Strengthening rules-based order in the Asia-Pacific

This paper explores the opportunities for both Australia and Japan jointly to promote their shared interest in strengthening the rule of law in the Asia–Pacific. Overview The rule of law is an essential condition if cooperation and orderly behaviour are to be advanced in the Asia–Pacific. We need norms and rules that guide—and govern—relations among regional states. Australia and Japan share an interest in minimising the role that coercion plays in the Asia–Pacific and maximising cooperation across the region. We’re both liberal democracies, with a strong bilateral security relationship, an alliance with the United States and a genuine commitment to the rule of law. All Asia–Pacific states would profit by following Australia and Japan’s example in promoting and abiding by the rule of law in their external policies. Indeed, our region would be a much safer place if they did. ASPI has this year worked on a project to explore the opportunities for both Australia and Japan jointly to promote our shared interest in strengthening the rule of law in the Asia–Pacific. This report sets out the project’s key findings and outlines policy proposals to enhance Australia–Japan cooperation to bolster the rule of law in the region

Shared political responsibiilty

This chapter explores the nature of political responsibilty in relation to climate change. It argues that rather than identify specific agents responsible for climate change - an approach that dominates legal and moral theory - a political responsibility framework provides ways of thinking about global dilemmas in terms of political actions that we may undertake together. It draws on the theoretical notion of 'shared responsibility' to develop this concept.Publisher PD

Thomas Hobbes: theorist of the law

This short article introduces the papers that follow on the topic of Hobbes as a theorist of the law. It provides an overview of Hobbes reputation as a theorist of law in both domestic and international theory. The paper summarizes the papers that follow and suggest how they fit into the wider literature on Hobbes, legal theory, and constitutional theory.PostprintPeer reviewe

Thomas Hobbes and a chastened 'global' constitution the contested boundaries of the law

Hobbes’ account of politics, law and obligation has long been read, especially by realists in international affairs, as leaving no space for international law or institutions. This paper argues that a more nuanced reading of Hobbes’ ideas about law and politics provides support for not only a defence of international law but a defence of a (chastened) global constitution. Hobbes’ constitutionalism does not derive from a separation or balance of powers but on two other elements of constitutionalism: the importance of the individual and the centrality of law. The paper proceeds as follows: The first section locates Hobbes theory of law in relation to his theory of authority, drawing on David Dyzenhaus’s emphasis on the rule of law in Hobbes. The second section draws on theorists such as Larry May to find a defence of international law and institutions, what I call international constitutionalism. The third section turns to Richard Flathman’s interpretation of Hobbes as a theorist of liberal self-making, suggesting how his insights can be applied globally. The conclusion brings these thoughts to bear on the relevance of Hobbes for global law and politics.PostprintPeer reviewe

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)

Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.

PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches

Characterization of hepatic enzyme activity in older adults with dementia: potential impact on personalizing pharmacotherapy

OBJECTIVE: To determine the frequency of pharmacogenomic variants and concurrent medications that may alter the efficacy and tolerability of acetylcholinesterase inhibitors (AChEIs). MATERIALS AND METHODS: A multisite cross-sectional study was carried out across four memory care practices in the greater Indianapolis area. Participants were adults aged 65 years and older with a diagnosis of probable or possible Alzheimer's disease (AD) (n=105). Blood samples and self-reported medication data were collected. Since two of the three AChEIs are metabolized by cytochrome P450 (CYP)-2D6, we determined the frequency of functional genetic variants in the CYP2D6 gene and calculated their predicted CYP2D6-activity scores. Concurrent medication data were collected from self-reported medication surveys, and their predicted effect on the pharmacokinetics of AChEIs was determined based on their known effects on CYP2D6 and CYP3A4/5 enzyme activities. RESULTS: Among the 105 subjects enrolled, 72% were female and 36% were African American. Subjects had a mean age of 79.6 years. The population used a mean of eight medications per day (prescription and nonprescription). The CYP2D6 activity score frequencies were 0 (3.8%), 0.5 (4.8%), 1.0 (36.2%), 1.5-2.0 (51.4%), and >2.0 (3.8%). Nineteen subjects (18.1%) used a medication considered a strong or moderate inhibitor of CYP2D6, and eight subjects (7.6%) used a medication considered a strong or moderate inhibitor of CYP3A4/5. In total, 28.6% of the study population was predicted to have reduced activity of the CYP2D6 or CYP3A4/5 enzymes due to either genetic variants or concomitant medications. CONCLUSION: Both pharmacogenetic variants and concurrent drug therapies that are predicted to alter the pharmacokinetics of AChEIs should be evaluated in older adults with AD. Pharmacogenetic and drug-interaction data may help personalize AD therapy and increase adherence by improving tolerability

Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson's disease.

PurposeCardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation.MethodsShort-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls.ResultsBeat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls.ConclusionsIncreased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD

Regulation and regeneration :how do development plans affect urban regeneration? a case study analysis of two Urban Development Corporations and the emerging Unitary Development Plans of their component local authorities

PhD ThesisUrban Development Corporations (UDCs) are perhaps the most outstanding examples of government action in the field of urban regeneration in the last twenty years. In order to promote regeneration UDCs were given development control powers over Urban Development Areas (UDAs). These powers were taken from local government and this caused well-documented resentment in many cases. However, local government retained all development plan-making powers. Following two town planning acts (in 1990 and 1991) central government gave the development plan more power in the development control process (through Section 54A). This created a situation in an UDA where, in relation to development control, the UDC had to have regard to a development plan that had been written by a local authority; often a local authority with which it had not seen eye to eye in planning matters. Thus there was a potential for conflict between an UDC and a local authority in both strategic and specific planning issues. There was possible tension between regulation (the development plan) and regeneration (the strategy and aims of the UDC). Most local authorities in urban areas were replacing old style development plans with new Unitary Development Plans which further complicated the issue. It became vitally important for UDCs to have an input to these emerging plans that the local authorities were preparing, in order to ensure that their aims and objectives for the UDAs would not be hindered by the new UDPs, which were to play a greater role in the development control process. This research firstly examines the concept of both the development plan and urban regeneration. It then presents the important links between the two in relation to the experience of UDCs. A series of questions are generated through the literature review which are answered in the final part of the work. Using these theoretical and practical standpoints as a basis, a conceptual framework for the study of the UDP preparation process, content and relationship between the local authorities and the UDCs with regard to the emerging plans is produced. It is formulated through theoretical study of literature concerning policy analysis and organisational relationships. In order to examine what occurred in the real world, this framework is then applied two case study areas - Tyne / Wear and London Docklands. Each area had a designated UDC over parts of composite unitary local authorities. The respective UDAs spread across a total of seven local authorities. The conceptual framework for this study was applied to the situation between the UDC and each of the seven local authorities in order to examine differences in working practices, differences in policy process and content, and differences in the relationships between the two organisations. UDCs were finally wound up in April 1998, and in the current climate it is unlikely that urban regeneration will ever be promoted in such a way again. However there are many important lessons to be learnt from the experience of UDCs and the development planning system. These are particularly pertinent to existing urban regeneration authorities such as English Partnerships and also to any possible citywide or regional development agencies. This study presents the range of practices that were evident in the case studies and examines what structured them. It concludes by outlining the most appropriate and relevant methods that were employed and making suggestions for better working practices in the future