to the clinical outcome. Results The in vitro assays showed utility in predicting QRS prolongation in the clinic. Optimal thresholds were defined for each assay (binding: IC20; membrane potential: IC10; patch clamp: IC20) and sensitivity (69–88%) and specificity (53–84%) values were shown to be similar between assay formats. Discussion The data provide clear statistical insight into the translatability of Nav1.5 antagonism data generated in vitro to potential clinical outcomes. These results improve our ability to understand the liability posed by such activity in novel development compounds at an early stage.

Japan is developing a grand strategy for “international cooperation,” a mix of official development assistance policy and other policy tools, most notably security policy, that is currently a feature of the Abe administration’s “proactive contribution to peace.” The research asks how this new aid is strategic and how it understands the concept of security. Finally, what does Japanese aid to Southeast Asia tell us about these two points? This chapter addresses these questions in two ways. First, it clarifies what is meant by “strategic aid” by analysing the concept through three lenses: strategic thinking, organization, and allocation of aid. Second, it provides an analytical framework for measuring strategic aid, through which Japan’s aid to Southeast Asia, in particular Myanmar, is analysed.

CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD-2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism-based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ-12,918 inhibited lens cholesterol biosynthesis (LCB). A 2-day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5-LO inhibitors. Thereafter, this 2-day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl-CoA desaturase-1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH-6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month.

Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity. Since prolactin signals through the JAK2 pathway, we hypothesized that these findings were off-target effects due to inhibition of PRL signaling via JAK2. The studies reported here were designed to investigate the interruption of PRL signaling pathways in Leydig cells. In isolated primary rat Leydig cells, PRL increased phosphorylated Signal Transducer and Activator of Transcription-5 protein, and mRNA levels for luteinizing hormone receptor. Tofacitinib, at concentrations observed in the rat carcinogenicity study, dose-dependently inhibited these effects. These observations illustrate a novel mechanism, the inhibition of prolactin signaling by which modulation of JAK activity can modulate PRL signaling pathways to induce Leydig cell tumors in rats. Since human Leydig cells lack this PRL dependence for normal function, these rodent tumors do not indicate a health risk to human patients.

Nerve growth factor (NGF) blocking therapies are an emerging and effective approach to pain management. However, concerns about the potential for adverse effects on the structure and function of the peripheral nervous system have slowed their development. Early studies using NGF antisera in adult rats reported effects on the size and number of neurons in the sympathetic chain ganglia. In the work described here, both young adult (6-8 week) and fully mature (7-8 month) rats were treated with muMab 911, a selective, murine, anti-NGF monoclonal antibody, to determine if systemic exposures to pharmacologically active levels of antibody for 1 month cause loss of neurons in the sympathetic superior cervical ganglia (SCG). State-of-the-art, unbiased stereology performed by two independent laboratories was used to determine the effects of muMab 911 on SCG neuronal number and size, as well as ganglion size. Following muMab 911 treatment, non-statistically significant trends toward smaller ganglia, and smaller and fewer neurons, were seen when routine, nonspecific stains were used in stereologic assessments. However, when noradrenergic neurons were identified using tyrosine hydroxylase (TH) immunoreactivity, trends toward fewer neurons observed with routine stains were not apparent. The only statistically significant effects detected were lower SCG weights in muMab 911-treated rats, and a smaller volume of TH immunoreactivity in neurons from younger rats treated with muMab 911. These results indicate that therapeutically relevant exposures to the anti-NGF monoclonal antibody muMab 911 for 1 month have no effect on neuron numbers within the SCG from young or old adult rats.

Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI-1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte co-culture (MPCC) model HepatoPac

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs. Conclusion: These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI. (Hepatology 2014;60:1015–1022)

The cyclisation of mono-protected and bis-protected guanidines 8a–j under standard iodocyclisation conditions (I2/K2CO3) gave the guanidine heterocycles 9–25 via either a direct cyclisation or by a cyclisation/ring-contraction process, which could be controlled by careful selection of conditions.

Since roughly 2000 Japan's foreign aid policy has been beset by two contradictory forces. On one hand, the foreign aid budget has been reduced almost yearly since its peak in 1998. On the other hand, the international development community has rallied around the banner of poverty reduction, especially as agreed in the Millennium Development Goals (MDGs) in 2001.The Japanese government pledged to assist in the attainment of the MDGs in 2000. Japan'sODA has only partially fulfilled the government's commitments, however, as aid fatigue anda structural public debt problem have led to decreases in ODA levels contrary to the spirit of these summits. Aid agencies have adopted a neoliberal rhetoric of partnership with private sector and civil society organizations. This article analyzes the contribution of Japan's NGOs to the MDGs and examines whether Japanese NGOs play complementary roles with ODA in meeting the country's commitments to those goals. It considers the countries and sectors in which NGOs are active and assesses whether ODA-subsidized NGO projects are aligned withthe MDGs or not. The article concludes with suggestions about how Japan's NGOs might more effectively enhance Japan's development assistance efforts toward the MDGs.

