As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the ...central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.
Kynurenic acid has well‐established activity as an antagonist at glutamate receptors, especially the glutamate and glycine co‐agonist binding sites, with possibly relevant actions on Aryl Hydrocarbon Receptors and the GPR35 binding site. A single proposal that it also acts on acetylcholine nicotinic receptors is analysed and discussed in the light of at least 12 failures to reproduce the activity, and a wide range of pharmacological arguments. It is concluded that there is no confirmed, reliable evidence for any effect at nicotinic acetylcholine receptors.
Mobile health (mHealth) is often reputed to be cost-effective or cost-saving. Despite optimism, the strength of the evidence supporting this assertion has been limited. In this systematic review the ...body of evidence related to economic evaluations of mHealth interventions is assessed and summarized.
Seven electronic bibliographic databases, grey literature, and relevant references were searched. Eligibility criteria included original articles, comparison of costs and consequences of interventions (one categorized as a primary mHealth intervention or mHealth intervention as a component of other interventions), health and economic outcomes and published in English. Full economic evaluations were appraised using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist and The PRISMA guidelines were followed.
Searches identified 5902 results, of which 318 were examined at full text, and 39 were included in this review. The 39 studies spanned 19 countries, most of which were conducted in upper and upper-middle income countries (34, 87.2%). Primary mHealth interventions (35, 89.7%), behavior change communication type interventions (e.g., improve attendance rates, medication adherence) (27, 69.2%), and short messaging system (SMS) as the mHealth function (e.g., used to send reminders, information, provide support, conduct surveys or collect data) (22, 56.4%) were most frequent; the most frequent disease or condition focuses were outpatient clinic attendance, cardiovascular disease, and diabetes. The average percent of CHEERS checklist items reported was 79.6% (range 47.62-100, STD 14.18) and the top quartile reported 91.3-100%. In 29 studies (74.3%), researchers reported that the mHealth intervention was cost-effective, economically beneficial, or cost saving at base case.
Findings highlight a growing body of economic evidence for mHealth interventions. Although all studies included a comparison of intervention effectiveness of a health-related outcome and reported economic data, many did not report all recommended economic outcome items and were lacking in comprehensive analysis. The identified economic evaluations varied by disease or condition focus, economic outcome measurements, perspectives, and were distributed unevenly geographically, limiting formal meta-analysis. Further research is needed in low and low-middle income countries and to understand the impact of different mHealth types. Following established economic reporting guidelines will improve this body of research.
Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was ...viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations.
The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter.
This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.
•The kynurenine pathway controls several neurotransmitters directly and indirectly.•Kynurenines may be involved in the etiology of psychiatric and neurological disorders.•Targeting the kynurenine pathway with new specific agents may prevent disease.
Gastro-intestinal (GI) microbiota and the ‘gut-brain axis’ are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the ...influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for
N
-methyl-
d
-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.
Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor. Transcatheter mitral-valve repair may improve their clinical outcomes.
At ...78 sites in the United States and Canada, we enrolled patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up. The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 88.0%.
Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval CI, 0.40 to 0.70; P<0.001). The rate of freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001).
Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079 .).
Summary Background Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting ...bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose. Methods A total of 14 963 patients treated with DAPT after coronary stenting—largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation—were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12–24 months) or short (3–6 months) treatment in relation to baseline bleeding risk. Findings The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61–0·85) in the derivation cohort, and 0·70 (0·65–0·74) in the PLATO trial validation cohort and 0·66 (0·61–0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (pinteraction =0·007), and exerted a significant ischaemic benefit only in this latter group. Interpretation The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration. Funding None.
How is the United States able to control the IMF with only 17 per cent of the votes? How are the rules of the global economy made? This book shows how a combination of formal and informal rules ...explains how international organizations really work. Randall W. Stone argues that formal rules apply in ordinary times, while informal power allows leading states to exert control when the stakes are high. International organizations are therefore best understood as equilibrium outcomes that balance the power and interests of the leading state and the member countries. Presenting a new model of institutional design and comparing the IMF, WTO, and EU, Stone argues that institutional variations reflect the distribution of power and interests. He shows that US interests influence the size, terms, and enforcement of IMF programs, and new data, archival documents, and interviews reveal the shortcomings of IMF programs in Mexico, Russia, Korea, Indonesia, and Argentina.
There is a paucity of data on the burden of in-stent restenosis (ISR) in the United States as well as on its presentation and appropriate treatment strategies.
This study aims to provide an analysis ...of the temporal trends, clinical presentation, treatment strategies, and in-hospital outcomes of patients undergoing percutaneous coronary intervention (PCI) for ISR in the United States.
This study is a retrospective analysis of data collected in the Diagnostic Catheterization and Percutaneous Coronary Intervention (CathPCI) registry of the National Cardiovascular Data Registry (NCDR) between 2009 and 2017. Of the total patients undergoing PCI, we identified those undergoing PCI for ISR lesions. For comparison of in-hospital outcomes, propensity-score matching was employed.
Among the 5,100,394 patients undergoing PCI, 10.6% of patients underwent PCI for ISR lesions. Patients with bare-metal stent ISR declined from 2.6% in 2009 Q3 to 0.9% in 2017 Q2 (p < 0.001), and drug-eluting stent ISR rose from 5.4% in 2009 Q3 to 6.3% in 2017 Q2 (p < 0.001). Patients with ISR PCI were less likely to present with non–ST-segment elevation myocardial infarction (MI) (18.7% vs. 22.5%; p < 0.001) or ST-segment elevation MI (8.5% vs. 15.7%; p < 0.001). In the propensity-matched population of patients, there were no significant differences between patients with ISR and non-ISR PCI for in-hospital complications and hospital length of stay.
ISR represents approximately 10% of all PCI and is treated most commonly with another stent. Approximately 25% of patients present with acute MI. In-hospital outcomes of patients with ISR PCI are comparable with those undergoing non-ISR PCI.
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Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk ...(HBR) may be present, making it unclear whether short- or long-term DAPT should be prioritized.
This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting.
Complex PCI was defined as ≥3 stents implanted and/or ≥3 lesions treated, bifurcation stenting and/or stent length >60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥25) or non-high (<25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT.
Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: −3.86%; 95% confidence interval: −7.71 to +0.06) and noncomplex PCI strata (absolute risk difference: −1.14%; 95% confidence interval: −2.26 to −0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity.
Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT.
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The Scope of IMF Conditionality Stone, Randall W.
International organization,
10/2008, Letnik:
62, Številka:
4
Journal Article
Recenzirano
International organizations are governed by two parallel sets of rules: formal rules, which embody consensual procedures, and informal rules, which allow exceptional access for powerful countries. A ...new data set drawn from the IMF's records of conditionality provides an opportunity to study the bargaining process within an important international organization and answer questions about the institution's autonomy. I find evidence of U.S. influence, which operates to constrain conditionality, but only in important countries that are vulnerable enough to be willing to draw on their influence with the United States. In ordinary countries under ordinary circumstances, broad authority is delegated to the IMF, which adjusts conditionality to accommodate local circumstances and domestic political opposition. The IMF has refrained from exploiting the vulnerability of particular countries to maximize the scope of conditionality.
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