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- Abgrall, N., et al.
(author)
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The large enriched germanium experiment for neutrinoless double beta decay (LEGEND)
- 2017
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In: AIP Conference Proceedings. - : Author(s). - 1551-7616 .- 0094-243X. ; 1894
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Conference paper (peer-reviewed)abstract
- The observation of neutrinoless double-beta decay (0νββ) would show that lepton number is violated, reveal that neu-trinos are Majorana particles, and provide information on neutrino mass. A discovery-capable experiment covering the inverted ordering region, with effective Majorana neutrino masses of 15 - 50 meV, will require a tonne-scale experiment with excellent energy resolution and extremely low backgrounds, at the level of ∼0.1 count /(FWHM·t·yr) in the region of the signal. The current generation 76Ge experiments GERDA and the Majorana Demonstrator, utilizing high purity Germanium detectors with an intrinsic energy resolution of 0.12%, have achieved the lowest backgrounds by over an order of magnitude in the 0νββ signal region of all 0νββ experiments. Building on this success, the LEGEND collaboration has been formed to pursue a tonne-scale 76Ge experiment. The collaboration aims to develop a phased 0νββ experimental program with discovery potential at a half-life approaching or at 1028 years, using existing resources as appropriate to expedite physics results.
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- Smartt, S. J., et al.
(author)
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A kilonova as the electromagnetic counterpart to a gravitational-wave source
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 551:7678, s. 75-
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Journal article (peer-reviewed)abstract
- Gravitational waves were discovered with the detection of binary black-hole mergers(1) and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova(2-5). The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate(6). Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short.-ray burst(7,8). The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 +/- 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 +/- 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 +/- 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.
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- Bruxvoort, K. J., et al.
(author)
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The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium
- 2017
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In: Am J Trop Med Hyg. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 97:4, s. 1170-1179
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Journal article (peer-reviewed)abstract
- Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400-432,513). mRDTs were associated with significantly lower ACT prescription (range 8-69% versus 20-100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.
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- Hopkins, H., et al.
(author)
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Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings
- 2017
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In: Bmj-British Medical Journal. - : BMJ. - 1756-1833 .- 0959-8138. ; 356
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Journal article (peer-reviewed)abstract
- OBJECTIVES To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. Analysis of nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study). Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda. Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings. Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole. Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription. This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined.
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- Romieu, Isabelle, et al.
(author)
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Energy balance and obesity : what are the main drivers?
- 2017
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In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 28:3, s. 247-258
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Journal article (peer-reviewed)abstract
- Purpose: The aim of this paper is to review the evidence of the association between energy balance and obesity. Methods: In December 2015, the International Agency for Research on Cancer (IARC), Lyon, France convened a Working Group of international experts to review the evidence regarding energy balance and obesity, with a focus on Low and Middle Income Countries (LMIC). Results: The global epidemic of obesity and the double burden, in LMICs, of malnutrition (coexistence of undernutrition and overnutrition) are both related to poor quality diet and unbalanced energy intake. Dietary patterns consistent with a traditional Mediterranean diet and other measures of diet quality can contribute to long-term weight control. Limiting consumption of sugar-sweetened beverages has a particularly important role in weight control. Genetic factors alone cannot explain the global epidemic of obesity. However, genetic, epigenetic factors and the microbiota could influence individual responses to diet and physical activity. Conclusion: Energy intake that exceeds energy expenditure is the main driver of weight gain. The quality of the diet may exert its effect on energy balance through complex hormonal and neurological pathways that influence satiety and possibly through other mechanisms. The food environment, marketing of unhealthy foods and urbanization, and reduction in sedentary behaviors and physical activity play important roles. Most of the evidence comes from High Income Countries and more research is needed in LMICs.
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- Sewiło, Marta, et al.
