| 1. |
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| 2. |
- Abe, K., et al.
(författare)
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J-PARC Neutrino Beamline Upgrade Technical Design Report
- 2019
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Rapport (refereegranskat)abstract
- In this document, technical details of the upgrade plan of the J-PARC neutrino beamline for the extension of the T2K experiment are described. T2K has proposed to accumulate data corresponding to 2×1022 protons-on-target in the next decade, aiming at an initial observation of CP violation with 3σ or higher significance in the case of maximal CP violation. Methods to increase the neutrino beam intensity, which are necessary to achieve the proposed data increase, are described.
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| 3. |
- Blunden, Jessica, et al.
(författare)
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State of the Climate in 2012
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Tidskriftsartikel (refereegranskat)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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| 4. |
- Adcox, K, et al.
(författare)
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PHENIX detector overview
- 2003
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - 0167-5087. ; 499:2-3, s. 469-479
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Tidskriftsartikel (refereegranskat)abstract
- The PHENIX detector is designed to perform a broad study of A-A, p-A, and p-p collisions to investigate nuclear matter under extreme conditions. A wide variety of probes, sensitive to all timescales, are used to study systematic variations with species and energy as well as to measure the spin structure of the nucleon. Designing for the needs of the heavy-ion and polarized-proton programs has produced a detector with unparalleled capabilities. PHENIX measures electron and muon pairs, photons, and hadrons with excellent energy and momentum resolution. The detector consists of a large number of subsystems that are discussed in other papers in this volume. The overall design parameters of the detector are presented. (C) 2002 Elsevier Science B.V. All rights reserved.
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| 5. |
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| 6. |
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| 7. |
- Lyons, A, et al.
(författare)
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Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand
- 2022
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Ingår i: Antiviral therapy. - : SAGE Publications. - 2040-2058 .- 1359-6535. ; 27:3, s. 13596535221092182-
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Tidskriftsartikel (refereegranskat)abstract
- Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. Methods Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. Results 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months ( n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start ( n=83) was 147 [16, 267] cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens–Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. Conclusion Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.
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| 8. |
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| 9. |
- Ovadia, C., et al.
(författare)
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Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis
- 2021
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 mu mol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67.8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0.7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0.6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1.04, 95% CI 0.35-3.07; p=0.95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0.29, 95% CI 0.04-2.42; p=0.25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1.28, 95% CI 0.86-1.91; p=0.22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0.60, 0.39-0.91; p=0.016). Interpretation Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Copyright (C) 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| 10. |
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| 11. |
- Ovadia, C., et al.
(författare)
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Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses
- 2019
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Ingår i: The Lancet. - : Elsevier BV. - 0140-6736. ; 393:10174, s. 899-909
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Tidskriftsartikel (refereegranskat)abstract
- Background Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. Methods We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. Findings We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0.83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0.32%) of 163 947 control pregnancies (odds ratio [OR] 1.46 [95% CI 0.73-2.89]; I-2 = 59.8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0.83 [95% CI 0.74-0.92]), but not alanine aminotransferase (ROC AUC 0.46 [0.35-0.57]). For singleton pregnancies, the prevalence of stillbirth was three (0.13%; 95% CI 0.02-0.38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 mu mol/L versus four (0.28%; 0.08-0.72) of 1412 cases with total bile acids of 40-99 mu mol/L (hazard ratio [HR] 2.35 [95% CI 0.52-10.50]; p=0.26), and versus 18 (3.44%; 2.05-5.37) of 524 cases for bile acids of 100 mu mol/L or more (HR 30.50 [8.83-105.30]; p<0.0001). Interpretation The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 mu mol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. Funding Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust. Copyright (c) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| 12. |
- Verra, L., et al.
(författare)
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Controlled Growth of the Self-Modulation of a Relativistic Proton Bunch in Plasma
- 2022
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Ingår i: Physical Review Accelerators and Beams. - : American Physical Society. - 2469-9888. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- A long, narrow, relativistic charged particle bunch propagating in plasma is subject to the self -modulation (SM) instability. We show that SM of a proton bunch can be seeded by the wakefields driven by a preceding electron bunch. SM timing reproducibility and control are at the level of a small fraction of the modulation period. With this seeding method, we independently control the amplitude of the seed wakefields with the charge of the electron bunch and the growth rate of SM with the charge of the proton bunch. Seeding leads to larger growth of the wakefields than in the instability case.
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| 13. |
- Zeng, Z. Z., et al.
(författare)
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A reversal in global terrestrial stilling and its implications for wind energy production
- 2019
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 9:12, s. 979-985
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Tidskriftsartikel (refereegranskat)abstract
- Wind power, a rapidly growing alternative energy source, has been threatened by reductions in global average surface wind speed, which have been occurring over land since the 1980s, a phenomenon known as global terrestrial stilling. Here, we use wind data from in situ stations worldwide to show that the stilling reversed around 2010 and that global wind speeds over land have recovered. We illustrate that decadal-scale variations of near-surface wind are probably determined by internal decadal ocean-atmosphere oscillations, rather than by vegetation growth and/or urbanization as hypothesized previously. The strengthening has increased potential wind energy by 17 +/- 2% for 2010 to 2017, boosting the US wind power capacity factor by similar to 2.5% and explains half the increase in the US wind capacity factor since 2010. In the longer term, the use of ocean-atmosphere oscillations to anticipate future wind speeds could allow optimization of turbines for expected speeds during their productive life spans.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Ma, Y., et al.
(författare)
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Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values
- 2021
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. Methods A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. Results We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R-2 except for converting P-tau between batches 1 and 3. Discussion Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.
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| 18. |
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| 19. |
- Fuselier, S. A., et al.
(författare)
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High-density O+ in Earth's outer magnetosphere and its effect on dayside magnetopause magnetic reconnection
- 2019
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 124:12, s. 10257-10269
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Tidskriftsartikel (refereegranskat)abstract
- The warm plasma cloak is a source of magnetospheric plasma that contain significant O+. When the O+ density in the magnetosphere near the magnetopause is >0.2 cm(-3) and the H+ density is <1.5 cm(-3), then O+ dominates the magnetospheric ion mass density by more than a factor of 2. A survey is conducted of such O+-rich warm plasma cloak intervals and their effect on reconnection at the Earth's magnetopause. The survey uses data from the Magnetospheric Multiscale mission (MMS) and the results are compared and combined with a previous survey of the warm plasma cloak. Overall, the warm plasma cloak and the O+-rich warm plasma cloak reduce the magnetopause reconnection rate by >20% due to mass-loading only about 2% to 4% of the time. However, during geomagnetic storms, O+ dominates the mass density of the warm plasma cloak and these mass densities are very high. Therefore, a separate study is conducted to determine the effect of the warm plasma cloak on magnetopause reconnection during geomagnetically disturbed times. This study shows that the warm plasma cloak reduces the reconnection rate significantly about 25% of the time during disturbed conditions.
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| 20. |
- Fuselier, S. A., et al.
(författare)
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Mass Loading the Earth's Dayside Magnetopause Boundary Layer and Its Effect on Magnetic Reconnection
- 2019
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Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 46:12, s. 6204-6213
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Tidskriftsartikel (refereegranskat)abstract
- When the interplanetary magnetic field is northward for a period of time, O+ from the high-latitude ionosphere escapes along reconnected magnetic field lines into the dayside magnetopause boundary layer. Dual-lobe reconnection closes these field lines, which traps O+ and mass loads the boundary layer. This O+ is an additional source of magnetospheric plasma that interacts with magnetosheath plasma through magnetic reconnection. This mass loading and interaction is illustrated through analysis of a magnetopause crossing by the Magnetospheric Multiscale spacecraft. While in the O+-rich boundary layer, the interplanetary magnetic field turns southward. As the Magnetospheric Multiscale spacecraft cross the high-shear magnetopause, reconnection signatures are observed. While the reconnection rate is likely reduced by the mass loading, reconnection is not suppressed at the magnetopause. The high-latitude dayside ionosphere is therefore a source of magnetospheric ions that contributes often to transient reduction in the reconnection rate at the dayside magnetopause.
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| 21. |
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| 22. |
- Geenes, V., et al.
(författare)
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The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.
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| 23. |
- Haaland, S., et al.
(författare)
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Estimation of cold plasma outflow during geomagnetic storms
- 2015
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 120:12, s. 10622-10639
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Tidskriftsartikel (refereegranskat)abstract
- Low-energy ions of ionospheric origin constitute a significant contributor to the magnetospheric plasma population. Measuring cold ions is difficult though. Observations have to be done at sufficiently high altitudes and typically in regions of space where spacecraft attain a positive charge due to solar illumination. Cold ions are therefore shielded from the satellite particle detectors. Furthermore, spacecraft can only cover key regions of ion outflow during segments of their orbit, so additional complications arise if continuous longtime observations, such as during a geomagnetic storm, are needed. In this paper we suggest a new approach, based on a combination of synoptic observations and a novel technique to estimate the flux and total outflow during the various phases of geomagnetic storms. Our results indicate large variations in both outflow rates and transport throughout the storm. Prior to the storm main phase, outflow rates are moderate, and the cold ions are mainly emanating from moderately sized polar cap regions. Throughout the main phase of the storm, outflow rates increase and the polar cap source regions expand. Furthermore, faster transport, resulting from enhanced convection, leads to a much larger supply of cold ions to the near-Earth region during geomagnetic storms.
