Women with PCOS have an increased risk for cardiovascular disease regardless of diagnostic criteria - a prospective population-based cohort study

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with many cardiovascular disease (CVD) risk factors, such as obesity, type 2 diabetes mellitus and hypertension. However, it remains debatable whether the presence of multiple CVD risk factors translates to increased CVD events. DESIGN: A prospective, population-based Northern Finland Birth Cohort 1966. METHODS: Individuals with an expected date of birth in 1966 in Northern Finland have been followed from birth. Women in the cohort were classified as having PCOS according to either the National Institute of Health (NIH) criteria (n = 144) or the Rotterdam criteria (n = 386) at age 31, and they were compared to women without any PCOS features. The study population was re-examined at age 46, and the incidence of major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke, heart failure and cardiovascular mortality, was recorded up to age 53. RESULTS: During the 22-year follow-up, both women with NIH-PCOS and women with Rotterdam-PCOS had a significantly higher risk for cardiovascular events than control women. The BMI-adjusted hazard ratio (HR) for MACE in the Rotterdam-PCOS group and the NIH-PCOS group was 2.33 (1.26-4.30) and 2.47 (1.18-5.17), respectively. The cumulative hazard curves in both diagnostic categories began to diverge at age 35. Regarding the individual CVD endpoints, MI was significantly more prevalent in both women with NIH-PCOS (P = .010) and women with Rotterdam-PCOS (P = .019), when compared to control women. CONCLUSIONS: PCOS should be considered a significant risk factor for CVD. Future follow-up will show how the risk of CVD events develops after menopausal age

SUMOylation of AMPK alpha 1 by PIAS4 specifically regulates mTORC1 signalling

AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of Z attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPK alpha 1 SUMOylation and the inhibition of AMPK alpha 1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPK alpha 1a mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKa-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPK alpha 1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.Peer reviewe

Role of microstructure and surface defects on the dissolution kinetics of CeO2, a UO2 fuel analogue.

The release of radionuclides from spent fuel in a geological disposal facility is controlled by the surface mediated dissolution of UO2 in groundwater. In this study we investigate the influence of reactive surface sites on the dissolution of a synthesised CeO2 analogue for UO2 fuel. Dissolution was performed on: CeO2 annealed at high temperature, which eliminated intrinsic surface defects (point defects and dislocations); CeO2-x annealed in inert and reducing atmospheres to induce oxygen vacancy defects; and on crushed CeO2 particles of different size fractions. BET surface area measurements were used as an indicator of reactive surface site concentration. Cerium stoichiometry, determined using X-ray Photoelectron Spectroscopy (XPS) and supported by X-ray Diffraction (XRD) analysis, was used to determine oxygen vacancy concentration. Upon dissolution in nitric acid medium at 90°C, a quantifiable relationship was established between the concentration of high energy surface sites and CeO2 dissolution rate; the greater the proportion of intrinsic defects and oxygen vacancies, the higher the dissolution rate. Dissolution of oxygen vacancy-containing CeO2-x gave rise to rates that were an order of magnitude greater than for CeO2 with fewer oxygen vacancies. While enhanced solubility of Ce3+ influenced the dissolution, it was shown that replacement of vacancy sites by oxygen significantly affected the dissolution mechanism due to changes in the lattice volume and strain upon dissolution and concurrent grain boundary decohesion. These results highlight the significant influence of defect sites and grain boundaries on the dissolution kinetics of UO2 fuel analogues and reduce uncertainty in the long-term performance of spent fuel in geological disposal

Apatites in Gale Crater

ChemCam is an active remote sensing instrument suite that has operated successfully on MSL since landing Aug. 6th, 2012. It uses laser pulses to remove dust and to analyze rocks up to 7 m away. Laser-induced breakdown spectroscopy (LIBS) obtains emission spectra of materials ablated from the samples in electronically excited states. The intensities of the emission lines scale with the abundances of the related element. ChemCam is sensitive to most major rock-forming elements as well as to a set of minor and trace elements such as F, Cl, Li, P, Sr, Ba, and Rb. The measured chemical composition can then be used to infer the mineralogical composition of the ablated material. Here, we report a summary of inferred apatite detections along the MSL traverse at Gale Crater. We present the geologic settings of these findings and derive some interpretations about the formation conditions of apatite in time and space

Association of accelerometer-derived sleep measures with lifetime psychiatric diagnoses : A cross-sectional study of 89,205 participants from the UK Biobank

Funding Information: The authors acknowledge Milos Milic for data curation assistance. MW and SJT acknowledge support from the Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC (RGPIN-2020-05834 and DGECR-2020-00048) and CIHR (NGN-171423). DF is supported by the Michael and Sonja Koerner Foundation New Scientist Program, Krembil Foundation, CAMH Discovery Fund, and the McLaughlin Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was conducted under the auspices of UK Biobank application 61530, ?Multimodal subtyping of mental illness across the adult lifespan through integration of multi-scale whole-person phenotypes?. The authors acknowledge Milos Milic for data curation assistance. This research was conducted under the auspices of UK Biobank application 61530, ?Multimodal subtyping of mental illness across the adult lifespan through integration of multi-scale whole-person phenotypes.? Publisher Copyright: Copyright: © 2021 Wainberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. Methods and findings In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures—bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration—were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was β = −0.11 (95% confidence interval −0.13 to −0.10, p = 3 × 10−56, FDR = 6 × 10−55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. Conclusions In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.Peer reviewe

Fluctuating lattice-Boltzmann model for complex fluids

We develop and test numerically a lattice-Boltzmann (LB) model for nonideal fluids that incorporates thermal fluctuations. The fluid model is a momentum-conserving thermostat, for which we demonstrate how the temperature can be made equal at all length scales present in the system by having noise both locally in the stress tensor and by shaking the whole system in accord with the local temperature. The validity of the model is extended to a broad range of sound velocities. Our model features a consistent coupling scheme between the fluid and solid molecular dynamics objects, allowing us to use the LB fluid as a heat bath for solutes evolving in time without external Langevin noise added to the solute. This property expands the applicability of LB models to dense, strongly correlated systems with thermal fluctuations and potentially nonideal equations of state. Tests on the fluid itself and on static and dynamic properties of a coarse-grained polymer chain under strong hydrodynamic interactions are used to benchmark the model. The model produces results for single-chain diffusion that are in quantitative agreement with theory.Peer reviewe

Vibrational Spectra of a Mechanosensitive Channel

We report the simulated vibrational spectra of a mechanosensitive membrane channel in different gating states. Our results show that while linear absorption is insensitive to structural differences, linear dichroism and sum-frequency generation spectroscopies are sensitive to the orientation of the transmembrane helices, which is changing during the opening process. Linear dichroism cannot distinguish an intermediate structure from the closed structure, but sum-frequency generation can. In addition, we find that two-dimensional infrared spectroscopy can be used to distinguish all three investigated gating states of the mechanosensitive membrane channel.

Calibration of the MSL/ChemCam/LIBS Remote Sensing Composition Instrument

The ChemCam instrument suite on board the 2011 Mars Science Laboratory (MSL) Rover, Curiosity, will provide remote-sensing composition information for rock and soil samples within seven meters of the rover using a laser-induced breakdown spectroscopy (LIBS) system, and will provide context imaging with a resolution of 0.10 mradians using the remote micro-imager (RMI) camera. The high resolution is needed to image the small analysis footprint of the LIBS system, at 0.2-0.6 mm diameter. This fine scale analytical capability will enable remote probing of stratigraphic layers or other small features the size of "blueberries" or smaller. ChemCam is intended for rapid survey analyses within 7 m of the rover, with each measurement taking less than 6 minutes. Repeated laser pulses remove dust coatings and provide depth profiles through weathering layers, allowing detailed investigation of rock varnish features as well as analysis of the underlying pristine rock composition. The LIBS technique uses brief laser pulses greater than 10 MW/square mm to ablate and electrically excite material from the sample of interest. The plasma emits photons with wavelengths characteristic of the elements present in the material, permitting detection and quantification of nearly all elements, including the light elements H, Li, Be, B, C, N, O. ChemCam LIBS projects 14 mJ of 1067 nm photons on target and covers a spectral range of 240-850 nm with resolutions between 0.15 and 0.60 nm FWHM. The Nd:KGW laser is passively cooled and is tuned to provide maximum power output from -10 to 0 C, though it can operate at 20% degraded energy output at room temperature. Preliminary calibrations were carried out on the flight model (FM) in 2008. However, the detectors were replaced in 2009, and final calibrations occurred in April-June, 2010. This presentation describes the LIBS calibration and characterization procedures and results, and details plans for final analyses during rover system thermal testing, planned for early March

Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016

Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016