Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic ...progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined.
In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival.
A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval CI, 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group.
In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).
An estimated 5.7 million Americans suffer from Alzheimer's disease in the United States, with no disease-modifying treatments to prevent or treat cognitive deficits associated with the disease. ...Genome-wide association studies suggest that an enhancement of clearance mechanisms and/or promotion of an anti-inflammatory response may slow or prevent disease progression. Increasing awareness of distinct roles of complement components in normal brain development and function and in neurodegenerative disorders align with complement-mediated responses, and thus, thorough understanding of these molecular pathways is needed to facilitate successful therapeutic design. Both beneficial and detrimental effects of C1q as well as contributions to local inflammation by C5a-C5aR1 signaling in brain highlight the need for precision of therapeutic design. The potential benefit of β-amyloid clearance from the circulation via CR1-mediated mechanisms is also reviewed. Therapies that suppress inflammation while preserving protective effects of complement could be tested now to slow the progression of this debilitating disease.
Human health is dependent upon environmental health. Air pollution is a leading cause of morbidity and mortality globally, and climate change has been identified as the single greatest public health ...threat of the 21st century. As a large, resource-intensive sector of the Canadian economy, healthcare itself contributes to pollutant emissions, both directly from facility and vehicle emissions and indirectly through the purchase of emissions-intensive goods and services. Together these are termed life cycle emissions. Here, we estimate the extent of healthcare-associated life cycle emissions as well as the public health damages they cause.
We use a linked economic-environmental-epidemiological modeling framework to quantify pollutant emissions and their implications for public health, based on Canadian national healthcare expenditures over the period 2009-2015. Expenditures gathered by the Canadian Institute for Health Information (CIHI) are matched to sectors in a national environmentally extended input-output (EEIO) model to estimate emissions of greenhouse gases (GHGs) and >300 other pollutants. Damages to human health are then calculated using the IMPACT2002+ life cycle impact assessment model, considering uncertainty in the damage factors used. On a life cycle basis, Canada's healthcare system was responsible for 33 million tonnes of carbon dioxide equivalents (CO2e), or 4.6% of the national total, as well as >200,000 tonnes of other pollutants. We link these emissions to a median estimate of 23,000 disability-adjusted life years (DALYs) lost annually from direct exposures to hazardous pollutants and from environmental changes caused by pollution, with an uncertainty range of 4,500-610,000 DALYs lost annually. A limitation of this national-level study is the use of aggregated data and multiple modeling steps to link healthcare expenditures to emissions to health damages. While informative on a national level, the applicability of these findings to guide decision-making at individual institutions is limited. Uncertainties related to national economic and environmental accounts, model representativeness, and classification of healthcare expenditures are discussed.
Our results for GHG emissions corroborate similar estimates for the United Kingdom, Australia, and the United States, with emissions from hospitals and pharmaceuticals being the most significant expenditure categories. Non-GHG emissions are responsible for the majority of health damages, predominantly related to particulate matter (PM). This work can guide efforts by Canadian healthcare professionals toward more sustainable practices.
Perceptions of a firm's stance on corporate social responsibility (CSR) are influenced by its corporate marketing efforts including branding, reputation building, and communications. The current ...research examines CSR from the consumer's perspective, focusing on antecedents and consequences of perceived CSR. The findings strongly support the fact that particular cues, namely perceived financial performance and perceived quality of ethics statements, influence perceived CSR which in turn impacts perceptions of corporate reputation, consumer trust, and loyalty. Both consumer trust and loyalty were also found to reduce the perceived risk that consumers experience in buying and using products. From these significant findings, we draw several conclusions and implications, including the importance of enhancing firm focus toward its ethical commitment and long-term reputation.
•Institutional design cannot account for the operation of power and therefore cannot guarantee adaptation outcomes.•Adaptation outcomes are profoundly shaped by struggles for authority and ...recognition.•Reframing ‘adaptation’ to capture how power and politics shape adaptation needs.•Actors compete to control new development resources and bolster their authority in climate change adaptation programs.•Citizens seek recognition of their needs and entitlements from the government in adaptation programs.
Throughout the world, climate change adaptation policies supported by the United Nations Framework Convention on Climate Change (UNFCCC) have provided significant sources of funding and technical support to developing countries. Yet often the adaptation responses proposed belie complex political realities, particularly in politically unstable contexts, where power and politics shape adaptation outcomes. In this paper, the concepts of authority and recognition are used to capture power and politics as they play out in struggles over governing changing resources. The case study in Nepal shows how adaptation policy formation and implementation becomes a platform in which actors seek to claim authority and assert more generic rights as political and cultural citizens. Focusing on authority and recognition helps illuminate how resource governance struggles often have very little to do with the resources themselves. Foundational to the argument is how projects which seek to empower actors to manage their resources, produce realignments of power and knowledge that then shape who is invested in what manner in adaptation. The analysis adds to calls for reframing ‘adaptation’ to encompass the socionatural processes that shape vulnerability by contributing theoretical depth to questions of power and politics.
Recent evidence suggests that the hippocampus may integrate overlapping memories into relational representations, or schemas, that link indirectly related events and support flexible memory ...expression. Here we explored the nature of hippocampal neural population representations for multiple features of events and the locations and contexts in which they occurred. Hippocampal networks developed hierarchical organizations of associated elements of related but separately acquired memories within a context, and distinct organizations for memories where the contexts differentiated object-reward associations. These findings reveal neural mechanisms for the development and organization of relational representations.
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•Hippocampal ensembles form hierarchical representations of multiple task dimensions•Different features of events are represented successively•New information is encoded in extant networks that represent common information
The hippocampus has been implicated in interleaving related memories into memory networks, called schemas. McKenzie et al. report that hippocampal neural ensembles form hierarchical representations that link related events by common dimensions, and these neural schemas rapidly assimilate new memories.
DNA chromosomal DSBs (double-strand breaks) are potentially hazardous DNA lesions, and their accurate repair is essential for the successful maintenance and propagation of genetic information. Two ...major pathways have evolved to repair DSBs: HR (homologous recombination) and NHEJ (non-homologous end-joining). Depending on the context in which the break is encountered, HR and NHEJ may either compete or co-operate to fix DSBs in eukaryotic cells. Defects in either pathway are strongly associated with human disease, including immunodeficiency and cancer predisposition. Here we review the current knowledge of how NHEJ and HR are controlled in somatic mammalian cells, and discuss the role of the chromatin context in regulating each pathway. We also review evidence for both co-operation and competition between the two pathways.
•A managerial approach to adaptation belies its nature as a socio-political process.•Adaptation can constitute as well as contest, authority, subjectivity and knowledges.•These struggles can open up ...or close down space for transformational adaptation•Subjectivities inherent to problem understandings need to be questioned.•Focus is needed on multiple adaptation knowledges and emancipatory subjectivities
This paper is motivated by a concern that adaptation and vulnerability research suffer from an under-theorization of the political mechanisms of social change and the processes that serve to reproduce vulnerability over time and space. We argue that adaptation is a socio-political process that mediates how individuals and collectives deal with multiple and concurrent environmental and social changes. We propose that applying concepts of subjectivity, knowledges and authority to the analysis of adaptation focuses attention on this socio-political process. Drawing from vulnerability, adaptation, political ecology and social theory literatures, we explain how power is reproduced or contested in adaptation practice through these three concepts. We assert that climate change adaptation processes have the potential to constitute as well as contest authority, subjectivity and knowledge, thereby opening up or closing down space for transformational adaptation. We expand on this assertion through four key propositions about how adaptation processes can be understood and outline an emergent empirical research agenda, which aims to explicitly examine these propositions in specific social and environmental contexts. We describe how the articles in this special issue are contributing to this nascent research agenda, providing an empirical basis from which to theorize the politics of adaptation. The final section concludes by describing the need for a reframing of adaptation policy, practice and analysis to engage with multiple adaptation knowledges, to question subjectivities inherent in discourses and problem understandings, and to identify how emancipatory subjectivities – and thus the potential for transformational adaptation – can be supported.
The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent ...and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.
Recombination is proposed to be critical for coronavirus (CoV) diversity and emergence of SARS-CoV-2 and other zoonotic CoVs. While RNA recombination is required during normal CoV replication, the ...mechanisms and determinants of CoV recombination are not known. CoVs encode an RNA proofreading exoribonuclease (nsp14-ExoN) that is distinct from the CoV polymerase and is responsible for high-fidelity RNA synthesis, resistance to nucleoside analogues, immune evasion, and virulence. Here, we demonstrate that CoVs, including SARS-CoV-2, MERS-CoV, and the model CoV murine hepatitis virus (MHV), generate extensive and diverse recombination products during replication in culture. We show that the MHV nsp14-ExoN is required for native recombination, and that inactivation of ExoN results in decreased recombination frequency and altered recombination products. These results add yet another critical function to nsp14-ExoN, highlight the uniqueness of the evolved coronavirus replicase, and further emphasize nsp14-ExoN as a central, completely conserved, and vulnerable target for inhibitors and attenuation of SARS-CoV-2 and future emerging zoonotic CoVs.
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