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| 24. |
- Manna, L. B., et al.
(författare)
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Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study
- 2019
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Ingår i: Bjog-an International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 126:13, s. 1633-1640
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate enzymatic total serum bile acid quantification as a monitoring strategy for women with intrahepatic cholestasis of pregnancy (ICP) treated with ursodeoxycholic acid (UDCA). Design Cohort. Setting One UK university hospital. Population 29 ICP cases treated with UDCA. Methods Serial samples were collected prospectively throughout gestation. Total serum bile acids were measured enzymatically and individual bile acids by high-performance liquid chromatography-tandem mass spectrometry. Data were log-transformed and analysed with random effects generalised least square regression. Main outcome measures The relationship between enzymatic total bile acid measurements and individual bile acid concentrations after UDCA treatment. Results In untreated women, cholic acid was the principal bile acid (51%) and UDCA concentrations were <0.5%, whereas UDCA constituted 60% (IQR 43-69) of serum bile acids following treatment and cholic acid fell to <20%. Changes in the total bile acid measurement reflected similar alterations in the concentrations of the pathologically elevated bile acids, e.g. a two-fold increase in enzymatic total bile acids is accompanied by approximately a two-fold increase in cholic acid and chenodeoxycholic acid at most UDCA doses (P < 0.001). Most of the effects of UDCA on cholic acid occur in the first week of treatment (60% relative reduction, P = 0.025, 95% CI 0.2-0.9, from 10 micromol/l (4.7-17.6) to 3.5 micromol/l (1.4-7.5). Conclusion Ursodeoxycholic acid becomes the main component of the bile acid measurement after treatment. Enzymatic total bile acid assays are good predictors of both cholic acid and chenodeoxycholic acid, the primary bile acids that are raised prior to treatment. Tweetable abstract Ursodeoxycholic acid constitutes approximately 60% of the bile acid measurement and reduces pathological cholic acid in treated women.
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| 25. |
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| 26. |
- Sachdev, P. S., et al.
(författare)
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STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease
- 2017
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 7, s. 11-23
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). Methods Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. Results Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3months to 21years. Discussion Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes. © 2016 The Authors
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| 27. |
- Shaffer, Carrie L., et al.
(författare)
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Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens
- 2016
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Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.
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| 28. |
- Abu-Hayyeh, S., et al.
(författare)
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Prognostic and Mechanistic Potential of Progesterone Sulfates in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum
- 2016
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 63:4, s. 1287-1298
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Tidskriftsartikel (refereegranskat)abstract
- A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
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| 29. |
- Andersson, R., et al.
(författare)
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Dose-response-time modelling: Second-generation turnover model with integral feedback control
- 2016
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 81, s. 189-200
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Tidskriftsartikel (refereegranskat)abstract
- © 2015 Elsevier B.V. All rights reserved. This study presents a dose-response-time (DRT) analysis based on a large preclinical biomarker dataset on the interaction between nicotinic acid (NiAc) and free fatty acids (FFA). Data were collected from studies that examined different rates, routes, and modes of NiAc provocations on the FFA time course. All information regarding the exposure to NiAc was excluded in order to demonstrate the utility of a DRT model. Special emphasis was placed on the selection process of the biophase model. An inhibitory Imax-model, driven by the biophase amount, acted on the turnover rate of FFA. A second generation NiAc/FFA model, which encompasses integral (slow buildup of tolerance - an extension of the previously used NiAc/FFA turnover models) and moderator (rapid and oscillatory) feedback control, was simultaneously fitted to all time courses in normal rats. The integral feedback control managed to capture an observed 90% adaptation (i.e., almost a full return to baseline) when 10 days constant-rate infusion protocols of NiAc were used. The half-life of the adaptation process had a 90% prediction interval between 3.5-12 in the present population. The pharmacodynamic parameter estimates were highly consistent when compared to an exposure-driven analysis, partly validating the DRT modelling approach and suggesting the potential of DRT analysis in areas where exposure data are not attainable. Finally, new numerical algorithms, which rely on sensitivity equations to robustly and efficiently compute the gradients in the parameter optimization, were successfully used for the mixed-effects approach in the parameter estimation.
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| 30. |
- Haider, L. Jamila, 1987-
(författare)
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Development and Resilience : Re-thinking poverty and intervention in biocultural landscapes
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The practices related to the growing, harvesting, preparation, and celebration of food over millennia have given rise to diverse biocultural landscapes the world over. These landscapes – rich in biological and cultural diversity – are often characterised by persistent poverty, and, as such, are often the target of development interventions. Yet a lack of understanding of the interdependencies between human well-being, nature, and culture in these landscapes means that such interventions are often unsuccessful - and can even have adverse effects, exacerbating the poverty they were designed to address. This thesis investigates different conceptualisations of persistent poverty in rural biocultural landscapes, the consequences of these conceptualisations, and the ways in which development interventions can benefit from, rather than erode, biocultural diversity.The thesis first reviews conceptualisations of persistent poverty and specifically, the notion of a poverty trap (Paper I), and examines the consequences of different conceptualisations of traps for efforts to alleviate poverty (Paper II). Paper I argues that the trap concept can be usefully broadened beyond a dominant development economics perspective to incorporate critical interdependencies between humans and nature. Paper II uses multi-dimensional dynamical systems models to show how nature and culture can be impacted by different development interventions, and, in turn, how the degradation of both can undermine the effectiveness of conventional poverty alleviation strategies in certain contexts.In the second section, the thesis focuses on the effects of, and responses to, trap-like situations and development interventions in a specific context of high biocultural diversity: the Pamir Mountains of Tajikistan. Paper III advances a typology of responses to traps based around the mismatch of desires, abilities and opportunities. Observing daily practice provides a way to study social-ecological relationships as a dynamic process, as practices can embody traditional and tacit knowledge in a holistic way. Paper IV examines the diverse effects of a development intervention on the coevolution of biocultural landscapes and the ways in which everyday practice – particularly around food – can be a source of both innovation and resilience.Papers I-IV together combine insights from diverse disciplines and methodologies, from systematic review to dynamic systems thinking and participant observation. Paper V provides a critical analysis of the opportunities and challenges involved in pursuing such an approach in sustainability science, underscoring the need to balance methodological groundedness with epistemological agility.Overall, the thesis contributes to understanding resilience and development, highlighting the value of viewing their interrelation as a dynamic, coevolving process. From this perspective, development should not be regarded as a normative endpoint to be achieved, but rather as a coevolving process between constantly changing ecological and social contexts. The thesis proposes that resilience can be interpreted as the active and passive filtering of practices via the constant discarding and retention of old and new, social and ecological, and endogenous and exogenous factors. This interpretation deepens understanding of resilience as the capacity to persist, adapt and transform, and ultimately shape new development pathways. The thesis also illustrates how daily practices, such as the growing, harvesting, and preparation of food, offer a powerful heuristic device for understanding this filtering process, and therefore the on-going impact of development interventions in rural landscapes across the world.
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| 31. |
- Janzen, David L. I., et al.
(författare)
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Three novel approaches to structural identifiability analysis in mixed-effects models
- 2019
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Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 1872-7565 .- 0169-2607. ; 171, s. 141-152
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Structural identifiability is a concept that considers whether the structure of a model together with a set of input-output relations uniquely determines the model parameters. In the mathematical modelling of biological systems, structural identifiability is an important concept since biological interpretations are typically made from the parameter estimates. For a system defined by ordinary differential equations, several methods have been developed to analyse whether the model is structurally identifiable or otherwise. Another well-used modelling framework, which is particularly useful when the experimental data are sparsely sampled and the population variance is of interest, is mixed-effects modelling. However, established identifiability analysis techniques for ordinary differential equations are not directly applicable to such models. Methods: In this paper, we present and apply three different methods that can be used to study structural identifiability in mixed-effects models. The first method, called the repeated measurement approach, is based on applying a set of previously established statistical theorems. The second method, called the augmented system approach, is based on augmenting the mixed-effects model to an extended state-space form. The third method, called the Laplace transform mixed-effects extension, is based on considering the moment invariants of the systems transfer function as functions of random variables. Results: To illustrate, compare and contrast the application of the three methods, they are applied to a set of mixed-effects models. Conclusions: Three structural identifiability analysis methods applicable to mixed-effects models have been presented in this paper. As method development of structural identifiability techniques for mixed-effects models has been given very little attention, despite mixed-effects models being widely used, the methods presented in this paper provides a way of handling structural identifiability in mixed-effects models previously not possible. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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| 32. |
- Li, Yu-Xuan, et al.
