Jesse Prinz presents a bravura argument for highly controversial claims about morality, which go to the heart of our understanding of ourselves. He argues that moral values are based on emotional ...responses, and that these are inculcated by culture, not hard-wired through natural selection. These two claims support a form of moral relativism.
The ultimate goal of our public health system is to reduce the incidence of disability and premature death. Evidence suggests that, by this standard, the USA falls behind most other developed ...countries largely as a function of disparities in health outcomes among significant portions of the US population. We present a framework for addressing these disparities that attributes them, not simply to differences in the behavioral and physical risk factors, but to social, environmental, and structural inequities such as poverty, discrimination, toxic physical setting, and the marketing of harmful products. These inequities result from de facto and instituted public policies. An analysis of the NIH research portfolio indicates a relative lack of investment in experimental evaluations of preventive interventions—especially studies targeting disadvantaged populations. Moreover, experimental research on reducing social inequities is almost entirely lacking. A line of research focusing on the drivers of inequities and their dissolution must include experimental evaluation of strategies for getting policies adopted that will reduce inequities. In conclusion, a summary is provided of the types of research that are needed and the challenges involved in conducting the experimental research that is essential for reducing inequities and disparities and, in turn, prolonging life.
DNA origami nanostructures are a versatile tool to arrange metal nanostructures and other chemical entities with nanometer precision. In this way gold nanoparticle dimers with defined distance can be ...constructed, which can be exploited as novel substrates for surface enhanced Raman scattering (SERS). We have optimized the size, composition and arrangement of Au/Ag nanoparticles to create intense SERS hot spots, with Raman enhancement up to 10(10), which is sufficient to detect single molecules by Raman scattering. This is demonstrated using single dye molecules (TAMRA and Cy3) placed into the center of the nanoparticle dimers. In conjunction with the DNA origami nanostructures novel SERS substrates are created, which can in the future be applied to the SERS analysis of more complex biomolecular targets, whose position and conformation within the SERS hot spot can be precisely controlled.
Summary
Background
Secukinumab, a fully human anti‐interleukin‐17A monoclonal antibody, demonstrated efficacy and safety in moderate‐to‐severe plaque psoriasis when administered via subcutaneous ...injection. Self‐administration by pre‐filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience.
Objectives
To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate‐to‐severe plaque psoriasis.
Materials and methods
Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co‐primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard‐free self‐injection and subject rating of acceptability by the Self‐Injection Assessment Questionnaire (SIAQ).
Results
Co‐primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self‐administered treatment at week 1, and subjects reported high SIAQ‐assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed.
Conclusions
Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Secukinumab is a fully human antibody targeting interleukin‐17A.
What does this study add?
Use of the secukinumab PFS was associated with high usability as determined by successful, hazard‐free, subject‐accepted self‐injection.
Self‐administration of secukinumab via PFS allows the delivery of its clinical benefits with improved convenience in disease management.
This phase 3 study in moderate‐to‐severe plaque psoriasis showed that secukinumab administration via pre‐filled syringe (PFS) demonstrated significant clinical efficacy vs. placebo, with an acceptable safety profile.
To what extent do aesthetic taste and our interest in the arts constitute who we are? In this paper, we present a series of empirical findings that suggest an
supporting the claim that our aesthetic ...engagements are a central component of our identity. Counterfactual changes in aesthetic preferences, for example, moving from liking classical music to liking pop, are perceived as altering us as a person. The Aesthetic Self Effect is as strong as the impact of moral changes, such as altering political partisanship or religious orientation, and significantly stronger than for other categories of taste, such as food preferences (Study 1). Using a multidimensional scaling technique to map perceived aesthetic similarities among musical genres, we determined that aesthetic distances between genres correlate highly with the perceived difference in identity (Study 2). Further studies generalize the Aesthetic Self Effect beyond the musical domain: general changes in visual art preferences, for example from more traditional to abstract art, also elicited a strong Self Effect (Study 3). Exploring the breadth of this effect we also found an
That is, hypothetical changes from aesthetic indifference to caring about music, art, or beauty are judged to have a significant impact on identity. This effect on identity is stronger for aesthetic fields compared to leisure activities, such as hiking or playing video games (Study 4). Across our studies, the Anaesthetic Self Effect turns out to be stronger than the Aesthetic Self Effect. Taken together, we found evidence for a link between aesthetics and identity: we are aesthetic selves. When our tastes in music and the arts or our aesthetic interests change we take these to be transformative changes.
