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2.
  • Adrian-Martinez, S., et al. (author)
  • The First Combined Search For Neutrino Point-Sources In The Southern Hemisphere With The Antares And Icecube Neutrino Telescopes
  • 2016
  • In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 823:1
  • Journal article (peer-reviewed)abstract
    • We present the results of searches for point-like sources of neutrinos based on the first combined analysis of data from both the ANTARES and IceCube neutrino telescopes. The combination of both detectors, which differ in size and location, forms a window in the southern sky where the sensitivity to point sources improves by up to a factor of 2 compared with individual analyses. Using data recorded by ANTARES from 2007 to 2012, and by IceCube from 2008 to 2011, we search for sources of neutrino emission both across the southern sky and from a preselected list of candidate objects. No significant excess over background has been found in these searches, and flux upper limits for the candidate sources are presented for E-2.5 and E-2 power-law spectra with different energy cut-offs.
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3.
  • Aartsen, M. G., et al. (author)
  • PINGU : a vision for neutrino and particle physics at the South Pole
  • 2017
  • In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 44:5
  • Journal article (peer-reviewed)abstract
    • The Precision IceCube Next Generation Upgrade (PINGU) is a proposed low-energy in-fill extension to the IceCube Neutrino Observatory. With detection technology modeled closely on the successful IceCube example, PINGU will provide a 6 Mton effective mass for neutrino detection with an energy threshold of a few GeV. With an unprecedented sample of over 60 000 atmospheric neutrinos per year in this energy range, PINGU will make highly competitive measurements of neutrino oscillation parameters in an energy range over an order of magnitude higher than long-baseline neutrino beam experiments. PINGU will measure the mixing parameters theta(23) and Delta m(32)(2), including the octant of theta(23) for a wide range of values, and determine the neutrino mass ordering at 3 sigma median significance within five years of operation. PINGU's high precision measurement of the rate of nu(T) appearance will provide essential tests of the unitarity of the 3 x 3 PMNS neutrino mixing matrix. PINGU will also improve the sensitivity of searches for low mass dark matter in the Sun, use neutrino tomography to directly probe the composition of the Earth's core, and improve IceCube's sensitivity to neutrinos from Galactic supernovae. Reoptimization of the PINGU design has permitted substantial reduction in both cost and logistical requirements while delivering performance nearly identical to configurations previously studied.
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4.
  • Aartsen, M. G., et al. (author)
  • The IceCube Neutrino Observatory : instrumentation and online systems
  • 2017
  • In: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221. ; 12
  • Journal article (peer-reviewed)abstract
    • The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.
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5.
  • Aartsen, M. G., et al. (author)
  • All-flavour search for neutrinos from dark matter annihilations in the Milky Way with IceCube/DeepCore
  • 2016
  • In: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 76:10
  • Journal article (peer-reviewed)abstract
    • We present the first IceCube search for a signal of dark matter annihilations in the Milky Way using all-flavour neutrino-induced particle cascades. The analysis focuses on the DeepCore sub-detector of IceCube, and uses the surrounding IceCube strings as a veto region in order to select starting events in the DeepCore volume. We use 329 live-days of data from IceCube operating in its 86-string configuration during 2011-2012. No neutrino excess is found, the final result being compatible with the background-only hypothesis. From this null result, we derive upper limits on the velocity-averaged self-annihilation cross-section, , for dark matter candidate masses ranging from 30 GeV up to 10 TeV, assuming both a cuspy and a flat-cored dark matter halo profile. For dark matter masses between 200 GeV and 10 TeV, the results improve on all previous IceCube results on , reaching a level of 10 cm s, depending on the annihilation channel assumed, for a cusped NFW profile. The analysis demonstrates that all-flavour searches are competitive with muon channel searches despite the intrinsically worse angular resolution of cascades compared to muon tracks in IceCube.
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6.
