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- Lumbers, R. T., et al.
(author)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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In: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Journal article (peer-reviewed)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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- Roselli, Carolina, et al.
(author)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Journal article (peer-reviewed)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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- Legius, E., et al.
(author)
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Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation
- 2021
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 23, s. 1506-1513
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Journal article (peer-reviewed)abstract
- Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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- Ashizawa, T., et al.
(author)
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Consensus-based care recommendations for adults with myotonic dystrophy type 1
- 2018
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In: Neurology-Clinical Practice. - : Ovid Technologies (Wolters Kluwer Health). - 2163-0402 .- 2163-0933. ; 8:6, s. 507-520
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Research review (peer-reviewed)abstract
- Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
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- Dickie, B., et al.
(author)
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A community-endorsed open-source lexicon for contrast agent-based perfusion MRI: A consensus guidelines report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI)
- 2024
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In: Magnetic Resonance in Medicine. - 0740-3194. ; 91:5, s. 1761-1773
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Journal article (peer-reviewed)abstract
- This manuscript describes the ISMRM OSIPI (Open Science Initiative for Perfusion Imaging) lexicon for dynamic contrast-enhanced and dynamic susceptibility-contrast MRI. The lexicon was developed by Taskforce 4.2 of OSIPI to provide standardized definitions of commonly used quantities, models, and analysis processes with the aim of reducing reporting variability. The taskforce was established in February 2020 and consists of medical physicists, engineers, clinicians, data and computer scientists, and DICOM (Digital Imaging and Communications in Medicine) standard experts. Members of the taskforce collaborated via a slack channel and quarterly virtual meetings. Members participated by defining lexicon items and reporting formats that were reviewed by at least two other members of the taskforce. Version 1.0.0 of the lexicon was subject to open review from the wider perfusion imaging community between January and March 2022, and endorsed by the Perfusion Study Group of the ISMRM in the summer of 2022. The initial scope of the lexicon was set by the taskforce and defined such that it contained a basic set of quantities, processes, and models to enable users to report an end-to-end analysis pipeline including kinetic model fitting. We also provide guidance on how to easily incorporate lexicon items and definitions into free-text descriptions (e.g., in manuscripts and other documentation) and introduce an XML-based pipeline encoding format to encode analyses using lexicon definitions in standardized and extensible machine-readable code. The lexicon is designed to be open-source and extendable, enabling ongoing expansion of its content. We hope that widespread adoption of lexicon terminology and reporting formats described herein will increase reproducibility within the field.
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- McMahon, J J, et al.
(author)
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CMP compatibility of partially cured benzocyclobutene (BCB) for a via-first 3D IC process
- 2005
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In: Chemical-Mechanical Planarization-Integration, Technology and Reliability. - WARRENDALE, PA : MATERIALS RESEARCH SOCIETY. - 1558998209 ; , s. 63-68
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Conference paper (peer-reviewed)abstract
- Wafer-level three dimensional (3D) IC technology offers the promise of decreasing RC delays by reducing long interconnect lines in high performance ICs. This paper focuses on a via-first 3D IC platform, which utilizes a back-end-of-line (BEOL) compatible damascene-patterned layer of copper and Benzocyclobutene (BCB). This damascene-patterned copper/BCB serves as a redistribution layer between two fully fabricated wafer sets of ICs and offers the potential of high bonding strength and low contact resistance for inter-wafer interconnects between the wafer pair. The process would thus combine the electrical advantages of 3D technology using Cu-to-Cu bonding with the mechanical advantages of 3D technology using BCB-to-BCB bonding. In this work, partially cured BCB has been evaluated for copper damascene patterning using commercially available CMP slurries as a key process step for a via-first 3D process flow. BCB is spin-cast on 200 mm wafers and cured at temperatures ranging from 190 degrees C to 250 degrees C, providing a wide range of crosslink percentage. These films are evaluated for CMP removal rate, surface damage (surface scratching and embedded abrasives), and planarity with commercially available copper CMP slurries. Under baseline process parameters, erosion, and roughness changes are presented for single-level damascene test patterns. After wafers are bonded under controlled temperature and pressure, the bonding interface is inspected optically using glass-to-silicon bonded wafers, and the bond strength is evaluated by a razor blade test.
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- McMahon, J J, et al.
(author)
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Unit processes for Cu/BCB redistribution layer bonding for 3D ICs
- 2006
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In: Advanced Metallization Conference 2005 (AMC 2005). - WARRENDALE : MATERIALS RESEARCH SOCIETY. - 1558998659 ; , s. 179-183
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Conference paper (peer-reviewed)abstract
- A novel via-first, back-end-of-the-line (BEOL) compatible, monolithic wafer-level three-dimensional (3D) interconnect technology platform is presented. This platform employs wafer bonding of damascene-patterned metal/adhesive redistribution layers on two wafers to provide both high density of inter-wafer electrical interconnects and strong adhesive bond of two wafers in a single unit processing step. Two key steps for this approach are 1) fabrication of a metal/adhesive redistribution layer on the BEOLprocessed wafers by damascene patterning and 2) face-to-face alignment and bonding of two wafers utilizing copper/tantalum (Cu/Ta) and benzocyclobutene (BCB) redistribution layers. A baseline process and two modified processes are investigated toward evaluation of 1) acceptable wafer-scale nonplanarity, removal rate, and surface damage after CMP and 2) seamless bonding at all three possible interfaces with sufficiently strong BCB-to-BCB critical adhesion energy and Cu-to-Cu contact resistance. Migration of voids in the sputtered copper during bonding and etch profiles for different etch processes are discussed.
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- Niklaus, Frank, et al.
(author)
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Adhesive wafer bonding using partially cured benzocyclobutene for three-dimensional integration
- 2006
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In: Journal of the Electrochemical Society. - : The Electrochemical Society. - 0013-4651 .- 1945-7111. ; 153:4, s. G291-G295
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Journal article (peer-reviewed)abstract
- Wafer-level three-dimensional integration (3D) is an emerging technology to increase the performance and functionality of integrated circuits (ICs), with adhesive wafer bonding a key step in one of the attractive technology platforms. In such an application, the dielectric adhesive layer needs to be very uniform, and precise wafer-to-wafer alignment accuracy (similar to 1 mu m) of the bonded wafers is required. In this paper we present a new adhesive wafer bonding process that involves partially curing (cross-linking) of the benzocyclobutene (BCB) coatings prior to bonding. The partially cured BCB layer essentially does not reflow during bonding, minimizing the impact of inhomogeneities in BCB reflow under compression and/or any shear forces at the bonding interface. The resultant nonuniformity of the BCB layer thickness after wafer bonding is less than 1% of the average layer thickness, and the wafers shift relative to each other during the wafer bonding process less than 1 mu m (average) for 200 mm diameter wafers. When bonding two silicon wafers using partially cured BCB, the critical adhesion energy is sufficiently high (>= 14 J/m(2)) for subsequent IC processing.
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- Niklaus, Frank, et al.
(author)
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Effects of bonding process parameters on wafer-to-wafer alignment accuracy in benzocyclobutene (BCB) dielectric wafer bonding
- 2005
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In: Materials, Technology and Reliability of Advanced Interconnects-2005. - WARRENDALE, PA : MATERIALS RESEARCH SOCIETY. - 1558998160 ; , s. 393-398
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Conference paper (peer-reviewed)abstract
- Wafer-level three-dimensional (3D) integration is an emerging technology to increase the performance and functionality of integrated circuits (ICs). Aligned wafer-to-wafer bonding with dielectric polymer layers (e.g., benzocyclobutene (BCB)) is a promising approach for manufacturing of 3D ICs, with minimum bonding impact on the wafer-to-wafer alignment accuracy essential. In this paper we investigate the effects of thermal and mechanical bonding parameters on the achievable post-bonding wafer-to-wafer alignment accuracy for polymer wafer bonding with 200 trim diameter wafers. Our baseline wafer bonding process with soft-baked BCB (similar to 35% cross-linked) has been modified to use partially cured (similar to 43% crosslinked) BCB. The partially cured BCB layer does not reflow during bonding, minimizing the impact of inhomogeneities in BCB reflow under compression and/or slight shear forces at the bonding interface. As a result, the non-uniformity of the BCB layer thickness after wafer bonding is less than 0.5% of the nominal layer thickness and the wafer shift relative to each other during the wafer bonding process is less than 1 mu m (average) for 200 mm diameter wafers. The critical adhesion energy of a bonded wafer pair with the partially cured BCB wafer bonding process is similar to that with soft-baked BCB.
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14. |
- Shah, S, et al.
(author)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Journal article (peer-reviewed)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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- Gutmann, R.J., et al.
