An increasing number of patients undergoing coronary stenting need lifelong anticoagulation and therefore require a triple therapy typically consisting of aspirin, clopidogrel, and a vitamin K antagonist. Triple therapy confers an elevated bleeding risk as compared with dual therapy; however, omission of either antiplatelet or anticoagulation therapy might increase the risk of stent thrombosis or thrombembolic events. Although guidelines recommend a duration of dual antiplatelet therapy of 6 to 12 months after drug-eluting stent (DES) implantation, the optimal duration of dual antiplatelet therapy in patients receiving oral anticoagulation is not known. We postulate that 6-week clopidogrel therapy after DES implantation as compared with 6-month therapy is associated with improved clinical outcomes in patients undergoing DES implantation receiving concomitant aspirin and vitamin K antagonists. The ISAR-TRIPLE is a randomized, open-label trial that examines the restriction of clopidogrel therapy from 6 months to 6 weeks after DES implantation in the setting of concomitant aspirin and oral anticoagulant. Patients are randomized in a 1:1 fashion to either 6-week or 6-month clopidogrel therapy. The primary end point is a composite of death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding. The secondary end point comprises ischemic and bleeding complications. According to sample size calculations, a total of 600 patients are required to be enrolled. Clinical follow-up is scheduled at 6 weeks and at 6 and 9 months after randomization. There is clinical equipoise regarding the optimal duration of triple therapy after DES implantation in patients who need vitamin K antagonist therapy. The ISAR-TRIPLE trial aims to test the hypothesis that a 6-week triple therapy compared with a 6-month triple therapy improves net clinical outcomes.
Background. The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Methods. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy. Results. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Conclusions. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day.
In recent years, socio-technical transitions literature has gained importance in addressing long-term, transformative change in various industries. In order to account for the inertia and path-dependency experienced in these sectors, the concept of the socio-technical regime has been formulated. Socio-technical regimes denote the paradigmatic core of a sector, which results from the co-evolution of institutions and technologies over time. Despite its widespread acceptance, the regime concept has repeatedly been criticized for lacking a clear operationalization. As a consequence, empirical applications tend to depict regimes as too ‘monolithic’ and ‘homogenous’, not adequately considering persistent institutional tensions and contradictions. These are however crucial for assessing transition dynamics. In this paper, we revisit two concepts from institutional theory that enable an explicit identification of socio-technical regimes and more generally a specification of the ‘semi-coherence’ of socio-technical systems. First, we will show that ‘levels of structuration’ can be conceptualized as degrees of institutionalization, thereby treating institutionalization as a variable with different effects on actors, the stability of the system and thus the potential for change. Secondly, we draw on the institutional logics approach to characterize the content of various structural elements present in a system and to trace conflicts and contradictions between them. We illustrate this approach with an empirical in-depth analysis of the transformation of the Australian urban water sector since the 1970ies.
This article explores how the relation between waste and electricity regimes changed in the Netherlands in a long-term perspective. The concept of socio-technical regime is used to investigate institutional, technological and social (network) changes. The conclusion is that the relationship changed from two regimes being separated into a much more symbiotic and integrated relationship through a multi-level and co-evolutionary process. The concept of ‘biomass’ has become a binding element in the relationship.
Both immediate and deferred switching from a PI/r-based to a DTG-based regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved lipid profiles. Abstract Background Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to a dolutegravir (DTG)-based regimen may improve lipid profile. Methods European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)-infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, -.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile. Clinical Trials Registration NCT02098837 and EudraCT: 2013-003704-39.
We propose joint spatial division and multiplexing (JSDM), an approach to multiuser MIMO downlink that exploits the structure of the correlation of the channel vectors in order to allow for a large number of antennas at the base station while requiring reduced-dimensional channel state information at the transmitter (CSIT). JSDM achieves significant savings both in the downlink training and in the CSIT uplink feedback, thus making the use of large antenna arrays at the base station potentially suitable also for frequency division duplexing (FDD) systems, for which uplink/downlink channel reciprocity cannot be exploited. In the proposed scheme, the multiuser MIMO downlink precoder is obtained by concatenating a prebeamforming matrix, which depends only on the channel second-order statistics, with a classical multiuser precoder, based on the instantaneous knowledge of the resulting reduced dimensional "effective" channel matrix. We prove a simple condition under which JSDM incurs no loss of optimality with respect to the full CSIT case. For linear uniformly spaced arrays, we show that such condition is approached in the large number of antennas limit. For this case, we use Szego's asymptotic theory of Toeplitz matrices to show that a DFT-based prebeamforming matrix is near-optimal, requiring only coarse information about the users angles of arrival and angular spread. Finally, we extend these ideas to the case of a 2-D base station antenna array, with 3-D beamforming, including multiple beams in the elevation angle direction. We provide guidelines for the prebeamforming optimization and calculate the system spectral efficiency under proportional fairness and max-min fairness criteria, showing extremely attractive performance. Our numerical results are obtained via asymptotic random matrix theory, avoiding lengthy Monte Carlo simulations and providing accurate results for realistic (finite) number of antennas and users.
Our aim is to understand the electronic and steric factors that determine the activity and selectivity of transition‐metal catalysts for cross‐coupling reactions. To this end, we have used the activation strain model to quantum‐chemically analyze the activity of catalyst complexes d 10 ‐M(L) n toward methane CH oxidative addition. We studied the effect of varying the metal center M along the nine d 10 metal centers of Groups 9, 10, and 11 (M=Co − , Rh − , Ir − , Ni, Pd, Pt, Cu + , Ag + , Au + ), and, for completeness, included variation from uncoordinated to mono‐ to bisligated systems ( n =0, 1, 2), for the ligands L=NH 3 , PH 3 , and CO. Three concepts emerge from our activation strain analyses: 1) bite‐angle flexibility, 2) d‐regime catalysts, and 3) s‐regime catalysts. These concepts reveal new ways of tuning a catalyst’s activity. Interestingly, the flexibility of a catalyst complex, that is, its ability to adopt a bent L‐M‐L geometry, is shown to be decisive for its activity, not the bite angle as such. Furthermore, the effect of ligands on the catalyst’s activity is totally different, sometimes even opposite, depending on the electronic regime (d or s) of the d 10 ‐M(L) n complex. Our findings therefore constitute new tools for a more rational design of catalysts. Ons doel is het begrijpen van de elektronische en sterische factoren die bepalend zijn voor de activiteit en selectiviteit van overgangsmetaalkatalysatoren voor koppelingsreacties. Hiervoor hebben wij, met behulp van het activeringsspanningsmodel, de activiteit van verschillende d 10 ‐M(L) n katalysatorcomplexen in de oxidatieve additie van de CH binding van methaan quantumchemisch geanalyseerd. Wij hebben de effecten bestudeerd van het variëren van het metaalcentrum M langs alle negen d 10 metaalcentra van groep 9, 10 en 11 (M=Co − , Rh − , Ir − , Ni, Pd, Pt, Cu + , Ag + , Au + ) voor zowel de ongecoördineerde metalen alsmede de enkel‐ en tweevoudig gecoördineerde complexen (n=0, 1, 2), met NH 3 , PH 3 en CO als liganden. Uit onze analyses komen drie concepten naar voren: 1) de ‘bite‐angle flexibiliteit′; 2) d‐regime katalysatoren; en 3) s‐regime katalysatoren. Deze concepten ontsluiten nieuwe wegen om de activiteit van katalysatoren nauwkeurig af te stellen. Een belangrijk nieuw inzicht is dat de activiteit van een katalysator niet zo zeer wordt bepaald door de waarde van de L‐M‐L hoek, maar vooral door het gemak waarmee deze hoek tijdens een reactie kan buigen. Tevens tonen onze analyses aan dat het effect van een ligand bepaald wordt door het elektronische regime (d of s) van het d 10 ‐M(L) n complex en, afhankelijk hiervan, zelfs volkomen kan omkeren. Onze vindingen vormen nieuwe gereedschappen voor het rationeler ontwerpen van katalysatoren. d or s regime? That is the question! A catalyst's orbital electronic regime (see illustration) and bite‐angle flexibility are proposed as unifying concepts that serve a more rational design of catalysts. They emerge from quantum‐chemical activation strain analyses of 72 different d 10 ‐M(L) n model catalyst mediated C H bond‐activation reactions.
Bark is a vital and very visible part of woody plants, yet only recently has bark characteristics started to be considered as key traits structuring communities and biomes. Bark thickness is very variable among woody plants, and I hypothesize that fire is a key factor selecting for a thick bark, and thus, at the global scale, a significant proportion of the variability in bark thickness is explained by the variability in fire regimes. Previous research has focused on the importance of bark thickness mainly in surface‐fire regimes; here I generalize this idea and present a conceptual framework to explain how the different drivers that affect fire intensity have shaped bark thickness, in conjunction with other plant traits. I first review methods used to study bark thickness and then provide examples of bark thickness patterns from a wide range of ecosystems subject to different fire regimes (understorey fires, grass‐fuelled surface fires, grass‐fuelled crown fires and infrequent fires). There are some fire regimes that select for thick barks, while some only in the base of the trunk (e.g. understorey fires), others select for a thick bark on the whole plant (e.g. grass‐fuelled crown fires). There are also fire regimes in which allocating resources to a thick bark is not adaptive (e.g. woody‐fulled crown fires). Fire regime can explain a large proportion of the variability of bark thickness at the global scale, and thus, this trait varies across ecosystems in a predictable manner; however, the current paucity of data limits a fully accurate analysis. Lay Summary