  • Aartsen, M. G., et al. (author)
  • Lowering Icecube'S Energy Threshold For Point Source Searches In The Southern Sky
  • 2016
  • In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 824:2
  • Journal article (peer-reviewed)abstract
    • Observation of a point source of astrophysical neutrinos would be a "smoking gun" signature of a cosmic-ray accelerator. While IceCube has recently discovered a diffuse flux of astrophysical neutrinos, no localized point source has been observed. Previous IceCube searches for point sources in the southern sky were restricted by either an energy threshold above a few hundred TeV or poor neutrino angular resolution. Here we present a search for southern sky point sources with greatly improved sensitivities to neutrinos with energies below 100 TeV. By selecting charged-current nu(mu) interacting inside the detector, we reduce the atmospheric background while retaining efficiency for astrophysical neutrino-induced events reconstructed with sub-degree angular resolution. The new event sample covers three years of detector data and leads to a factor of 10 improvement in sensitivity to point sources emitting below 100 TeV in the southern sky. No statistically significant evidence of point sources was found, and upper limits are set on neutrino emission from individual sources. A posteriori analysis of the highest-energy (similar to 100 TeV) starting event in the sample found that this event alone represents a 2.8 sigma deviation from the hypothesis that the data consists only of atmospheric background.
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7.
  • Aartsen, M. G., et al. (author)
  • Searches for Sterile Neutrinos with the IceCube Detector
  • 2016
  • In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 117:7
  • Journal article (peer-reviewed)abstract
    • The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous nu(mu) or (nu) over bar (mu) disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3 + 1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin(2)2 theta(24) <= 0.02 at Delta m(2) similar to 0.3 eV(2) at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of vertical bar U-e4 vertical bar(2).
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8.
  • Aartsen, M. G., et al. (author)
  • The Contribution Of Fermi-2Lac Blazars To Diffuse Tev-Pev Neutrino Flux
  • 2017
  • In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 835:1
  • Journal article (peer-reviewed)abstract
    • The recent discovery of a diffuse cosmic neutrino flux extending up to PeV energies raises the question of which astrophysical sources generate this signal. Blazars are one class of extragalactic sources which may produce such high-energy neutrinos. We present a likelihood analysis searching for cumulative neutrino emission from blazars in the 2nd Fermi-LAT AGN catalog (2LAC) using IceCube neutrino data set 2009-12, which was optimized for the detection of individual sources. In contrast to those in previous searches with IceCube, the populations investigated contain up to hundreds of sources, the largest one being the entire blazar sample in the 2LAC catalog. No significant excess is observed, and upper limits for the cumulative flux from these populations are obtained. These constrain the maximum contribution of 2LAC blazars to the observed astrophysical neutrino flux to 27% or less between around 10 TeV and 2 PeV, assuming the equipartition of flavors on Earth and a single power-law spectrum with a spectral index of -2.5. We can still exclude the fact that 2LAC blazars (and their subpopulations) emit more than 50% of the observed neutrinos up to a spectral index as hard as -2.2 in the same energy range. Our result takes into account the fact that the neutrino source count distribution is unknown, and it does not assume strict proportionality of the neutrino flux to the measured 2LAC gamma-ray signal for each source. Additionally, we constrain recent models for neutrino emission by blazars.
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9.
  • Aartsen, M. G., et al. (author)
  • A Combined Maximum-Likelihood Analysis Of The High-Energy Astrophysical Neutrino Flux Measured With Icecube
  • 2015
  • In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 809:1
  • Journal article (peer-reviewed)abstract
    • Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies greater than or similar to 30 TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, nu(mu)-induced tracks from the Northern Hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle, and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index -2.50 +/- 0.09 and a flux at 100 TeV of (6.7(-1.2)(+1.1)) x 10(-18) GeV-1 s(-1) sr(-1) cm(-2). Under the same assumptions, an unbroken power law with index -2 is disfavored with a significance of 3.8 sigma (p = 0.0066%) with respect to the best fit. This significance is reduced to 2.1 sigma (p = 1.7%) if instead we compare the best fit to a spectrum with index -2 that has an exponential cut-off at high energies. Allowing the electron-neutrino flux to deviate from the other two flavors, we find a nu(e) fraction of 0.18 +/- 0.11 at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay-dominated sources, is rejected with a significance of 3.6 sigma ( p = 0.014%).
