Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks.

The genetic structure in Europe was mostly shaped by admixture between the Western Hunter-Gatherers, Early European Farmers and Steppe Bronze Age ancestral components. Such structure is regarded as a confounder in GWAS and follow-up studies, and gold-standard methods exist to correct for it. However, it is still poorly understood to which extent these ancestral components contribute to complex trait variation in present-day Europe. In this work we harness the UK Biobank to address this question. By extensive demographic simulations, exploiting data on siblings and incorporating previous results we obtained from the Estonian Biobank, we carefully evaluate the significance and scope of our findings. Heart rate, platelet count, bone mineral density and many other traits show stratification similar to height and pigmentation traits, likely targets of selection and divergence across ancestral groups. We show that the reported ancestry-trait associations are not driven by environmental confounders by confirming our results when using between-sibling differences in ancestry. The consistency of our results across biobanks further supports this and indicates that these genetic predispositions that derive from post-Neolithic admixture events act as a source of variability and as potential confounders in Europe as a whole.

Left ventricular unloading via percutaneous assist device during extracorporeal membrane oxygenation in acute myocardial infarction and cardiac arrest.

INTRODUCTION: A feared complication of an acute myocardial infarction (AMI) is cardiac arrest (CA). Even if return of spontaneous circulation is achieved, cardiogenic shock (CS) is common. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) supports patients with CS and is often used in conjunction with an Impella device (2.5 and CP) to off-load the left ventricle, although limited evidence supports this approach. METHODS: The goal of this study was to determine whether a mortality difference was observed in VA-ECMO alone versus VA-ECMO with Impella (ECPELLA) in patients with CS from AMI and CA. A retrospective chart review of 50 patients with AMI-CS and CA and were supported with VA-ECMO (n = 34) or ECPELLA (n = 16) was performed. The primary outcome was all-cause mortality at 6-months from VA-ECMO or Impella implantation. Secondary outcomes included in-hospital mortality and complication rates between both cohorts and intensive care unit data. RESULTS: Baseline characteristics were similar, except patients with ST-elevation myocardial infarction were more likely to be in the VA-ECMO group (p = 0.044). The ECPELLA cohort had significantly worse survival after VA-ECMO (SAVE) score (p = 0.032). Six-month all-cause mortality was not significantly different between the cohorts, even when adjusting for SAVE score. Secondary outcomes were notable for an increased rate of minor complications without an increased rate of major complications in the ECPELLA group. CONCLUSIONS: Randomized trials are needed to determine if a mortality difference exists between VA-ECMO and ECPELLA platforms in patients with AMI complicated by CA and CS.

Cobalt Ferrite Nanorods Synthesized with a Facile "Green" Method in a Magnetic Field.

We report a new facile method for the synthesis of prolate cobalt ferrite nanoparticles without additional stabilizers, which involves a co-precipitation reaction of Fe3+ and Co2+ ions in a static magnetic field. The magnetic field is demonstrated to be a key factor for the 1D growth of cobalt ferrite nanocrystals in the synthesis. Transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy are applied to characterize the morphology and structure of the obtained nanoparticles. According to TEM, they represent nanorods with a mean length of 25 nm and a diameter of 3.4 nm that have a monocrystalline structure with characteristic plane spacing of 2.9 Å. XRD and Raman spectroscopy confirm the spinel CoFe2O4 structure of the nanorods. After aging, the synthesized nanorods exhibit maximum saturation magnetization and coercivity equal to 30 emu/g and 0.3 kOe, respectively. Thus, the suggested method is a simple and "green" way to prepare CoFe2O4 nanorods with high aspect ratios and pronounced magnetic properties, which are important for various practical applications, including biomedicine, energy storage, and the preparation of anisotropic magnetic nanocomposites.

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.