Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Achievement of combined goals of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol with three different statins: Results from VOYAGER

AbstractBackgroundGuidelines suggest that the combination of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) is the most clinically relevant goal for lipid-lowering treatments.MethodsData from VOYAGER, an individual patient data meta-analysis including 32,258 patients from 37 clinical trials, was used to determine the percentage of patients reaching combined goals of LDL-C and non-HDL-C following treatment with simvastatin, atorvastatin, or rosuvastatin. Paired comparisons were made between each dose of rosuvastatin and the same or higher doses of simvastatin and atorvastatin.ResultsEach dose of rosuvastatin brought significantly more patients to the combined goal of LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL than the same or double dose of atorvastatin; atorvastatin 80 mg was significantly superior to rosuvastatin 10 mg (all p < 0.001). Each dose of rosuvastatin helped significantly more patients reach the combined goal than any dose of simvastatin (all p < 0.001), except for rosuvastatin 10 mg versus simvastatin 80 mg (non-significant). Also, each dose of rosuvastatin helped significantly more patients to reach the combined goal of LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL than the same or double dose of atorvastatin (all p < 0.001). Every dose of rosuvastatin was significantly superior to all doses of simvastatin (all p ≤ 0.020), except for rosuvastatin 10 mg versus simvastatin 40 mg and 80 mg (non-significant).ConclusionsPhysicians' choice of statin and dose is important in helping patients achieve the combined LDL-C and non-HDL-C goals recommended in established guidelines

New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease

Over the past few decades, atherogenic dyslipidaemia has become one of the most common phenotypic presentations of lipid abnormalities, being strongly and unequivocally associated with an increased risk of cardiovascular (CV) disease. Despite the excellent results achieved from statin and non-statin management of LDL cholesterol and CV events prevention, there still remains a significant residual risk, associated with the prevalence of non-LDL cholesterol lipid patterns characterised by elevated triglyceride levels, low HDL cholesterol, a preponderance of small and dense LDL particles, accumulation of remnant lipoproteins and postprandial hyperlipidaemia. These qualitative and quantitative lipid modifications are largely associated with insulin resistance, type 2 diabetes and obesity, the prevalence of which has grown to epidemic proportions throughout the world. In this review, we analyse the pathophysiology of this particular dyslipidaemia, its relationship with the development of atherosclerotic CV disease and, finally, briefly describe the therapeutic approaches, including changes in lifestyle and current pharmacological interventions to manage these lipid alterations aimed at preventing CV events

Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion

Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels

Geothermal Energy Market Study on the Atlantic Coastal Plain. The Demand Specified Model for Direct Applications of Geothermal Energy: A User's Guide

The Applied Physics Laboratory and the Center for Metropolitan Planning and Research of The Johns Hopkins University support the Department of Energy's Division of Geothermal Energy (DOE/DGE) in planning and assisting the development of geothermal energy in the eastern United States. This effort includes development scenarios, energy market surveys, development of tools to analyze and optimize the cost of geothermal energy, the methodology for prediction of market penetration technical assistance to states, groups, and individuals and general support to DOE/DGE. This report documents one of the economic tools developed under that program. Related reports are listed as references

Public Health Governance and Population Health Outcomes

Research reviews have identified a gap in understanding the diversity of health department governance structures and in understanding how the variations in governing relates to health outcomes. This report details the categorization of local public health governance and reveals that certain governance types may be better suited to achieve better population health outcomes. State systems achieve the poorest health outcomes, but the best health outcomes are achieved when the political branches have a key role in local public health governance. Public health systems should consider greater local control and involvement in governance; but local governance should include the political branches -- and even the state -- to achieve more positive health outcomes

Discovery of Interstellar Hydrogen Fluoride

We report the first detection of interstellar hydrogen fluoride. Using the Long Wavelength Spectrometer (LWS) of the Infrared Space Observatory (ISO), we have detected the 121.6973 micron J = 2 - 1 line of HF in absorption toward the far-infrared continuum source Sagittarius B2. The detection is statistically significant at the 13 sigma level. On the basis of our model for the excitation of HF in Sgr B2, the observed line equivalent width of 1.0 nm implies a hydrogen fluoride abundance of 3E-10 relative to H2. If the elemental abundance of fluorine in Sgr B2 is the same as that in the solar system, then HF accounts for ~ 2% of the total number of fluorine nuclei. We expect hydrogen fluoride to be the dominant reservoir of gas-phase fluorine in Sgr B2, because it is formed rapidly in exothermic reactions of atomic fluorine with either water or molecular hydrogen; thus the measured HF abundance suggests a substantial depletion of fluorine onto dust grains. Similar conclusions regarding depletion have previously been reached for the case of chlorine in dense interstellar clouds. We also find evidence at a lower level of statistical significance (~ 5 sigma) for an emission feature at the expected position of the 4(3,2)-4(2,3) 121.7219 micron line of water. The emission line equivalent width of 0.5 nm for the water feature is consistent with the water abundance of 5E-6 relative to H2 that has been inferred previously from observations of the hot core of Sgr B2.Comment: 11 pages (AASTeX using aaspp4.sty) plus 2 figures; to appear in ApJ Letter

Tissue Determinants of Human NK Cell Development, Function, and Residence.

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT

Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-golgi junctions

Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein-related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism