Non-adherence to ivabradine and placebo and outcomes in chronic heart failure: an analysis from SHIFT

Aims In heart failure, non-adherence increases events; in turn, the effect of hospitalization on adherence is incompletely understood. We explored the relationship of non-adherence to outcomes, hospitalizations with non-adherence, and the influence of non-adherence on treatment effects of heart rate lowering with ivabradine. Methods and results In the randomized, controlled Systolic Heart failure treatment with the If-inhibitor ivabradine Trial (SHIFT), we studied the effect of non-adherence (n = 1287) compared with adherence (n = 5204) on cardiovascular outcomes. After adjustment, non-adherence was associated with the primary composite endpoint of cardiovascular death and heart failure hospitalization (hazard ratio 3.47, 95% confidence interval 2.91–4.13, P < 0.0001). No interaction with the treatment groups of placebo or ivabradine (P for interaction 0.54) occurred. Similar results for cardiovascular death and heart failure hospitalization, as well as for cardiovascular hospitalization, heart failure death, and total death were observed. The effect of ivabradine was maintained in patients being adherent or becoming non-adherent during the trial (P for interaction = 0.54). Patients with a previous hospitalization were more likely to become non-adherent thereafter. Conclusions Non-adherence identifies a group at particularly high cardiovascular event risk independent of treatment allocation. Non-adherent patients in the ivabradine group maintain a treatment benefit. Patients with previous hospitalizations are more likely to become non-adherent and represent a group of particularly high-risk patients in whom special attention to stimulate adherence may be valuable

The collaborative and contested interplay between business and civil society in circular economy transitions

Copyright © 2022 The Authors. We know from the corporate social responsibility (CSR) literature that civil society organizations (CSOs) play a crucial role in helping businesses transition towards more responsible and sustainable business models. Yet, in the circular economy (CE) field, such understanding is still scarce. This article develops a theoretical framework for understanding the dynamic interplay between business and civil society in CE transitions, understanding their mechanisms and strategies for cooperation and contestation. We develop the concept of ‘CE boundary work’ to understand how CSOs interact with firms to bring about CE innovation, outlining three ideal types: campaign based, resource efficiency based and circular design based. This contributes to our understanding of how CE transitions can be brought about effectively through cross-sectoral interplays between civil society and business

Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.

Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre(+) heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre(+) transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre(+) recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination

The Molecular Condensations Ahead of Herbig-Haro Objects. I. Multi-transition Observations of HH 2

We present a CSO and BIMA molecular line survey of the dense, quiescent molecular environment ahead of HH2. The molecular gas is cold, 13 K, and moderately dense, 3x10^5 cm^-3. A total of 14 species has been detected (including different isotopes and deuterated species). The relative abundances of the clump are compared with other dense molecular environments, including quiescent dark clouds, and active low and high mass star forming regions. This comparison confirms the peculiar chemical composition of the quiescent gas irradiated by the HH objects. Thus, from this comparison, we found that the HCO+, CH3OH and H2CO are strongly enhanced. SO and SO2 are weakly enhanced, whereas HCN and CS are underabundant. The CN abundance is within the range of value found in starless dark clouds, but it is low with respect to high mass star forming regions. Finally, the chemical composition of HH2 confirms the qualitative results of the Viti & Williams (1999) complex chemical model that follows the chemical behavior of a molecular clump irradiated by a HH object.Comment: 12 pages, 7 figures, to be published in Astronomy & Astrophysic

Temporal and Spatial Profiling of Root Growth Revealed Novel Response of Maize Roots under Various Nitrogen Supplies in the Field

A challenge for Chinese agriculture is to limit the overapplication of nitrogen (N) without reducing grain yield. Roots take up N and participate in N assimilation, facilitating dry matter accumulation in grains. However, little is known about how the root system in soil profile responds to various N supplies. In the present study, N uptake, temporal and spatial distributions of maize roots, and soil mineral N (Nmin) were thoroughly studied under field conditions in three consecutive years. The results showed that in spite of transient stimulation of growth of early initiated nodal roots, N deficiency completely suppressed growth of the later-initiated nodal roots and accelerated root death, causing an early decrease in the total root length at the rapid vegetative growth stage of maize plants. Early N excess, deficiency, or delayed N topdressing reduced plant N content, resulting in a significant decrease in dry matter accumulation and grain yield. Notably, N overapplication led to N leaching that stimulated root growth in the 40–50 cm soil layer. It was concluded that the temporal and spatial growth patterns of maize roots were controlled by shoot growth and local soil Nmin, respectively. Improving N management involves not only controlling the total amount of chemical N fertilizer applied, but also synchronizing crop N demand and soil N supply by split N applications

Dissection of QTL effects for root traits using a chromosome arm-specific mapping population in bread wheat

A high-resolution chromosome arm-specific mapping population was used in an attempt to locate/detect gene(s)/QTL for different root traits on the short arm of rye chromosome 1 (1RS) in bread wheat. This population consisted of induced homoeologous recombinants of 1RS with 1BS, each originating from a different crossover event and distinct from all other recombinants in the proportions of rye and wheat chromatin present. It provides a simple and powerful approach to detect even small QTL effects using fewer progeny. A promising empirical Bayes method was applied to estimate additive and epistatic effects for all possible marker pairs simultaneously in a single model. This method has an advantage for QTL analysis in minimizing the error variance and detecting interaction effects between loci with no main effect. A total of 15 QTL effects, 6 additive and 9 epistatic, were detected for different traits of root length and root weight in 1RS wheat. Epistatic interactions were further partitioned into inter-genomic (wheat and rye alleles) and intra-genomic (rye–rye or wheat–wheat alleles) interactions affecting various root traits. Four common regions were identified involving all the QTL for root traits. Two regions carried QTL for almost all the root traits and were responsible for all the epistatic interactions. Evidence for inter-genomic interactions is provided. Comparison of mean values supported the QTL detection

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article

Mechanisms of Autoantibody-Induced Pathology

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein