The relation of overweight to dementia is controversial. We aimed to examine the association of midlife overweight and obesity with dementia, Alzheimer disease (AD), and vascular dementia (VaD) in ...late life, and to verify the hypothesis that genetic and early-life environmental factors contribute to the observed association.
From the Swedish Twin Registry, 8,534 twin individuals aged ≥65 (mean age 74.4) were assessed to detect dementia cases (DSM-IV criteria). Height and weight at midlife (mean age 43.4) were available in the Registry. Data were analyzed as follows: 1) unmatched case-control analysis for all twins using generalized estimating equation (GEE) models and 2) cotwin matched case-control approach for dementia-discordant twin pairs by conditional logistic regression taking into account lifespan vascular disorders and diabetes.
Among all participants, dementia was diagnosed in 350 subjects, and 114 persons had questionable dementia. Overweight (body mass index BMI >25-30) and obesity (BMI >30) at midlife were present in 2,541 (29.8%) individuals. In fully adjusted GEE models, compared with normal BMI (20-25), overweight and obesity at midlife were related to dementia with odds ratios (ORs) (95% CIs) of 1.71 (1.30-2.25) and 3.88 (2.12-7.11), respectively. Conditional logistic regression analysis in 137 dementia-discordant twin pairs led to an attenuated midlife BMI-dementia association. The difference in ORs from the GEE and the matched case-control analysis was statistically significant (p = 0.019).
Both overweight and obesity at midlife independently increase the risk of dementia, AD, and VaD. Genetic and early-life environmental factors may contribute to the midlife high adiposity-dementia association.
Interindividual variation in response to metformin, first‐line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the ...effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.–66T→C, rs2252281) and MATE2 (g.–130G→A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose‐lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post‐metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.
Clinical Pharmacology & Therapeutics (2013); 93 2, 186–194. doi:10.1038/clpt.2012.210
Abstract
Nuclear charge radii globally scale with atomic mass number
A
as
A
1∕3
, and isotopes with an odd number of neutrons are usually slightly smaller in size than their even-neutron neighbours. ...This odd–even staggering, ubiquitous throughout the nuclear landscape
1
, varies with the number of protons and neutrons, and poses a substantial challenge for nuclear theory
2–4
. Here, we report measurements of the charge radii of short-lived copper isotopes up to the very exotic
78
Cu (with proton number
Z
= 29 and neutron number
N
= 49), produced at only 20 ions s
–1
, using the collinear resonance ionization spectroscopy method at the Isotope Mass Separator On-Line Device facility (ISOLDE) at CERN. We observe an unexpected reduction in the odd–even staggering for isotopes approaching the
N
= 50 shell gap. To describe the data, we applied models based on nuclear density functional theory
5,6
and
A
-body valence-space in-medium similarity renormalization group theory
7,8
. Through these comparisons, we demonstrate a relation between the global behaviour of charge radii and the saturation density of nuclear matter, and show that the local charge radii variations, which reflect the many-body polarization effects, naturally emerge from
A
-body calculations fitted to properties of
A
≤ 4 nuclei.
Following the recent isolation of monolayer CrI3 (ref. 1), many more two-dimensional van der Waals magnetic materials have been isolated2–12. Their incorporation in van der Waals heterostructures ...offers a new platform for spintronics5–9, proximity magnetism13 and quantum spin liquids14. A primary question in this field is how exfoliating crystals to the few-layer limit influences their magnetism. Studies of CrI3 have shown a different magnetic ground state for ultrathin exfoliated films1,5,6 compared with the bulk, but the origin is not yet understood. Here, we use electron tunnelling through few-layer crystals of the layered antiferromagnetic insulator CrCl3 to probe its magnetic order and find a tenfold enhancement of the interlayer exchange compared with bulk crystals. Moreover, temperature- and polarization-dependent Raman spectroscopy reveals that the crystallographic phase transition of bulk crystals does not occur in exfoliated films. This results in a different low-temperature stacking order and, we hypothesize, increased interlayer exchange. Our study provides insight into the connection between stacking order and interlayer interactions in two-dimensional magnets, which may be relevant for correlating stacking faults and mechanical deformations with the magnetic ground states of other more exotic layered magnets such as RuCl3 (ref. 14).
Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼ 150 – 350 MeV . We use ...Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma's final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.
Abstract On 2022 September 5, Parker Solar Probe (Parker) observed a large solar energetic particle (SEP) event at the unprecedented distance of only 15 R S from the Sun. The observations from the ...Integrated Science Investigation of the Sun (IS⊙IS) obtained over the course of this event are remarkably rich, and an overview is presented here. IS⊙IS is capable of measuring ions from 20 keV to over 100 MeV nuc −1 and electrons from 30 keV to 6 MeV; here, we primarily focus on the proton and helium measurements above 80 keV. Among the surprising results are evidence of inverse velocity dispersion at energies above 1 MeV during the onset of the event, a sharp decrease in the energetic particle intensities at all energies at the interplanetary shock crossing, and repeated short durations of highly anisotropic sunward flow. Many changes in the SEP intensities, anisotropy, and spectral steepness are coincident with solar wind structure boundaries identified using the Parker solar wind magnetic field and plasma data. However, there are significant changes that are not correlated with any clearly visible solar wind variation. The observations presented here serve as an introduction to a complex event with numerous opportunities for future, more in-depth studies.
Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
PDF