(author)
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Complex Organic Molecules in Star-Forming Regions of the Magellanic Clouds
- 2019
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In: ACS Earth and Space Chemistry. - : American Chemical Society (ACS). - 2472-3452. ; 3:10, s. 2088-2109
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Research review (peer-reviewed)abstract
- The Large and Small Magellanic Clouds (LMC and SMC), gas-rich dwarf companions of the Milky Way, are the nearest laboratories for detailed studies on the formation and survival of complex organic molecules (COMs) under metal-poor conditions. To date, only methanol, methyl formate, and dimethyl ether have been detected in these galaxies-all three toward two hot cores in the N113 star-forming region in the LMC, the only extragalactic sources exhibiting complex hot-core chemistry. We describe a small and diverse sample of the LMC and SMC sources associated with COMs or hot-core chemistry, and compare the observations to theoretical model predictions. Theoretical models accounting for the physical conditions and metallicity of hot molecular cores in the Magellanic Clouds have been able to broadly account for the existing observations, but they fail to reproduce the dimethyl ether abundance by more than an order of magnitude. We discuss future prospects for research in the field of complex chemistry in the low-metallicity environment. The detection of COMs in the Magellanic Clouds has important implications for astrobiology. The metallicity of the Magellanic Clouds is similar to that of galaxies in the earlier epochs of the universe; thus, the presence of COMs in the LMC and SMC indicates that a similar prebiotic chemistry leading to the emergence of life, as it happened on Earth, is possible in low-metallicity systems in the earlier universe.
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- Startin, C. M., et al.
(author)
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Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease
- 2019
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Journal article (peer-reviewed)abstract
- BackgroundDown syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid- peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS).MethodsWe used ultrasensitive assays to compare plasma concentrations of the amyloid- peptides A(40) and A(42), total tau (t-tau), and the cytokines IL1, IL10, IL6, and TNF between adults with DS (n=31), adults with sAD (n=27), and controls age-matched to the group with DS (n=27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS.ResultsA(40), A(42), and IL1 concentrations were higher in DS, with a higher A(42)/A(40) ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both A(42) and IL1. Only NfL concentration in the group with DS showed a significant positive association with age.ConclusionsConcentrations of A(40) and A(42) were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the A(42)/A(40) ratio between those with DS and sAD may indicate similar processing and deposition of A(40) and A(42) in these groups. Higher concentrations of IL1 in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1 and t-tau in DS may indicate IL1 is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.
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- Wiseman, Frances K, et al.
(author)
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Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP.
- 2018
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 141:8, s. 2457-2474
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Journal article (peer-reviewed)abstract
- Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.
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| 24. |
- Wiseman, J., et al.
(author)
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Generation of a functional humanized Delta-like ligand 4 transgenic mouse model
- 2017
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In: Transgenic Research. - : Springer Science and Business Media LLC. - 0962-8819 .- 1573-9368. ; 26:6, s. 791-798
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Journal article (peer-reviewed)abstract
- Humanized mouse models are important tools in many areas of biological drug development including, within oncology research, the development of antagonistic antibodies that have the potential to block tumor growth by controlling vascularization and are key to the generation of in vivo proof-of-concept efficacy data. However, due to cross reactivity between human antibodies and mouse target such studies regularly require mouse models expressing only the human version of the target molecule. Such humanized knock-in/knock-out, KIKO, models are dependent upon the generation of homozygous mice expressing only the human molecule, compensating for loss of the mouse form. However, KIKO strategies can fail to generate homozygous mice, even though the human form is expressed and the endogenous mouse locus is correctly targeted. A typical strategy for generating KIKO mice is by ATG fusion where the human cDNA is inserted downstream of the endogenous mouse promoter elements. However, when adopting this strategy it is possible that the mouse promoter fails to express the human form in a manner compensating for loss of the mouse form or alternatively the human protein is incompatible in the context of the mouse pathway being investigated. So to understand more around the biology of KIKO models, and to overcome our failure with a number of ATG fusion strategies, we developed a range of humanized models focused on Delta-like 4 (Dll4), a target where we initially failed to generate a humanized model. By adopting a broader biologic strategy, we successfully generated a humanized DLL4 KIKO which led to a greater understanding of critical biological aspects for consideration when developing humanized models.
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