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10.
  • Aartsen, M. G., et al. (author)
  • An All-Sky Search For Three Flavors Of Neutrinos From Gamma-Ray Bursts With The Icecube Neutrino Observatory
  • 2016
  • In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 824:2
  • Journal article (peer-reviewed)abstract
    • We present the results and methodology of a search for neutrinos produced in the decay of charged pions created in interactions between protons and gamma-rays during the prompt emission of 807 gamma-ray bursts (GRBs) over the entire sky. This three-year search is the first in IceCube for shower-like Cherenkov light patterns from electron, muon, and tau neutrinos correlated with GRBs. We detect five low-significance events correlated with five GRBs. These events are consistent with the background expectation from atmospheric muons and neutrinos. The results of this search in combination with those of IceCube's four years of searches for track-like Cherenkov light patterns from muon neutrinos correlated with Northern-Hemisphere GRBs produce limits that tightly constrain current models of neutrino and ultra high energy cosmic ray production in GRB fireballs.
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11.
  • Aartsen, M. G., et al. (author)
  • Anisotropy In Cosmic-Ray Arrival Directions In The Southern Hemisphere Based On Six Years Of Data From The Icecube Detector
  • 2016
  • In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 826:2
  • Journal article (peer-reviewed)abstract
    • The IceCube Neutrino Observatory accumulated a total of 318 billion cosmic-ray-induced muon events between 2009 May and 2015 May. This data set was used for a detailed analysis of the sidereal anisotropy in the arrival directions of cosmic rays in the TeV to PeV energy range. The observed global sidereal anisotropy features large regions of relative excess and deficit, with amplitudes of the order of 10(-3) up to about 100 TeV. A decomposition of the arrival direction distribution into spherical harmonics shows that most of the power is contained in the low-multipole (l <= 4) moments. However, higher multipole components are found to be statistically significant down to an angular scale of less than 10 degrees, approaching the angular resolution of the detector. Above 100 TeV, a change in the morphology of the arrival direction distribution is observed, and the anisotropy is characterized by a wide relative deficit whose amplitude increases with primary energy up to at least 5 PeV, the highest energies currently accessible to IceCube. No time dependence of the large-and small-scale structures is observed in the period of six years covered by this analysis. The high-statistics data set reveals more details of the properties of the anisotropy and is potentially able to shed light on the various physical processes that are responsible for the complex angular structure and energy evolution.
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12.
  • Aartsen, M. G., et al. (author)
  • Improved limits on dark matter annihilation in the Sun with the 79-string IceCube detector and implications for supersymmetry
  • 2016
  • In: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :4
  • Journal article (peer-reviewed)abstract
    • We present an improved event-level likelihood formalism for including neutrino telescope data in global fits to new physics. We derive limits on spin-dependent dark matter-proton scattering by employing the new formalism in a re-analysis of data from the 79-string IceCube search for dark matter annihilation in the Sun, including explicit energy information for each event. The new analysis excludes a number of models in the weak-scale minimal supersymmetric standard model (MSSM) for the first time. This work is accompanied by the public release of the 79-string IceCube data, as well as an associated computer code for applying the new likelihood to arbitrary dark matter models.
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13.
  • Aartsen, M. G., et al. (author)
  • Neutrino oscillation studies with IceCube-DeepCore
  • 2016
  • In: Nuclear Physics B. - : Elsevier BV. - 0550-3213 .- 1873-1562. ; 908, s. 161-177
  • Journal article (peer-reviewed)abstract
    • IceCube, a gigaton-scale neutrino detector located at the South Pole, was primarily designed to search for astrophysical neutrinos with energies of PeV and higher. This goal has been achieved with the detection of the highest energy neutrinos to date. At the other end of the energy spectrum, the DeepCore extension lowers the energy threshold of the detector to approximately 10 GeV and opens the door for oscillation studies using atmospheric neutrinos. An analysis of the disappearance of these neutrinos has been completed, with the results produced being complementary with dedicated oscillation experiments. Following a review of the detector principle and performance, the method used to make these calculations, as well as the results, is detailed. Finally, the future prospects of IceCube-DeepCore and the next generation of neutrino experiments at the South Pole (IceCube-Gen2, specifically the PINGU sub-detector) are briefly discussed.
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14.
  • Aartsen, M. G., et al. (author)
  • Search for astrophysical tau neutrinos in three years of IceCube data
  • 2016
  • In: Physical Review D. - 1550-7998 .- 1550-2368. ; 93:2
  • Journal article (peer-reviewed)abstract
    • The IceCube Neutrino Observatory has observed a diffuse flux of TeV-PeVastrophysical neutrinos at 5.7 sigma significance from an all-flavor search. The direct detection of tau neutrinos in this flux has yet to occur. Tau neutrinos become distinguishable from other flavors in IceCube at energies above a few hundred TeV, when the cascade from the tau neutrino charged current interaction becomes resolvable from the cascade from the tau lepton decay. This paper presents results from the first dedicated search for tau neutrinos with energies between 214 TeV and 72 PeV in the full IceCube detector. The analysis searches for IceCube optical sensors that observe two separate pulses in a single event-one from the tau neutrino interaction and a second from the tau decay. No candidate events were observed in three years of IceCube data. For the first time, a differential upper limit on astrophysical tau neutrinos is derived around the PeV energy region, which is nearly 3 orders of magnitude lower in energy than previous limits from dedicated tau neutrino searches.
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15.
  • Aartsen, M. G., et al. (author)
  • Searches for relativistic magnetic monopoles in IceCube
  • 2016
  • In: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 76:3
  • Journal article (peer-reviewed)abstract
    • Various extensions of the Standard Model motivate the existence of stable magnetic monopoles that could have been created during an early high-energy epoch of the Universe. These primordial magnetic monopoles would be gradually accelerated by cosmic magnetic fields and could reach high velocities that make them visible in Cherenkov detectors such as IceCube. Equivalently to electrically charged particles, magnetic monopoles produce direct and indirect Cherenkov light while traversing through matter at relativistic velocities. This paper describes searches for relativistic (nu >= 0.76 c) and mildly relativistic (nu >= 0.51 c) monopoles, each using one year of data taken in 2008/2009 and 2011/2012, respectively. No monopole candidate was detected. For a velocity above 0.51 c the monopole flux is constrained down to a level of 1.55 x 10(-18) cm(-2) s(-1) sr(-1). This is an improvement of almost two orders of magnitude over previous limits.
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16.
  • Aartsen, M. G., et al. (author)
  • The Search For Transient Astrophysical Neutrino Emission With Icecube-Deepcore
  • 2016
  • In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 816:2
  • Journal article (peer-reviewed)abstract
    • We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (-5 degrees < delta < 90 degrees) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae.
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17.
  • Hudson, Thomas J., et al. (author)
  • International network of cancer genome projects
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
  • Journal article (peer-reviewed)abstract
    • The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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18.
  • Willer, Cristen J., et al. (author)
  • Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
  • 2009
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
  • Journal article (peer-reviewed)abstract
    • Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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19.
  • Langefeld, Carl D., et al. (author)
  • Transancestral mapping and genetic load in systemic lupus erythematosus
  • 2017
  • In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
  • Journal article (peer-reviewed)abstract
    • Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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20.
  • Bousquet, Jean, et al. (author)
  • ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
  • 2021
  • In: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
  • Research review (peer-reviewed)abstract
    • Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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21.
  • Micah, Angela E., et al. (author)
  • Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
  • 2021
  • In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
  • Research review (peer-reviewed)abstract
    • Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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22.