This review examines the potential roles of parental self-efficacy (PSE) in parent and child adjustment and the role of parental cognitions in understanding behaviors and emotions within families. ...The areas in this review include parental competence and psychological functioning, as well as child behaviors, socio-emotional adjustment, school achievement, and maltreatment. There is strong evidence linking PSE to parental competence, and more modest linkage to parental psychological functioning. Some findings suggest that PSE impacts child adjustment directly but also indirectly via parenting practices and behaviors. Although the role of PSE likely varies across parents, children, and cultural–contextual factors, its influence cannot be overlooked as a possible predictor of parental competence and child functioning, or perhaps an indicator of risk. PSE may also be an appropriate target for prevention and intervention efforts. Limitations in the literature include measurement problems, variability in conceptualizations and definitions of the construct, and the lack of research exploring causality. Future research should focus on clarifying the measurement of PSE, studying potential bias in self-report of PSE, and utilizing experimental and longitudinal designs to untangle the issues of causal direction and potential transactional processes.
The prevention of child maltreatment necessitates a public health approach. In the U.S. Triple P System Population Trial, 18 counties were randomly assigned to either dissemination of the Triple ...P—Positive Parenting Program system or to the services-as-usual control condition. Dissemination involved Triple P professional training for the existing workforce (over 600 service providers), as well as universal media and communication strategies. Large effect sizes were found for three independently derived population indicators: substantiated child maltreatment, child out-of-home placements, and child maltreatment injuries. This study is the first to randomize geographical areas and show preventive impact on child maltreatment at a population level using evidence-based parenting interventions.
Summary
Background
Evaluation of the dosing flexibility and long‐term efficacy of biological agents is limited.
Objectives
To evaluate the long‐term efficacy and safety of ustekinumab with and ...without dosing adjustment in the 5‐year PHOENIX 2 study.
Methods
Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed‐over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long‐term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively.
Results
In the overall population, 70% (849 of 1212) of ustekinumab‐treated patients completed treatment through week 244, with high proportions of patients responding to the 45‐mg and 90‐mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment.
Conclusions
Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.
What's already known about this topic?
Data regarding dosing adjustment from PHOENIX 1 are limited. Protocol‐defined dose‐interval adjustment was permitted only early in the study based on clinical response.
What does this study add?
PHOENIX 2 evaluated both protocol‐defined and investigator‐initiated dose and/or dose‐interval adjustment.
Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify the actual incremental benefits.
Some patients may desire treatment goals beyond 75% improvement in Psoriasis Area and Severity Index.
Summary
Background
Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA‐B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 ...receptor (IL23R)/IL12R are genetic risk factors. IL‐23 regulates IL‐17A, which controls the recruitment and activation of neutrophils.
Objectives
To determine pathological changes in BD skin lesions related to the complex genetic predisposition.
Methods
We characterized the expression of IL‐17A and IL‐23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA‐class I‐associated T‐cell‐mediated autoimmune disease in which excessive T‐cell‐derived IL‐17A production promotes neutrophil activation.
Results
We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL‐17A. IL‐17A+ CD8+ T (Tc17) cells outnumbered infiltrating IL‐17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co‐localised with a marked IL‐23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL‐17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs).
Conclusions
In BD, the genetic predisposition may mediate antigen‐specific activation and differentiation of a Tc17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL‐17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL‐23/IL‐17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen‐specific CD8+ T‐cell response.
What is already known about this topic?
Behçet disease (BD) is a systemic vasculitis of unknown aetiology.
HLA‐B*51 and the endoplasmic reticulum aminopeptidase 1 (ERAP1), which cooperate in antigen processing and presentation to CD8+ T cells, and interleukin 23 receptor (IL23R)/IL12R are the main risk genes.
IL‐17A is thought as a key cytokine in BD, which is produced under the control of IL‐23 and activates neutrophils.
What does this study add?
As a clinical correlate of the risk association with HLA‐B*51, ERAP1, and IL23R/IL12R, activated CD8+ T cells in the acute papulopustular skin lesions of BD massively express IL‐17A under the control of IL‐23A, which is expressed mainly by CD11c+ dendritic cells with a histiocytic morphology.
Lymphocytic vasculitis by IL‐17A+ CD8+ T (Tc17) cells in BD presumably mediates neutrophil recruitment and prominent neutrophil extracellular trap (NET) release.
These data reveal that, as in psoriasis, potentially autoreactive CD8+ T cells with marked IL‐17A production play an important pathogenic role in BD.
What is the translational message?
The results may link three major BD risk genes in a pathogenic concept, in which HLA‐B*51‐restricted endoplasmic reticulum aminopeptidase 1‐dependent antigens activate a CD8+ T‐cell response whose IL‐17A production is enhanced by an IL‐23R risk variant, leading to neutrophil recruitment and NET formation (NETosis).
These findings may inspire therapeutic interventions targeting the IL‐17/IL‐23 axis or NETosis to resolve or suppress attacks of BD.
An IL‐23‐driven Tc17 response dominates in skin lesions of Behcet’s disease.
Plain language summary available online
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