Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target

Cost-effectiveness of an insertable cardiac monitor in a high-risk population in the US

Background Insertable cardiac monitors (ICMs) are a clinically effective means of detecting atrial fibrillation (AF) in high-risk patients, and guiding the initiation of non-vitamin K oral anticoagulants (NOACs). Their cost-effectiveness from a US clinical payer perspective is not yet known. The objective of this study was to evaluate the cost-effectiveness of ICMs compared to standard of care (SoC) for detecting AF in patients at high risk of stroke (CHADS2 ≥ 2), in the US. Methods Using patient data from the REVEAL AF trial (n = 393, average CHADS2 score = 2.9), a Markov model estimated the lifetime costs and benefits of detecting AF with an ICM or with SoC (specifically intermittent use of electrocardiograms and 24-h Holter monitors). Ischemic and hemorrhagic strokes, intra- and extra-cranial hemorrhages, and minor bleeds were modelled. Diagnostic and device costs, costs of treating stroke and bleeding events and medical therapy—specifically costs of NOACs were included. Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3% per annum, in line with standard practice in the US setting. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results Lifetime per-patient cost for ICM was $31,116 versus$25,330 for SoC. ICMs generated a total of 7.75 QALYs versus 7.59 for SoC, with 34 fewer strokes projected per 1000 patients. The model estimates a number needed to treat of 29 per stroke avoided. The incremental cost-effectiveness ratio was $35,528 per QALY gained. ICMs were cost-effective in 75$50,000 per QALY threshold, and a 100% probability of being cost-effective at a WTP threshold of $150,000 per QALY. Conclusions The use of ICMs to identify AF in a high-risk population is likely to be cost-effective in the US healthcare setting

Attitudes and perceptions regarding entrepreneurship around the world : a cluster analysis approach

Nowadays it is believed that entrepreneurship could be a driving force in growth and development. For the achievement of a relevant national entrepreneurship rate the social and economic business environment can be crucial. However, despite the international attention given to entrepreneurship, it is not known if it is a global phenomenon or if there are particular regions where the entrepreneurial activity is specially recognized by society. Applying cluster analysis statistical techniques to a dataset gathered by the Global Entrepreneurship Monitor (GEM) and that includes, in 2010, 59 countries this paper intends to identify groups of countries with the same population attitude and perception regarding entrepreneurship

Death of the high street: identification, prevention, reinvention

Location is of paramount importance within the retail sector, yet defining locational obsolescence remains overlooked, despite significant concerns over the viability of parts of the complex sector. This paper reviews the existing literature and, through this, explores retail locational obsolescence, including the multi-spatial nature of the driving forces that range from the global economy, local markets and submarkets, to individual property-specific factors; and, crucially, the need to disentangle locational obsolescence from other important concepts such as depreciation and functional obsolescence that are often mistakenly used. Through this, a conceptual model, definition and diagnostic criteria are presented to guide future studies, policy development and the allocation of resources. Importantly, three stages are presented to enable the operationalization of the model, essential to future academic and industry studies as well as the ongoing development of policy in this economically important, complex and contentious area

Attitudes and perceptions regarding entrepreneurship around the world : a cluster analysis approach

Nowadays it is believed that entrepreneurship could be a driving force in growth and develop-ment. For the achievement of a relevant national entrepreneurship rate the social and economic business environment can be crucial. However, despite the international attention given to entrepreneurship, it is not known if it is a global phenomenon or if there are particular regions where the entrepreneurial activity is specially recognized by society. Applying cluster analysis statistical techniques to a dataset gathered by the Global Entrepreneurship Monitor (GEM) and that includes, in 2010, 59 countries this paper intends to identify groups of countries with the same population attitude and perception regarding entrepreneurship

High Tumour Cannabinoid CB1 Receptor Immunoreactivity Negatively Impacts Disease-Specific Survival in Stage II Microsatellite Stable Colorectal Cancer

BACKGROUND: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. METHODOLOGY/PRINCIPAL FINDINGS: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB(1)IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB(1)IR<2 and CB(1)IR≥2 groups, respectively. CONCLUSIONS/SIGNIFICANCE: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients

Reversible Disruption of Pre-Pulse Inhibition in Hypomorphic-Inducible and Reversible CB1-/- Mice

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout (-/-) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1-/- mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1-/-) only in absence of doxycycline (Dox). In such mice, under Dox+ or vehicle, as well as in wild-type (WT) and CB1-/-, two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1-/- and IRh-CB1-/- showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1-/- animals, was on the contrary highly and significantly disrupted only in Dox+ IRh-CB1-/- mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1-/- mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1-/- mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders

An ordinal game theory approach to the analysis and selection of partners in public:Private partnership projects

Nowadays, public–private partnership projects have become a standard for delivering public services in both developed and developing countries. In this paper, we are concerned with the analysis of private sector proposals and the selection of the private sector partner to whom to award the contract. To the best of our knowledge, this problem has not been addressed within a game theory framework. To fill this gap, we model this decision problem as a static non-cooperative game of complete information and propose a new ordinal game theory algorithm for finding an optimal generalized Nash equilibrium. The proposed algorithm determines a single ranking of proposals or bidders that takes account of multiple performance criteria and reflects both the public sector and the private sector perspectives, and can handle any number of private sector players and any number of contractual terms. An illustrative scenario is provided to guide the reader through the workings of the proposed ordinal game theory algorithm. The proposed ordinal game theory-based analysis framework can be used by the private sector to analyse any set of potential proposals most likely to be submitted by bidders and to assist with the choice of bidding strategies, and by the public sector player to analyse any set of potential proposals most likely to be submitted under any set of contractual terms and to assist with the choice of a realistic set of contractual terms and their performance measures

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis