A Current Induced Transition in atomic-sized contacts of metallic Alloys

We have measured conductance histograms of atomic point contacts made from the noble-transition metal alloys CuNi, AgPd, and AuPt for a concentration ratio of 1:1. For all alloys these histograms at low bias voltage (below 300 mV) resemble those of the noble metals whereas at high bias (above 300 mV) they resemble those of the transition metals. We interpret this effect as a change in the composition of the point contact with bias voltage. We discuss possible explanations in terms of electromigration and differential diffusion induced by current heating.Comment: 5 pages, 6 figure

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers

Background In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival beneft of BRRM over BC surveillance has been reported yet. Methods In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specifc mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20–0.90) for overall mortality and 0.06 (95% CI 0.01–0.46) for BC-specifc mortality. BC-specifc survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15–1.36). BC-specifc survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specifc survival as surveillance. Our fndings support a more individualized counseling based on BRCA mutation type

Long-term morbidity and health after early menopause due to oophorectomy in women at increased risk of ovarian cancer: Protocol for a nationwide cross-sectional study with prospective follow-up (HARMOny Study)

Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO

Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Verifying elementary ITER maintenance actions with the MS2 benchmark product

A new facility has been taken in operation to investigate the influence of visual and haptic feedback on the performance of remotely executed ITER RH maintenance tasks. A reference set of representative ITER remote handling maintenance tasks was included the master slave manipulator system (MS2) benchmark product. The benchmark product was used in task performance tests in a representative two-handed dexterous manipulation test bed at NRG. In the setup, the quality of visual feedback was varied by exchanging direct view with indirect view setups in which visual feedback is provided via video cameras. Interaction forces were measured via an integrated force sensor. The impact of feedback quality on the performance of maintenance tasks at the level of handling individual parts was measured and analysed. Remote execution of the maintenance actions took roughly 3-5 times more time than hands-on. Visual feedback was identified as the dominant factor, including aspects like (lack of) operator control over camera placement, pan, tilt and zoom, lack of 3D perception, image quality, and latency. Haptic feedback was found to be important, but only in specific contact transition and constrained motion tasks. (C) 2011 Elsevier B.V. All rights reserved

How operator admittance affects the response of a teleoperation system to assistive forces – A model analytic study and simulation

Haptic shared control is a promising approach to increase the effectiveness of remote handling operations. While in haptic shared control the operator is continuously guided with assistive forces, the operator's response to forces is not fully understood. This study describes the development of a computational model of a human operator controlling a teleoperation system based on feedforward control. In a simulation, the operator's response to repulsive forces in free-space motions was modeled for two degrees of freedom, for two operator endpoint admittances (estimated by means of closed-loop identification techniques). The simulation results show that similar repulsive forces lead to substantial discrepancies in response when admittance settings mismatch; wrongly estimated operator admittances can lead to assistive forces that are either not perceived, or deflect the combined system of human operator and telemanipulator. It is concluded that assistive forces should be tailored to the arm configuration and the type of task performed. In order to utilize haptic shared control to its full potential, it is required to study, measure and quantitatively model operator behavior for teleoperated tasks in more detail

Interactive virtual mock-ups for Remote Handling compatibility assessment of heavy components

ITER standards Tesini (2009) require hardware mock-ups to validate the Remote Handling (RH) compatibility of RH class 1- and critical class 2-components. Full-scale mock-ups of large ITER components are expensive, have a long lead time and lose their relevance in case of design changes. Interactive Virtual Reality simulations with real time rigid body dynamics and contact interaction allow for RH Compatibility Assessment during the design iterations. This paper explores the use of interactive virtual mock-ups to analyze the RH compatibility of heavy component handling and maintenance. It infers generic maintenance operations from the analysis and proposes improvements to the simulator capabilities

Evaluating ITER remote handling middleware concepts

Remote maintenance activities in ITER will be performed by a unique set of hardware systems, supported by an extensive software kit. A layer of middleware will manage and control a complex set of interconnections between teams of operators, hardware devices in various operating theatres, and databases managing tool and task logistics. The middleware is driven by constraints on amounts and timing of data like real-time control loops, camera images, and database access. The Remote Handling Study Centre (RHSC), located at FOM institute DIFFER, has a 4-operator work cell in an ITER relevant RH Control Room setup which connects to a virtual hot cell back-end. The centre is developing and testing flexible integration of the Control Room components, resulting in proof-of-concept tests of this middleware layer. SW components studied include generic human-machine interface software, a prototype of a RH operations management system, and a distributed virtual reality system supporting multi-screen, multi-actor, and multiple independent views. Real-time rigid body dynamics and contact interaction simulation software supports simulation of structural deformation, “augmented reality” operations and operator training. The paper presents generic requirements and conceptual design of middleware components and Operations Management System in the context of a RH Control Room work cell. The simulation software is analyzed for real-time performance and it is argued that it is critical for middleware to have complete control over the physical network to be able to guarantee bandwidth and latency to the components

ITER Upper Port Plug handling cask system assessment and design proposals

The current design of the ITER cask for Upper Port Plugs has been evaluated. Careful reduction of the number of mechanical degrees of freedom is an opportunity to relax the tolerances in the design, resulting in cost reduction and reliability increase. A new kinematical design for the tractor module has a higher stiffness to weight ratio, reduces actuator forces by a factor four and minimizes cross-talk between lift and rotation motion. Non-cantilevered handling is recommended to reduce wheel loads on the tractor by a factor six and to simplify guidance. At the system level the tubular guide (TG) is proposed, a semipermanent 3.5 m long tube which is an extension of the Upper Port. Cask docking is simplified and the risk of the cask tilting is prevented. Redesigning the system concept is recommended and the TG looks promising. Since a system level redesign impacts the external interfaces, overall feasibility has to be investigated. (C) 2011 Elsevier B.V. All rights reserved