(author)
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Wafer-Level Via-First 3D Integration with Hybrid-Bonding of Cu/BCB Redistribution Layers
- 2005
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Conference paper (other academic/artistic)abstract
- Three-dimensional (3D) integration with through-die viasoffer improved electrical performance compared to edgeconnectedwire bonds in stacked-die assemblies for wirelessapplications. Monolithic wafer-level 3D integration offersthe potential for a high density of micron-sized through-dievias necessary for highest performance memory stacks,microprocessors with large L2 caches and ASICs with largeembedded memories. In addition, such wafer-leveltechnologies offer the potential of lowest cost in largemanufacturing volume of any heterogeneous integrationplatform, incorporating the inherent low cost of monolithicIC interconnectivity. After a brief summary of current wafer-level 3D integrationplatforms, a recently introduced platform that offers theprocess integration advantage of copper-to-copper (Cu-to-Cu) bonding with the increased adhesion strength andenvironmental robustness of dielectric adhesive bondingusing benzocyclobutene (BCB) is discussed. Criticalprocessing challenges of the new platform include BCBpartial curing compatible with damascene patterning, postdamascene-patterning cleaning and surface activation,bonding process parameters, and wafer-level planarizationrequirements. The inherent incorporation of a redistributionlayer into the bonding layer process further reduces theprocess flow and is compatible with wafer-level packaging(WLP) technologies.
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- Liu, E. J., et al.
(author)
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Aerial strategies advance volcanic gas measurements at inaccessible, strongly degassing volcanoes
- 2020
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In: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:44
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Journal article (peer-reviewed)abstract
- Volcanic emissions are a critical pathway in Earth's carbon cycle. Here, we show that aerial measurements of volcanic gases using unoccupied aerial systems (UAS) transform our ability to measure and monitor plumes remotely and to constrain global volatile fluxes from volcanoes. Combining multi-scale measurements from ground-based remote sensing, long-range aerial sampling, and satellites, we present comprehensive gas fluxes-3760 ± [600, 310] tons day-1 CO2 and 5150 ± [730, 340] tons day-1 SO2-for a strong yet previously uncharacterized volcanic emitter: Manam, Papua New Guinea. The CO2/ST ratio of 1.07 ± 0.06 suggests a modest slab sediment contribution to the sub-arc mantle. We find that aerial strategies reduce uncertainties associated with ground-based remote sensing of SO2 flux and enable near-real-time measurements of plume chemistry and carbon isotope composition. Our data emphasize the need to account for time averaging of temporal variability in volcanic gas emissions in global flux estimates.
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- Niklaus, Frank, et al.
(author)
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Adhesive wafer bonding
- 2006
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In: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 99:3
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Research review (peer-reviewed)abstract
- Wafer bonding with intermediate polymer adhesives is an important fabrication technique for advanced microelectronic and microelectromechanical systems, such as three-dimensional integrated circuits, advanced packaging, and microfluidics. In adhesive wafer bonding, the polymer adhesive bears the forces involved to hold the surfaces together. The main advantages of adhesive wafer bonding include the insensitivity to surface topography, the low bonding temperatures, the compatibility with standard integrated circuit wafer processing, and the ability to join different types of wafers. Compared to alternative wafer bonding techniques, adhesive wafer bonding is simple, robust, and low cost. This article reviews the state-of-the-art polymer adhesive wafer bonding technologies, materials, and applications.
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- Niklaus, Frank, et al.
(author)
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Wafer-Level 3D Integration Technology Platforms for ICs and MEMS
- 2005
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In: TWENTY SECOND INTERNATIONAL VLSI MULTILEVEL INTERCONNECTION (VMIC). ; , s. 486-493
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Conference paper (other academic/artistic)abstract
- Wafer-level three-dimensional (3D) integration is an emerging technology to increase theperformance and functionality of integrated circuits (ICs) and microelectromechanical systems(MEMS). In ICs, wafer-level 3D integration based on wafer bonding offers the potential for a highdensity of micron-sized through-die vias necessary for highest performance memory stacks,microprocessors with large L2 caches and ASICs with large embedded memories. In MEMS devices,wafer-level 3D integration based on wafer bonding offers the potential for integrating highperformance transducer materials such as various monocrystalline semiconductor materials withelectronic circuits for arrayed, highly integrated sensor and actuator components. This invited paperpresents an overview of current wafer-level 3D integration platforms that use wafer bonding withpolymer adhesives for ICs and MEMS applications.
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- Wray, Selina, et al.
(author)
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Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Journal article (peer-reviewed)abstract
- Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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