  • Bousquet, J. Jean, et al. (author)
  • Next-generation ARIA care pathways for rhinitis and asthma : a model for multimorbid chronic diseases
  • 2019
  • In: Clinical and Translational Allergy. - : BMC. - 2045-7022. ; 9
  • Research review (peer-reviewed)abstract
    • Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Sante as a Good Practice in the field of digitally-enabled, integrated, person-centred care.Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
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23.
  • Lindgren, Cecilia M, et al. (author)
  • Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
  • 2009
  • In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
  • Journal article (peer-reviewed)abstract
    • To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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24.
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25.
  • Gaziano, Liam, et al. (author)
  • Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
  • 2022
  • In: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
  •  
26.
  • Chiang, Michael F., et al. (author)
  • International Classification of Retinopathy of Prematurity, Third Edition
  • 2021
  • In: Ophthalmology. - : Elsevier. - 0161-6420 .- 1549-4713. ; 128:10, s. 51-68
  • Journal article (peer-reviewed)abstract
    • Purpose: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., antievascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system.Design: Review of evidence-based literature, along with expert consensus opinion. Participants: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men.Methods: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification.Main Outcome Measures: Consensus statement.Results: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae.Conclusions: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.
  •  
27.
  • Ivanics, Tommy, et al. (author)
  • Outcomes after liver transplantation using deceased after circulatory death donors : A comparison of outcomes in the UK and the US
  • 2023
  • In: Liver international. - : Wiley-Blackwell. - 1478-3223 .- 1478-3231. ; 43:5, s. 1107-1119
  • Journal article (peer-reviewed)abstract
    • Background and Aims: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight.Methods: Adult (>= 18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes.Results: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001).Conclusions: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.
  •  
28.
  • Anney, Richard, et al. (author)
  • A genome-wide scan for common alleles affecting risk for autism.
  • 2010
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
  • Journal article (peer-reviewed)abstract
    • Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
  •  
29.
  • Anney, Richard, et al. (author)
  • Individual common variants exert weak effects on the risk for autism spectrum disorders.
  • 2012
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
  • Journal article (peer-reviewed)abstract
    • While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
  •  
30.
  • Buckley, Patrick G., et al. (author)
  • Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
  • 2005
  • In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:6, s. 540-9
  • Journal article (peer-reviewed)abstract
    • Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.
  •  
31.
  • Canevelli, Marco, et al. (author)
  • Frailty is associated with the clinical expression of neuropsychological deficits in older adults
  • 2024
  • In: European Journal of Neurology. - 1351-5101 .- 1468-1331. ; 31:1
  • Journal article (peer-reviewed)abstract
    • Background and purpose: The aim was to determine whether frailty is associated with the relationship between neuropsychological markers and global cognition in older adults.Methods: Cross-sectional analyzes were conducted of baseline data from three large cohort studies: National Alzheimer's Coordinating Center (NACC), Rush Memory and Aging Project (MAP) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Studies recruited North American participants along the spectrum of cognitive functioning (44% no cognitive impairment at baseline). A frailty index was computed in each dataset. Frailty indices, neuropsychological tests (including measures of processing speed, episodic, semantic and working memory) and Mini-Mental State Examination (MMSE) scores were the variables of interest, with age, sex, education and apolipoprotein E ε4 evaluated as confounders.Results: Across all studies, 23,819 participants aged 55–104 (57% female) were included in analyzes. Frailty index scores were significantly and inversely associated with MMSE scores and significantly moderated relationships between neuropsychological test scores and MMSE scores. In participants with higher frailty index scores, lower neuropsychological test scores were more strongly associated with lower MMSE scores (standardized interaction coefficients ranged from −0.19 to −1.17 in NACC, −0.03 to −2.27 in MAP and −0.04 to −0.38 in ADNI, depending on the neuropsychological test). These associations were consistent across the different databases and were mostly independent of the composition of frailty indices (i.e., after excluding possible symptoms of dementia).Conclusions: Amongst older Americans, frailty is associated with the cognitive expression of neuropsychological deficits. Implementation of frailty assessment in routine neurological and neuropsychological practice should be considered to optimize care outcomes for older adults.
  •  
32.
  • Casey, Jillian P, et al. (author)
  • A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
  • 2012
  • In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
  • Journal article (peer-reviewed)abstract
    • Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
  •  
33.
  • Cesarini, David, et al. (author)
  • The behavioral genetics of behavioral anomalies
  • Other publication (other academic/artistic)abstract
    • A number of recent papers have examined the environmental and genetic sources of individual differences in economic and financial decision making. Here we contribute to this burgeoning literature by extending it to a number of key behavioral anomalies that are thought to be of importance for consumption, savings, and portfolio selection decisions. Using survey-based evidence from more than 11,000 Swedish twins, we demonstrate that a number of anomalies such as, for instance, the conjunction fallacy, default bias, and loss aversion are moderately heritable. In contrast, our estimates imply that variation in common environment explains only a small share of individual differences. We also report suggestive evidence in favor of a shared genetic architecture between cognitive reflection and a subset of the studied anomalies. These results offer some support for the proposition that the heritable variation in behavioral anomalies is partly mediated by genetic variance in cognitive ability. Taken together with previous findings, our results underline the importance of genetic differences as a source of heterogeneity in economic and financial decision making.
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34.
  • Costa, Soraia K. P. F., et al. (author)
  • Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352) : A Role for Endogenous Cannabinoids
  • 2020
  • In: Antioxidants and Redox Signaling. - : Mary Ann Liebert. - 1523-0864 .- 1557-7716. ; 33:14, s. 1003-1009
  • Journal article (peer-reviewed)abstract
    • Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia.Results: ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352.Innovation: Ketoprofen is a potent analgesic, but its clinical use, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness.Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H2S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.
  •  
35.
  • Ferreira, Isabel, et al. (author)
  • Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study
  • 2017
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1
  • Journal article (peer-reviewed)abstract
    • Background: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. Methods: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. Results: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. Conclusions: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.
  •  
36.
  • Flenady, Vicki, et al. (author)
  • Stillbirths : recall to action in high-income countries.
  • 2016
  • In: The Lancet. - 0140-6736 .- 1474-547X. ; 387:10019, s. 691-702
  • Journal article (peer-reviewed)abstract
    • Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.
  •  
37.
  • Giorgakis, Emmanouil, et al. (author)
  • Disparities in the Use of Older Donation After Circulatory Death Liver Allografts in the United States Versus the United Kingdom
  • 2022
  • In: Transplantation. - : Lippincott Williams & Wilkins. - 0041-1337 .- 1534-6080. ; 106:8, s. E358-E367
  • Journal article (peer-reviewed)abstract
    • Background. This study aimed to assess the differences between the United States and the United Kingdom in the characteristics and posttransplant survival of patients who received donation after circulatory death (DCD) liver allografts from donors aged >60 y. Methods. Data were collected from the UK Transplant Registry and the United Network for Organ Sharing databases. Cohorts were dichotomized into donor age subgroups (donor >60 y [D >60]; donor <= 60 y [D <= 60]). Study period: January 1, 2001, to December 31, 2015. Results. 1157 DCD LTs were performed in the United Kingdom versus 3394 in the United States. Only 13.8% of US DCD donors were aged >50 y, contrary to 44.3% in the United Kingdom. D >60 were 22.6% in the United Kingdom versus 2.4% in the United States. In the United Kingdom, 64.2% of D >60 clustered in 2 metropolitan centers. In the United States, there was marked inter-regional variation. A total of 78.3% of the US DCD allografts were used locally. One- and 5-y unadjusted DCD graft survival was higher in the United Kingdom versus the United States (87.3% versus 81.4%, and 78.0% versus 71.3%, respectively; P < 0.001). One- and 5-y D >60 graft survival was higher in the United Kingdom (87.3% versus 68.1%, and 77.9% versus 51.4%, United Kingdom versus United States, respectively; P < 0.001). In both groups, grafts from donors <= 30 y had the best survival. Survival was similar for donors aged 41 to 50 versus 51 to 60 in both cohorts. Conclusions. Compared with the United Kingdom, older DCD LT utilization remained low in the United States, with worse D >60 survival. Nonetheless, present data indicate similar survivals for older donors aged <= 60, supporting an extension to the current US DCD age cutoff.
