We report direct-detection constraints on light dark matter particles interacting with electrons. The results are based on a method that exploits the extremely low levels of leakage current of the ...DAMIC detector at SNOLAB of 2–6×10−22 A cm−2. We evaluate the charge distribution of pixels that collect <10e− for contributions beyond the leakage current that may be attributed to dark matter interactions. Constraints are placed on so-far unexplored parameter space for dark matter masses between 0.6 and 100 MeV c−2. We also present new constraints on hidden-photon dark matter with masses in the range 1.2–30 eV c−2.
Summary Background Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate ...reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. Methods Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7·5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. Findings 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22·9 (IQR 18–28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0·82, 95% CI 0·75–0·90, p<0·0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 21% placebo vs 514 16% ivabradine; HR 0·74, 0·66–0·83; p<0·0001) and deaths due to heart failure (151 5% vs 113 3%; HR 0·74, 0·58–0·94, p=0·014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0·025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0·0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0·0001). Interpretation Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. Funding Servier, France.
The circular economy (CE) aims to radically improve resource efficiency by eliminating the concept of waste and leading to a shift away from the linear take-make-waste model. In a CE, resources are ...flowing in a circular manner either in a biocycle (biomass) or technocycle (inorganic materials). While early studies indicate that 3D printing (3DP) holds substantial promise for sustainability and the creation of a CE, there is no guarantee that it will do so. There is great uncertainty regarding whether the current trajectory of 3DP adoption is creating more circular material flows or if it is leading to an alternative scenario in which less eco-efficient localised production, demands for customised goods, and a higher rate of product obsolescence combine to bring about increased resource consumption. It is critical that CE principles are embedded into the new manufacturing system before the adoption of 3DP reaches a critical inflection point in which negative practices become entrenched. This paper, authored by both academic and industry experts, proposes a research agenda to determine enablers and barriers for 3DP to achieve a CE. We explore the two following overarching questions to discover what specific issues they entail: (1) How can a more distributed manufacturing system based on 3DP create a circular economy of closed-loop material flows? (2) What are the barriers to a circular 3D printing economy? We specifically examine six areas—design, supply chains, information flows, entrepreneurship, business models and education—with the aim of formulating a research agenda to enable 3DP to reach its full potential for a CE.
•Circular economy (CE) principles need to be embedded into new manufacturing system.•3D Printing (3DP) holds the potential to enable the shift towards a CE.•We propose a research agenda to explore the role and impact of 3DP in a CE.•A collection of research questions in six key areas was identified.
Site-selective dihalogenated heteroarene cross-coupling with organometallic reagents usually occurs at the halogen proximal to the heteroatom, enabled by intrinsic relative electrophilicity, ...particularly in strongly polarized systems. An archetypical example is the Suzuki–Miyaura cross-coupling (SMCC) of 2,4-dibromopyridine with organoboron species, which typically exhibit C2-arylation site-selectivity using mononuclear Pd (pre)catalysts. Given that Pd speciation, particularly aggregation, is known to lead to the formation of catalytically competent multinuclear Pd n species, the influence of these species on cross-coupling site-selectivity remains largely unknown. Herein, we disclose that multinuclear Pd species, in the form of Pd3-type clusters and nanoparticles, switch arylation site-selectivity from C2 to C4, in 2,4-dibromopyridine cross-couplings with both organoboronic acids (SMCC reactions) and Grignard reagents (Kumada-type reactions). The Pd/ligand ratio and the presence of suitable stabilizing salts were found to be critically important in switching the site-selectivity. More generally, this study provides experimental evidence that aggregated Pd catalyst species not only are catalytically competent but also alter reaction outcomes through changes in product selectivity.
Third-harmonic scattering is a nonlinear optical process that involves the molecular second-hyperpolarizability, γ. This work presents a rigorous quantum electrodynamical analysis of the scattering ...process, involving a partially index-symmetric construction of the fourth-rank γ tensordispensing with the Kleinman symmetry condition. To account for stochastic molecular rotation in fluids, methods of isotropic averaging must be employed to relate the molecular properties to accessible experimental quantities such as depolarization ratio. A complete eighth-rank tensor rotational average yields results for observable third-harmonic scattering rates, cast as a function of the natural-invariant γ components, and the polarization geometry of the experiment. Decomposing the tensor γ into irreducible weights allows specific predictions to be made for each molecular point group, allowing greater discrimination between the results for different molecular symmetries.
Background and Purpose
Growing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti‐tumour activity, although ...whether iron chelators show activity against oesophageal cancer is not known.
Experimental Approach
The effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed.
Key Results
Deferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels.
Conclusions and Implications
The clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.
Linked Article
This article is commented on by Keeler and Brookes, pp. 1313–1315 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12093
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and ...well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
•We develop a systematic approach to measuring adaptation progress at a country level.•We test eight hypotheses about factors of adaptive capacity that may impact national adaptation.•Analysis ...produces key results relating five factors to adaptation outcomes.•Results suggest that GDP, population, and governance may be critical.
Our understanding of whether adaptive capacity on a national level is being translated into adaptation policies, programs, and projects is limited. Focusing on health adaptation in Annex I Parties to the UNFCCC, we examine whether statistically significant relationships exist between regulatory, institutional, financial, and normative aspects of national-level adaptive capacity and systematically measured adaptation. Specifically, we (i) quantify adaptation actions in Annex I nations, (ii) identify potential factors that might impact progress on adaptation and select measures for these factors, and (iii) calculate statistical relationships between factors and adaptation actions across countries. Statistically significant relationships are found between progress on adaptation and engagement in international environmental governance, national environmental governance, perception of corruption in the public sector, population size, and national wealth, as well as between responsiveness to health vulnerabilities, population size and national wealth. This analysis contributes two key early empirical findings to the growing literature concerning factors facilitating or constraining adaptation. While country size and wealth are necessary for driving higher levels of adaptation, they may be insufficient in the absence of policy commitments to environmental governance. Furthermore, governance and/or incentive frameworks for environmental governance at the national level may be an important indicator of the strength of national commitments to addressing health impacts of climate change.
Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate ...cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP.
Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP.
A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82–1.65); failure-free survival HR=0.51 (95% CI 0.39–0.67); progression-free survival HR=0.65 (95% CI 0.48–0.88); metastasis-free survival HR=0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR=1.02 (0.70–1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.
This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.
Clinicaltrials.gov: NCT00268476.
Abstract Purpose This study aimed to evaluate the impact on overall survival following palliative surgery to remove the primary lesion in unresectable metastatic small intestinal (SI-NET) and ...pancreatic neuroendocrine tumours (P-NET). Methods A systematic review of the literature and meta-analysis was performed. MEDLINE and Embase databases were searched to identify articles comparing patients undergoing palliative primary tumour resection without metastatectomy vs. no resection. Relevant articles were identified in accordance with PRISMA guidelines. The primary outcome was overall survival. Included studies were evaluated for heterogeneity and publication bias. Results 13 studies met the inclusion criteria, of which 6 presented data suitable for meta-analysis. No randomised controlled trials were identified. Analysis of pooled multivariate hazard ratios demonstrated significantly longer overall survival in patients undergoing resection of both P-NETs (HR 0.43; 95% CI: 0.34 - 0.57, p<0.001) and SI-NETs (HR 0.47; 95% CI: 0.35 - 0.55, p=0.007). The increase in median survival in patients treated surgically relative to non-surgically ranged from 14 to 46 months in P-NET, and 22 to 112 months in SI-NET. The number needed to treat in order that one additional patient was alive at five years, ranged from 3.0 to 4.2, and 1.7 to 7.7 respectively. Conclusions Meta-analysis demonstrates that palliative resection of primary SI-NETs and P-NETs in the setting of unresectable metastatic disease can increase survival. Although these results should be interpreted with caution due to potential selection and publication bias, the data supports consideration of surgery, particularly in patients with low tumour burdens and good functional status.
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