(författare)
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Quantification of Cold-Ion Beams in a Magnetic Reconnection Jet
- 2021
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Ingår i: Frontiers in Astronomy and Space Sciences. - : Frontiers Media S.A.. - 2296-987X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Cold (few eV) ions of ionospheric origin are widely observed in the lobe region of Earth's magnetotail and can enter the ion jet region after magnetic reconnection is triggered in the magnetotail. Here, we investigate a magnetotail crossing with cold ions in one tailward and two earthward ion jets observed by the Magnetospheric Multiscale (MMS) constellation of spacecraft. Cold ions co-existing with hot plasma-sheet ions form types of ion velocity distribution functions (VDFs) in the three jets. In one earthward jet, MMS observe cold-ion beams with large velocities parallel to the magnetic fields, and we perform quantitative analysis on the ion VDFs in this jet. The cold ions, together with the hot ions, are reconnection outflow ions and are a minor population in terms of number density inside this jet. The average bulk speed of the cold-ion beams is approximately 38% larger than that of the hot plasma-sheet ions. The cold-ion beams inside the explored jet are about one order of magnitude colder than the hot plasma-sheet ions. These cold-ion beams could be accelerated by the Hall electric field in the cold ion diffusion region and the shrinking magnetic field lines through the Fermi effect.
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| 33. |
- Thompson, Robin N., et al.
(författare)
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Key questions for modelling COVID-19 exit strategies
- 2020
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 287:1932
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Tidskriftsartikel (refereegranskat)abstract
- Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.
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| 34. |
- Toledo-Redondo, S., et al.
(författare)
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Impacts of Ionospheric Ions on Magnetic Reconnection and Earth's Magnetosphere Dynamics
- 2021
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Ingår i: Reviews of geophysics. - : John Wiley & Sons. - 8755-1209 .- 1944-9208. ; 59:3
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Forskningsöversikt (refereegranskat)abstract
- Ionospheric ions (mainly H+, He+, and O+) escape from the ionosphere and populate the Earth's magnetosphere. Their thermal energies are usually low when they first escape the ionosphere, typically a few electron volt to tens of electron volt, but they are energized in their journey through the magnetosphere. The ionospheric population is variable, and it makes significant contributions to the magnetospheric mass density in key regions where magnetic reconnection is at work. Solar wind—magnetosphere coupling occurs primarily via magnetic reconnection, a key plasma process that enables transfer of mass and energy into the near-Earth space environment. Reconnection leads to the triggering of magnetospheric storms, auroras, energetic particle precipitation and a host of other magnetospheric phenomena. Several works in the last decades have attempted to statistically quantify the amount of ionospheric plasma supplied to the magnetosphere, including the two key regions where magnetic reconnection occurs: the dayside magnetopause and the magnetotail. Recent in situ observations by the Magnetospheric Multiscale spacecraft and associated modeling have advanced our current understanding of how ionospheric ions alter the magnetic reconnection process, including its onset and efficiency. This article compiles the current understanding of the ionospheric plasma supply to the magnetosphere. It reviews both the quantification of these sources and their effects on the process of magnetic reconnection. It also provides a global description of how the ionospheric ion contribution modifies the way the solar wind couples to the Earth's magnetosphere and how these ions modify the global dynamics of the near-Earth space environment.Plain Language SummaryAbove the neutral atmosphere, space is filled with charged particles, which are tied to the Earth's magnetic field. The particles come from two sources, the solar wind and the Earth's upper atmosphere. Most of the solar wind particles are deflected by the Earth´s magnetic field, but some can penetrate into near-Earth space. The ionized layer of the upper atmosphere is continuously ejecting particles into space, which have low energies and are difficult to measure. We investigate the relative importance of the two charged particle sources for the dynamics of plasma processes in near-Earth space. In particular, we consider the effects of these sources in magnetic reconnection. Magnetic reconnection allows initially separated plasma regions to become magnetically connected and mix, and converts magnetic energy to kinetic energy of charged particles. Magnetic reconnection is the main driver of geomagnetic activity in the near-Earth space, and is responsible for the release of energy that drives a variety of space weather effects. We highlight the fact that plasma from the ionized upper atmosphere contributes a significant part of the density in the key regions where magnetic reconnection is at work, and that this contribution is larger when the geomagnetic activity is high.