  •  
38.
  •  
39.
  • Hanly, John G., et al. (author)
  • A Longitudinal Analysis of Outcomes of Lupus Nephritis in an International Inception Cohort Using a Multistate Model Approach
  • 2016
  • In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:8, s. 1932-1944
  • Journal article (peer-reviewed)abstract
    • Objective: To study bidirectional change and predictors of change in estimated glomerular filtration rate (GFR) and proteinuria in lupus nephritis (LN) using a multistate modeling approach. Methods: Patients in the Systemic Lupus International Collaborating Clinics inception cohort were classified annually into estimated GFR state 1 (>60 ml/minute), state 2 (30–60 ml/minute), or state 3 (3.0 gm/day), or end-stage renal disease (ESRD) or death. Using multistate modeling, relative transition rates between states indicated improvement and deterioration. Results: Of 1,826 lupus patients, 700 (38.3%) developed LN. During a mean ± SD follow-up of 5.2 ± 3.5 years, the likelihood of improvement in estimated GFR and estimated proteinuria was greater than the likelihood of deterioration. After 5 years, 62% of patients initially in estimated GFR state 3 and 11% of patients initially in estimated proteinuria state 3 transitioned to ESRD. The probability of remaining in the initial states 1, 2, and 3 was 85%, 11%, and 3%, respectively, for estimated GFR and 62%, 29%, and 4%, respectively, for estimated proteinuria. Male sex predicted improvement in estimated GFR states; older age, race/ethnicity, higher estimated proteinuria state, and higher renal biopsy chronicity scores predicted deterioration. For estimated proteinuria, race/ethnicity, earlier calendar years, damage scores without renal variables, and higher renal biopsy chronicity scores predicted deterioration; male sex, presence of lupus anticoagulant, class V nephritis, and mycophenolic acid use predicted less improvement. Conclusion: In LN, the expected improvement or deterioration in renal outcomes can be estimated by multistate modeling and is preceded by identifiable risk factors. New therapeutic interventions for LN should meet or exceed these expectations.
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40.
  • Lai, Heidi T. M., et al. (author)
  • Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes : Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE)
  • 2022
  • In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:4, s. 854-863
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.RESEARCH DESIGN AND METHODS: We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged >= 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.RESULTS: During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P >= 0.1).CONCLUSIONS: Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
  •  
41.
  • Pinto, Dalila, et al. (author)
  • Functional impact of global rare copy number variation in autism spectrum disorders.
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
  • Journal article (peer-reviewed)abstract
    • The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
  •  
42.
  • Rojo, R, et al. (author)
  • Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
  • 2019
  • In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3215-
  • Journal article (peer-reviewed)abstract
    • The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.
  •  
43.
  • Smith, Gustav, et al. (author)
  • The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans.
  • 2012
  • In: Circulation: Cardiovascular Genetics. - 1942-325X. ; 5:6, s. 647-655
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: -Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. METHODS AND RESULTS: -First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5x10(-8)) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2x10(-15)) and ATP1B1 (rs1320976, p=2x10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10(-5)) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. CONCLUSIONS: -We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans.
  •  
44.
  • Szatmari, Peter, et al. (author)
  • Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
  • 2007
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
  • Journal article (peer-reviewed)abstract
    • Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
  •  
45.
  • Wormser, David, et al. (author)
  • Adult height and the risk of cause-specific death and vascular morbidity in 1 million people : individual participant meta-analysis
  • 2012
  • In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:5, s. 1419-1433
  • Journal article (peer-reviewed)abstract
    • BackgroundThe extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.MethodsWe calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.ResultsFor people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.ConclusionAdult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
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