To determine the sensitivity of male reproductive toxicity endpoints in NHPs we performed a power analysis of routine and triggered endpoints using control data from sexually mature Asian and Mauritian NHPs. The power to detect a 50% change from control was 13-30% for male reproductive organ weights, ∼30% for testicular volume, 6-66% for seminal analyses and 10-78% for male hormones. Overall, male reproductive endpoints have poor power (less than 80%) to detect a 50% change from control with a group size of 3 monkeys. Confidently identifying adverse male reproductive effects with these endpoints would likely require specialized study designs with larger group sizes. Triggering of non-routine endpoints in cases where there is special concern for male reproductive toxicity is unlikely to increase sensitivity to detect adverse effects.

It may appear odd to subtitle a presentation on United States-Japan relations with a locale associated with natural disaster. In fact, I was somewhat taken aback when I first saw it in print. After all, what do the 2011 Great Eastern Japan earthquake and tsunami and the subsequent nuclear power disaster at Fukushima have to do with Japan’s foreign policy? But, when I reflected upon the title I realized that it includes all of the elements of an old alliance: perennial issues, medium-term changes, and acute incidents. Newly-elected Japanese Prime Minister Noda Yasuhiko’s state visit to the United Nations and his discussions with President Obama in early September, and we might add Foreign Minister Genba’s discussions with Secretary of State Clinton just before, also demonstrate those elements. So, it is in those terms, the pe-rennial, the medium-term, and the acute, that I would like to frame today’s discus-sion about Japan’s relationship with the United States.

The objective of this study was to determine the shortest period of time necessary to detect histologic evidence of estrous cycle disruption in Sprague-Dawley rats treated for up to 28 days with the aromatase inhibitor exemestane at 1,000 mg/kg. Rats were evaluated on day 5, 8, 15, or 29. Vaginal mucification, uterine and cervical epithelial atrophy, uterine luminal epithelial vacuolation, decreased uterine granulocytes, and hypertrophy/hyperplasia of mammary ducts and alveoli were noted by day 5 and persisted throughout the study. From day 8 to day 29, absence of recent basophilic corpora lutea, increased atresia of antral follicles, interstitial cell hyperplasia, and increased luteinized follicles were present in the ovaries of treated rats. Vaginal smears detected persistent diestrus, confirming estrous cycle disruption between days 5 and 8. Ovary and uterine weights were largely unaffected. Serum hormone levels were not useful due to the study design employed. Other effects of exemestane included decreased adrenal weights and decreased cell size in both the adrenal zona fasciculata and the pituitary pars distalis. While early histologic changes were evident on day 5, only after 8 days of treatment were findings considered sufficient to clearly identify exemestane-induced estrous cycle disruption using microscopy alone.

Policy uncertainty is often cited as a cause of the CNN effect. In fact, many argue that an uncertain policy environment is a necessary condition for media-driven foreign policy. While the logic appears compelling, rigorous empirical analyses of the influence of the news media on Japanese foreign disaster aid allocations indicates that, as the global policy environment became more uncertain with the end of the Cold War, media influence went from being a prominent factor in foreign disaster aid allocations to being statistically insignificant. This finding is contrary to the logic of the policy uncertainty argument for media-driven foreign policy as a generalization but it is consistent with the earlier findings for the US disaster assistance program. This lends additional evidence for the argument that the most significant aspect of the CNN effect, the presumed rise of a media-driven foreign policy environment in the 1990s, may have been illusory.

The iodocyclisation of a range N -allyl and N -homoallylguanidines using I 2 /K 2 CO 3 has been found to lead to a series of novel heterocycles which undergo selective rearrangements on variation of the reaction conditions, and predictable protecting group migration in the presence of trifluoroacetic acid in methanol.

This article compares the evolution and characteristics of Chinese and Japanese aid, assessing the impact of their aid policies in sub-Saharan Africa from the 1950s to the present. It argues that China and Japan's aid programmes share more similarities than dissimilarities. Both pursue aid strategies that spread allocations across a region rather than concentrating upon specific countries. The article seeks to clarify the following questions. In what way are Chinese and Japanese aid strategies different from each other and Western donors? Should their aid be seen as a form of South–South co-operation that provides an alternative to the West's hegemony in Africa? Or is aid from these donors simply another strategy to control African resources and state elites in the guise of a partnership of equals?

This chapter provides a survey of key nonclinical safety assays. For each study type, we discuss the typical study designs employed, including a summary of the type of endpoints collected. We then provide an overview of common statistical approaches in each setting. There are some general themes that are common across the study types (e.g., trend testing). At the same time, the different study types may have features that require special consideration (e.g., cross-over designs for safety pharmacology studies, intra-litter correlation in reproductive toxicology studies). While some of the design aspects of these studies are to some extent “fixed” by precedent across the industry, we do address sample size and power considerations, as this information can be valuable to understanding how statistical results can contribute to the overall interpretation of these studies. Finally, for any discussion of statistical approaches, there are likely to be multiple reasonable approaches. We’ve attempted to cover some of the more common approaches in detail, but we recognize that our treatment is not exhaustive. Where possible, we have provided references for further reading.

This chapter analyses the evolution of Japan’s international security cooperation since the 1990s, based on the expansion of a security perspective within the official development assistance (ODA) programme and the parallel dispatch of the Self-Defense Forces (SDF) overseas. It asks why the securitization of aid in Japan occurred the way it did and how security thinking has affected aid allocations. It assesses whether the Ministry of Foreign Affairs (MOFA) and the Japan International Cooperation Agency (JICA) have used this new security thinking to expand aid activities and secure budgetary resources.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.

This study explores the role that news coverage plays in the allocation of Japanese development aid. Conceptually, it is expected that democratic foreign policy officials, including those working in bureaucratic governmental structures will try to match the magnitude of their actions with what they expect is the public's perception of the importance of the recipient. News media salience serves an easily accessible indicator of that domestic political importance and, in the case of foreign aid, this suggests that higher levels of news coverage of a less-developed country will lead to higher aid commitments. The statistical analysis demonstrates that the level of news coverage is a statistically significant factor in Japanese aid distributions. More significantly, the analysis demonstrates that separating grant aid from other forms of aid is critical for the empirical examination of the determinants of Japanese aid.

This article revisits the thesis put forward by Kent Calder that Japan's foreign policy is made by a reactive state incapable of sustained, innovative policy. Reviewing six recent books, we find that, while the reactive state thesis continues to inform scholarsip on the subject, new frameworks offer possibilities for seeing Japan's foreign policy as innovative and at times strategic. This article considers the strengths and weaknesses in recent attempts to create a more proactive foreign policy.

Purpose: To retrospectively compare the clinical outcome for cervical cancer patients treated with high-dose-rate (HDR) vs. low-dose-rate (LDR) brachytherapy. Methods and Materials: One hundred ninety-one LDR patients were treated from 1977 to 1988 and compared to 173 HDR patients treated from 1989 to 1996. Patients of similar stage and tumor volumes were treated with identical external beam fractionation schedules. Brachytherapy was given in either 1 or 2 LDR implants for the earlier patient cohort, and 5 HDR implants for the latter cohort. For both patient groups, Point A received a minimum total dose of 80 Gy. The linear-quadratic formula was used to calculate the LDR dose-equivalent contribution to Point A for the HDR treatments. The primary endpoints assessed were survival, pelvic control, relapse-free survival, and distant metastases. Endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. Results: The median follow-up was 65 months (2 to 208 months) in the LDR group and 22 months (1 to 85 months) in the HDR group. For all stages combined there was no difference in survival, pelvic control, relapse-free survival, or distant metastases between LDR and HDR patients. For Stage IB and II HDR patients, the pelvic control rates were 85% and 80% with survival rates of 86% and 65% at 3 years, respectively. In the LDR group, Stage IB and II patients had 91% and 78% pelvic control rates, with 82% and 58% survival rates at 3 years, respectively. No difference was seen in survival or pelvic control for bulky Stage I and II patients combined (> 5 cm). Pelvic control at 3 years was 44% (HDR) versus 75% (LDR) for Stage IIIB patients ( p = 0.002). This difference in pelvic control was associated with a lower survival rate in the Stage IIIB HDR versus LDR population (33% versus 58%, p = 0.004). The only major difference, with regard to patient characteristics, between the Stage IIIB patients was the incidence of hydronephrosis in the HDR vs. LDR group—28% vs. 12%, respectively ( p = 0.05). For Stage IIIB patients treated with HDR, our analysis suggested that pelvic control rates improved when the first brachytherapy insertion was performed after the majority of external beam radiotherapy had been delivered. Conclusion: Similar outcome was observed for Stage IB and II patients treated with either HDR or LDR brachytherapy—regardless of tumor volume. However, poorer survival and pelvic control rates were observed for Stage IIIB patients treated with HDR brachytherapy. If HDR is used for Stage IIIB patients, our results suggest the majority of external beam radiotherapy should be delivered prior to initiating the brachytherapy to allow for adequate tumor regression. HDR brachytherapy is more convenient for patients, decreases the radiation exposure for health care workers, and should be considered a standard therapy for women with Stage I or II cervical cancer.

(1998). Exporting a Japanese Model? Collusion in the Foreign Aid Program. Journal of Economic Issues: Vol. 32, Papers From The 1998 Afee Meeting, pp. 403-409.

Although the governments of the United States and Japan differ markedly in racial ideology, official crime statistics in both nations reflect political arrangements which marginalize minority populations. In both nations, official crime statistics reveal more about the attempts of majority populations to label minority populations as a criminal class than about variations in criminal behavior across racial populations. While there is no racially pure Black population in the United States, there is a “black” category within official statistics, and the statistics are used to justify crime control policies which have a disparate impact on the diverse peoples who are socially‐perceived as Black. While there are undeniably non‐Japanese populations in Japan, there are no racial categories for them in official statistics which define them out of existence; except where crime statistics are concerned, so that the police can monitor the criminality of “foreigners.” In both societies, official categorization of ra...

This article describes the sources of electoral corruption in postwar Japan, in particular the relationship between demand for political funds by politicians and its supply by corporate donors. The weakness of legal and political sanctions, it is argued, allows this relationship to continue. The article concludes by examining the possibilities and limitations of recent efforts to curb electoral corruption.

Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) being developed for the treatment of HIV-1 infection. Like other NNRTIs, lersivirine is a potent enzyme inducer in rodents capable of inducing a number of hepatic enzymes including those involved in its own metabolism. Preclinically lersivirine has been associated with hepatocellular hypertrophy and thyroid gland follicular cell hypertrophy in rats, mice, and dogs. In rodents, we show that development of thyroid hypertrophy is related to the classic mechanism, namely increased thyroxine (T4) clearance secondary to induction of uridine-diphosphoglucuronosyltransferase (UDPGT) in the liver and a resulting increase in thyroid-stimulating hormone. Similarly, lersivirine-exposed dogs exhibit a significant increase in hepatic UDPGT enzyme activity along with increased T4 clearance although clear effects on serum thyroid hormone levels were less apparent. These effects on thyroid hormonal clearance in the dog suggest that thyroid gland hypertrophy in this species is due to the same mechanism shown to occur in rodents although, as expected, dogs better adapt to these effects and therefore maintain relatively normal thyroid hormonal balance. It is also notable that the minimal thyroid follicular hypertrophy that occurs in dogs does not progress as is seen in rodents. As is the case with rodents, these adaptive changes in the dog are not considered indicative of a human health risk.

Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk. To address this, we analyzed data from 100 small molecules to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package. These models range from the assessment of in-vitro binding and functional profiles at receptors or transporters typically associated with abuse through in-vivo models including locomotor activity, drug discrimination, and self-administration in rodents. Data from subjective report assessments in humans following acute dosing of compounds were also included. The predictive value of each model was then evaluated relative to the scheduling status of each drug in the USA. In recognition of the fact that drug scheduling can be influenced by factors other than the pharmacology of the drug, we also evaluated the predictive value of each assay for the outcome of the human subjective effects assessment. This approach provides an objective and statistical assessment of the predictive value of many of the models typically applied within the pharmaceutical industry to evaluate abuse potential risk. In addition, the impact of combining information from multiple models was examined. This analysis adds to our understanding of the predictive value of each model, allows us to critically evaluate the benefits and limitations of each model, and provides a method for identifying opportunities for improving our assessment and prediction of abuse liability risk in the future.

Historians have a habit of explaining the important decisions of the past in terms of principles. On this basis, it is easy to say that the Republicans rejected compromise because they were committed to the principle of antislavery and that they rejected secession because they were committed to the principle of union. But in the realities of the historical past, principles frequently come into conflict with other principles, and those who make decisions have to choose which principle shall take precedence. When principles thus conflict, as they frequently do, it is meaningless to show merely that a person or a group favors a given principle: the operative question is what priority they give to it. For instance, before the secession crisis arose, there were many Northerners who believed in both the principle of antislavery and the principle of union, but who differed in the priority which they would give to one or the other: William Lloyd Garrison gave the priority to antislavery and proclaimed that there should be “no union with slaveholders.” Abraham Lincoln gave, or seemed to give, the priority to union and during the war wrote the famous letter to Horace Greeley in which he said: “My paramount object is to save the Union and it is not either to save or to destroy slavery. What I do about slavery and the colored race, I do because I believe it helps to save the Union, and what I forbear, I forbear because I do not believe it would help to save the Union.”

A rapidly ageing society and the rise of an invigorated non-profit sector have been parallel trends in Japan in the last two decades. As the central and prefectural governments have begun to realize their economic and administrative limitations in coping with demographic change, localities and non-profits are called upon to fill in policy gaps. This chapter surveys Non-Profit Organization (NPOs) engaged in service provision for the elderly in Japan's 47 prefectures. It examines opinion polls and government policy pronouncements to identify public expectations about NPO roles in coping with ageing population. The chapter attempts to measure the degree of NPO involvement in elderly care provision and examines the kinds of activities that NPOs themselves define as elderly care. It concludes by assessing to what degree NPO activities reflect public expectations about their roles. Keywords: ageing society; elderly care; government policy; Non-Profit Organization (NPO)

A cryogenic propellant tank is the common element of trans‐planetary transportation systems, in‐space storage depots, lunar landers, in‐space habitats/laboratories, ascent/descent, and launch vehicles. Lockheed Martin’s (LM) cryogenic tank approach integrates Friction Stir Welding (FSW) with thin‐gage aluminum monocoque structural design, common spin formed FSW domes and variable tank lengths to tailor the cryogenic tank from smaller stages, such as landers or ascent/descent stages, to very large on‐orbit or In Space Resource Utilization (ISRU) storage systems. Thin gage corrosion resistant steel (CRES) construction combined with normal fusion welding as used on LM’s Centaur has already been demonstrated to provide the highest cryogenic tank mass fraction (∼.90) for large scale, cryogenic propellant storage. However, current fusion welding technology is limited by the alloys that are considered weldable and typically achieves only 50% of the parent material ultimate strength at the weld joint. Preliminary...

A computational approach is described that can predict the VD(ss) of new compounds in humans, with an accuracy of within 2-fold of the actual value. A dataset of VD values for 384 drugs in humans was used to train a hybrid mixture discriminant analysis-random forest (MDA-RF) model using 31 computed descriptors. Descriptors included terms describing lipophilicity, ionization, molecular volume, and various molecular fragments. For a test set of 23 proprietary compounds not used in model construction, the geometric mean fold-error (GMFE) was 1.78-fold (+/-11.4%). The model was also tested using a leave-class out approach wherein subsets of drugs based on therapeutic class were removed from the training set of 384, the model was recast, and the VD(ss) values for each of the subsets were predicted. GMFE values ranged from 1.46 to 2.94-fold, depending on the subset. Finally, for an additional set of 74 compounds, VD(ss) predictions made using the computational model were compared to predictions made using previously described methods dependent on animal pharmacokinetic data. Computational VD(ss) predictions were, on average, 2.13-fold different from the VD(ss) predictions from animal data. The computational model described can predict human VD(ss) with an accuracy comparable to predictions requiring substantially greater effort and can be applied in place of animal experimentation.

Interdigital cysts are chronic inflammatory lesions that can be found in dogs. In order to better understand their etiology, we completed a retrospective analysis of epidemiologic factors by using the clinical records from 743 research Beagles at our research site. Factors examined included age, gender, weight, body condition score, location of the cyst, and type of cage flooring. Statistical analysis revealed that age, body condition score, and type of flooring were all significant factors in the occurrence of interdigital cysts. The epidemiological evidence supports the hypothesis that interdigital dermatitis is the inciting cause of interdigital cysts.

Any argument connecting media coverage and foreign aid inevitably brings to mind the massive humanitarian relief efforts made in response to the Sahal drought in the mid-1980s, Somalia in the early 1990s, or perhaps the global response to one of the handful of other catastrophic disasters from the past few decades. As discussed later in this chapter, these well-known events are extreme outliers and in many ways are more misleading than helpful. However, what is more curious is the simple fact that even though disaster aid events are at the top of everyone’s awareness, the substantial U.S. program devoted to providing humanitarian assistance to the victims of foreign disasters is almost always overlooked in the discussion or the empirical study of U.S. foreign aid.