IMPORTANCE: Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused ...because of a high risk of adverse events. OBJECTIVE: To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug. INTERVENTIONS: Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days. MAIN OUTCOMES AND MEASURES: The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate. RESULTS: The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 90% CI, 0.68-0.91; P = .004; for 10 mg/d, 0.76 90% CI, 0.65-0.88; P = .001; for 15 mg/d, 0.67 90% CI, 0.58-0.77; P<.001; for 20 mg/d, 0.62 90% CI, 0.54-0.72; P < .001). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups. CONCLUSIONS AND RELEVANCE: Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT1874431
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•Indentation-induced cracking in small specimens renders realistic glass strengths.•Nonlinear acoustic method gives a measure of the amount and size of the defects.•Non-destructive ...test of the glass strength for small samples (10 × 10 cm2).•Failure stress vs. normalized defect value (NDV) gives a linear correlation.
The present paper describes a method for non-destructive testing of the glass strength. Square 10 × 10 cm2 samples of annealed float glass was inflicted with a controlled defect in the centre of the atmospheric side using Vickers microindentation-induced cracking with a force of 2 N, 5 N and 10 N and compared to an un-indented reference. The samples were non-destructively tested using a nonlinear acoustic wave method resulting in defect values. The average of the defect values was found to linearly correlate to the indentation force in a log–log relationship. The samples were subsequently tested in a ring-on-ring setup that allows for an equibiaxial stress state. The indentation-induced cracking gave practically realistic strength values in the range of 45 to 110 MPa. The individual sample values for failure stress as a function of normalized defect value show linear trends with approximately half of the data within 95% confidence limit. In summary, this study provides an initial proof-of-concept for a non-destructive testing of the strength of glass.
IMPORTANCE: The public health success of diabetic retinopathy (DR) screening programs depends on patients’ adherence to the timetable of follow-up eye care recommended by the screening program. ...African Americans are among those at highest risk for DR and have one of the lowest rates of eye care use. OBJECTIVES: To assess the rate of adhering to recommended follow-up eye care in a DR screening program administered in a safety-net health care facility and to examine factors associated with follow-up eye care use. DESIGN, SETTING, AND PARTICIPANTS: Prospective follow-up study of persons with type 1 or type 2 diabetes. The setting was an internal medicine clinic of a publicly funded health system in Alabama, serving a population largely uninsured and African American, that had implemented a DR screening program using a nonmydriatic camera for ocular imaging and remote reading centers for evaluation of images. Patients with physician appointments between January 26 and July 24, 2012, were eligible for screening if they had a diagnosis of type 1 or type 2 diabetes and were 19 years or older. Data from the county health system’s administrative database were obtained from January 26, 2012 (date of first enrollee), through May 1, 2015, to establish participants’ eye care use in the ophthalmology clinic after screening. MAIN OUTCOMES AND MEASURES: Adherence to the recommended interval of follow-up eye appointments in the facility’s ophthalmology service as determined by administrative records, as well as factors associated with adherence. RESULTS: Diabetic retinopathy screening was completed in 949 adults with diabetes, of whom 84.5% (802 of 949) were African American, 64.5% (612 of 949) were women, and 71.7% (680 of 949) lacked health insurance. Participants ranged in age from 21 to 95 years, and their mean (SD) age was 53.9 (10.4) years. The mean (SD) age at diabetes diagnosis was 44.3 (12.5) years, and the mean (SD) duration of diabetes was 9.6 (9.4) years. Across interval recommendation types, 29.9% (284 of 949) adhered to obtaining comprehensive follow-up eye care within the recommended time frame. Two years after a participant’s screening date, 50.9% (483 of 949) had no record of having received eye care. Factors associated with adhering to interval appointments were having an advanced age (odds ratio, 1.02; 95% CI, 1.01-1.04) and knowing one’s glycated hemoglobin level (odds ratio, 2.00; 95% CI, 1.34-2.97). Agreeing to assistance in making a follow-up eye care appointment was associated with nonadherence (odds ratio, 0.67; 95% CI, 0.45-0.99). CONCLUSIONS AND RELEVANCE: After a DR screening program in a public clinic largely serving an African American population, only one-third of participants adhered to interval recommendations for follow-up eye appointments, even though cost and accessibility were minimized as barriers to care. Our findings suggest that DR screening programs are not likely to meet their public health goals without incorporation of eye health education initiatives successfully promoting adherence to recommended comprehensive eye care for preventing vision loss.
Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To ...test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-9-39 (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.
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•Intestinally secreted GLP-1 is presumed to regulate glucose via incretin action•Exendin-9 does not alter glucose in mice that only produce GLP-1 in the intestine•Exendin-9 does impair glucose in mice that only produce GLP-1 in the pancreas•Alternative to the incretin model, islet GLP-1 is crucial for gluco-regulation
GLP-1 is necessary for normal gluco-regulation, and it has been widely presumed that this function is the action of peptide released from enteroendocrine L cells. The data from Chambers et al. challenge this dogma and find that intestinally produced GLP-1 is dispensable, while pancreatic production of GLP-1 is necessary for gluco-regulation.
We report the final result of the CUORICINO experiment. Operated between 2003 and 2008, with a total exposure of 19.75 kg*y of Te, CUORICINO was able to set a lower bound on the Te Ovββhalf-life of ...2.8 ×10years at 90% C.L. The limit here reported includes the effects of systematic uncertainties that are examined in detail in the paper. The corresponding upper bound on the neutrino Majorana mass is in the range 300-710 meV, depending on the adopted nuclear matrix element evaluation.
Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. ...Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).
A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.
Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.
Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.
Clinicaltrials.gov NCT01106157.
The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.
Gradient Forest (GF) is a machine learning algorithm designed to analyze spatial patterns of biodiversity as a function of environmental gradients. An offset measure between the GF‐predicted ...environmental association of adapted alleles and a new environment (GF Offset) is increasingly being used to predict the loss of environmentally adapted alleles under rapid environmental change, but remains mostly untested for this purpose. Here, we explore the robustness of GF Offset to assumption violations, and its relationship to measures of fitness, using SLiM simulations with explicit genome architecture and a spatial metapopulation. We evaluate measures of GF Offset in: (1) a neutral model with no environmental adaptation; (2) a monogenic “population genetic” model with a single environmentally adapted locus; and (3) a polygenic “quantitative genetic” model with two adaptive traits, each adapting to a different environment. We found GF Offset to be broadly correlated with fitness offsets under both single locus and polygenic architectures. However, neutral demography, genomic architecture, and the nature of the adaptive environment can all confound relationships between GF Offset and fitness. GF Offset is a promising tool, but it is important to understand its limitations and underlying assumptions, especially when used in the context of predicting maladaptation.
Increasing evidence suggests that ecosystem functions are strongly linked to morphological plant traits, like specific leaf area (SLA) and its variability, which serve as a proxy of functional ...diversity (FD). Functional diversity is rarely studied at regional scales, and its scale dependence is poorly understood. Capturing trait variations at distinct spatial scales and in differently managed grasslands remains challenging, mainly because a limited number of trait measurements are available and field campaigns are time-consuming. Here, we derived α- and β-FD indices based on SLA measured in the field and estimated from optical satellite data by using molecular absorption profiles of leaves in canopies. We inverted the 1-D columnar radiative transfer model PROSAIL using Sentinel-2 reflectance data at canopy level. From the inversion we were able to distinguish different alpine management types based on retrieved SLA. Model uncertainties were mainly related to the different local plant communities, here represented by functional diversity indices and community-weighted means of traits. Thus, successful PROSAIL application was affected by management type. Management categories displaying lower α-FD, like mowed and fertilized, delivered the most reliable results. Further, we compared FD (i.e., richness, evenness, divergence) from local to regional scales. Locally, management determines the magnitude of FD, whereas on a regional scale, parcel size and the uniformity of agricultural practices control trait diversity. Our results highlight the importance of quantifying β-FD from space as it delivers additional information on the impact of management types, differing from locally measured α-FD values.
•CWM of SLA estimable from Sentinel-2 datasets with PROSAIL.•Alpha functional diversity influences remotely sensed plant trait retrieval.•It is crucial to quantify an area-wide beta functional diversity.•Management types impact spatial components of functional diversity differently.
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