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| 35. |
- Wagener, Thorsten, et al.
(författare)
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Knowledge gaps in our perceptual model of Great Britain's hydrology
- 2021
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Ingår i: Hydrological Processes. - : John Wiley & Sons. - 0885-6087 .- 1099-1085. ; 35:7
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Tidskriftsartikel (refereegranskat)abstract
- There is a no lack of significant open questions in the field of hydrology. How will hydrological connectivity between freshwater bodies be altered by future human alterations to the hydrological cycle? Where does water go when it rains? Or what is the future space-time variability of flood and drought events? However, the answers to these questions will vary with location due to the specific and often poorly understood local boundary conditions and system properties that control the functional behaviour of a catchment or any other hydrologic control volume. We suggest that an open, shared and evolving perceptual model of a region's hydrology is critical to tailor our science questions, as it would be for any other study domain from the plot to the continental scale. In this opinion piece, we begin to discuss the elements of and point out some knowledge gaps in the perceptual model of the terrestrial water cycle of Great Britain. We discuss six major knowledge gaps and propose four key ways to reduce them. While the specific knowledge gaps in our perceptual model do not necessarily transfer to other places, we believe that the development of such perceptual models should be at the core of the debate for all hydrologic communities, and we encourage others to have a similar debate for their hydrologic domain.
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| 36. |
- Wheeler, A. J., et al.
(författare)
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Roof cavity dust as an exposure proxy for extreme air pollution events
- 2020
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535. ; 244
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Tidskriftsartikel (refereegranskat)abstract
- Understanding exposure to air pollution during extreme events such as fire emergencies is critical for assessing their potential health impacts. However, air pollution emergencies often affect places without a network of air quality monitoring and characterising exposure retrospectively is methodologically challenging due to the complex behaviour of smoke and other air pollutants. Here we test the potential of roof cavity (attic) dust to act as a robust household-level exposure proxy, using a major air pollution event associated with a coal mine fire in the Latrobe Valley, Australia, as an illustrative study. To assess the relationship between roof cavity dust composition and mine fire exposure, we analysed the elemental and polycyclic aromatic hydrocarbon composition of roof cavity dust (<150 mu m) from 39 homes along a gradient of exposure to the mine fire plume. These homes were grouped into 12 zones along this exposure gradient: eight zones across Morwell, where mine fire impacts were greatest, and four in other Latrobe Valley towns at increasing distance from the fire. We identified two elements-barium and magnesium-as 'chemical markers' that show a clear and theoretically grounded relationship with the brown coal mine fire plume exposure. This relationship is robust to the influence of plausible confounders and contrasts with other, non-mine fire related elements, which showed distinct and varied distributional patterns. We conclude that targeted components of roof cavity dust can be a useful empirical marker of household exposure to severe air pollution events and their use could support epidemiological studies by providing spatially-resolved exposure estimates post-event. (C) 2019 Elsevier Ltd. All rights reserved.
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| 37. |
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| 38. |
- Zhang, G. F., et al.
(författare)
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Rapid urbanization induced daily maximum wind speed decline in metropolitan areas: A case study in the Yangtze River Delta (China)
- 2022
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Ingår i: Urban Climate. - : Elsevier BV. - 2212-0955. ; 43
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Tidskriftsartikel (refereegranskat)abstract
- Wind extremes cause many environmental and natural hazard related problems globally, particularly in heavily populated metropolitan areas. However, the underlying causes of maximum wind speed variability in urbanized regions remain largely unknown. Here, we investigated how rapid urbanization in the Yangtze River Delta (YRD), China, impacted daily maximum wind speed (DMWS) between 1990 and 2015, based on near-surface (10 m height) DMWS observations, reanalysis datasets, and night-time lighting data (a proxy for urbanization). The station observation shows that annual DMWS in the YRD significantly (p < 0.05) declined during 1990-2015, by -0.209 m s(-1) decade(-1), while slightly (p > 0.1) positive trends were found in NCEP-NCAR1 (+0.048 m s(-1) decade(-1)) and ERA5 (+0.027 m s(-1) decade(-1)). An increasing divergence between the reanalysis output and the station observation since 2005 was found, and those stations located in areas with high rates of urbanization show the strongest negative annual DMWS trend, implying the key role of urbanization in weakening DMWS. This finding is supported by sensitivity experiments conducted using a regional climate model (RegCM4) forced with both 1990 and 2015 land-use and land-cover (LULC) data, where the simulated DMWS using the 2015 LULC data was lower than that simulated using the 1990 LULC data.
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