Severe Diabetes and Leptin Resistance Cause Differential Hepatic and Renal Transporter Expression in Mice

Background: Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites. Results: Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice. Conclusion: A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels

The Hyper Suprime-Cam Software Pipeline

In this paper, we describe the optical imaging data processing pipeline developed for the Subaru Telescope's Hyper Suprime-Cam (HSC) instrument. The HSC Pipeline builds on the prototype pipeline being developed by the Large Synoptic Survey Telescope's Data Management system, adding customizations for HSC, large-scale processing capabilities, and novel algorithms that have since been reincorporated into the LSST codebase. While designed primarily to reduce HSC Subaru Strategic Program (SSP) data, it is also the recommended pipeline for reducing general-observer HSC data. The HSC pipeline includes high level processing steps that generate coadded images and science-ready catalogs as well as low-level detrending and image characterizations.Comment: 39 pages, 21 figures, 2 tables. Submitted to Publications of the Astronomical Society of Japa

The Super-Seniors Study: Phenotypic Characterization of a Healthy 85+ Population

Background To understand why some people live to advanced age in good health and others do not, it is important to study not only disease, but also long-term good health. The Super-Seniors Study aims to identify factors associated with healthy aging. Methods 480 healthy oldest-old ‘Super-Seniors’ aged 85 to 105 years and never diagnosed with cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease, were compared to 545 mid-life controls aged 41–54, who represent a group that is unselected for survival from late-life diseases. Health and lifestyle information, personal and family medical history, and blood samples were collected from all participants. Super-Seniors also underwent four geriatric tests. Results Super-Seniors showed high cognitive (Mini-Mental State Exam mean = 28.3) and functional capacity (Instrumental Activities of Daily Living Scale mean = 21.4), as well as high physical function (Timed Up and Go mean = 12.3 seconds) and low levels of depression (Geriatric Depression Scale mean = 1.5). Super-Seniors were less likely to be current smokers than controls, but the frequency of drinking alcohol was the same in both groups. Super-Seniors were more likely to have 4 or more offspring; controls were more likely to have no children. Female Super-Seniors had a mean age of last fertility 1.9 years older than controls, and were 2.3 times more likely to have had a child at ≥ 40 years. The parents of Super-Seniors had mean ages of deaths of 79.3 years for mothers, and 74.5 years for fathers, each exceeding the life expectancy for their era by a decade. Conclusions Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age, representing the approximately top 1% for healthspan. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype

Hyper Suprime-Cam Year 3 Results: Cosmology from Cosmic Shear Two-point Correlation Functions

We perform a blinded cosmology analysis with cosmic shear two-point correlation functions (2PCFs) measured from more than 25 million galaxies in the Hyper Suprime-Cam three-year shear catalog in four tomographic redshift bins ranging from 0.3 to 1.5. After conservative masking and galaxy selection, the survey covers 416 deg$^2$ of the northern sky with an effective galaxy number density of 15 arcmin$^{-2}$ over the four redshift bins. The 2PCFs adopted for cosmology analysis are measured in the angular range: $7.1 < \theta/{\rm arcmin} < 56.6$ for $\xi_+$ and $31.2 <\theta/{\rm arcmin} < 248$ for $\xi_-$, with a total signal-to-noise ratio of 26.6. We apply a conservative, wide, flat prior on the photometric redshift errors on the last two tomographic bins, and the relative magnitudes of the cosmic shear amplitude across four redshift bins allow us to calibrate the photometric redshift errors. With this flat prior on redshift errors, we find $\Omega_{\rm m}=0.256_{-0.044}^{+0.056}$ and $S_8\equiv \sigma_8 \sqrt{\Omega_{\rm m}/0.3}=0.769_{-0.034}^{+0.031}$ (both 68\% CI) for a flat $\Lambda$ cold dark matter cosmology. We find, after unblinding, that our constraint on $S_8$ is consistent with the Fourier space cosmic shear and the 3$\times$2pt analyses on the same HSC dataset. We carefully study the potential systematics from astrophysical and systematic model uncertainties in our fiducial analysis using synthetic data, and report no biases (including projection bias in the posterior space) greater than $0.5\sigma$ in the estimation of $S_8$. Our analysis hints that the mean redshifts of the two highest tomographic bins are higher than initially estimated. In addition, a number of consistency tests are conducted to assess the robustness of our analysis. Comparing our result with Planck-2018 cosmic microwave background observations, we find a ~$2\sigma$ tension for the $\Lambda$CDM model.Comment: 38 pages, 32 figures, 4 tables (PRD in press.

Hyper Suprime-Cam Year 3 results: Cosmology from cosmic shear two-point correlation functions

We perform a blinded cosmology analysis with cosmic shear two-point correlation functions measured from more than 25 million galaxies in the Hyper Suprime-Cam three-year shear catalog in four tomographic redshift bins ranging from 0.3 to 1.5. After conservative masking and galaxy selection, the survey covers 416 deg2 of the northern sky with an effective galaxy number density of 15 arcmin-2 over the four redshift bins. The 2PCFs adopted for cosmology analysis are measured in the angular range; 7.1&lt;θ/arcmin&lt;56.6 for ζ+ and 31.2&lt;θ/arcmin&lt;248 for ζ-, with a total signal-to-noise ratio of 26.6. We apply a conservative, wide, flat prior on the photometric redshift errors on the last two tomographic bins, and the relative magnitudes of the cosmic shear amplitude across four redshift bins allow us to calibrate the photometric redshift errors. With this flat prior on redshift errors, we find ωm=0.256-0.044+0.056 and S8σ8ωm/0.3=0.769-0.034+0.031 (both 68% C.I.) for a flat Λ cold dark matter cosmology. We find, after unblinding, that our constraint on S8 is consistent with the Fourier space cosmic shear and the 3×2 pt analyses on the same HSC dataset. We carefully study the potential systematics from astrophysical and systematic model uncertainties in our fiducial analysis using synthetic data, and report no biases (including projection bias in the posterior space) greater than 0.5σ in the estimation of S8. Our analysis hints that the mean redshifts of the two highest tomographic bins are higher than initially estimated. In addition, a number of consistency tests are conducted to assess the robustness of our analysis. Comparing our result with Planck-2018 cosmic microwave background observations, we find a ∼2σ tension for the ΛCDM model

A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: A case control study in an Italian population

<p>Abstract</p> <p>Background</p> <p>Inherited genetic factors such as E-cadherin (<it>CDH1</it>) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for <it>CDH1 </it>transcription has been identified in <it>CDH1 </it>intron 2.</p> <p>Methods</p> <p>We genotyped all known polymorphisms located within conserved sequences of <it>CDH1 </it>intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using χ²-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis.</p> <p>Results</p> <p>We observed a significant (p < 0.0004) association of the <it>CDH1 </it>163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09–9.93) and 1.38 (95%CI = 0.75–2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and <it>H. pylori </it>infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied.</p> <p>Conclusion</p> <p>The <it>CDH1 </it>163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.</p

Hyper Suprime-Cam Year 3 results: cosmology from cosmic shear power spectra

We measure weak lensing cosmic shear power spectra from the 3-year galaxy shear catalog of the Hyper Suprime-Cam (HSC) Subaru Strategic Program imaging survey. The shear catalog covers 416  deg2 of the northern sky, with a mean i-band seeing of 0.59 arcsec and an effective galaxy number density of 15  arcmin−2 within our adopted redshift range. With an i-band magnitude limit of 24.5 mag, and four tomographic redshift bins spanning 0.3≤zph≤1.5 based on photometric redshifts, we obtain a high-significance measurement of the cosmic shear power spectra, with a signal-to-noise ratio of approximately 26.4 in the multipole range 300<ℓ<1800. The accuracy of our power spectrum measurement is tested against realistic mock shear catalogs, and we use these catalogs to get a reliable measurement of the covariance of the power spectrum measurements. We use a robust blinding procedure to avoid confirmation bias, and model various uncertainties and sources of bias in our analysis, including point spread function systematics, redshift distribution uncertainties, the intrinsic alignment of galaxies and the modeling of the matter power spectrum. For a flat ΛCDM model, we find S8≡σ8(Ωm/0.3)0.5=0.776+0.032−0.033, which is in excellent agreement with the constraints from the other HSC Year 3 cosmology analyses, as well as those from a number of other cosmic shear experiments. This result implies a ∼2σ-level tension with the Planck 2018 cosmology. We study the effect that various systematic errors and modeling choices could have on this value, and find that they can shift the best-fit value of S8 by no more than ∼0.5σ, indicating that our result is robust to such systematics

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden