Summary Background Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering ...therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. Methods The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy—a prespecified tertiary endpoint of the main study—was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Findings Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 3·4% patients on fenofibrate vs 238 4·9% on placebo; hazard ratio HR 0·69, 95% CI 0·56–0·84; p=0·0002; absolute risk reduction 1·5% 0·7–2·3). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 9·6% patients on fenofibrate vs 57 12·3% on placebo; p=0·19) or in the subset of patients without pre-existing retinopathy (43 11·4% vs 43 11·7%; p=0·87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three 3·1% patients vs 14 14·6%; p=0·004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0·66, 95% CI 0·47–0·94; p=0·022). Interpretation Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.
The clumped isotopic composition of carbonate‐derived CO2 (denoted Δ47) is a function of carbonate formation temperature and in natural samples can act as a recorder of paleoclimate, burial, or ...diagenetic conditions. The absolute abundance of heavy isotopes in the universal standards VPDB and VSMOW (defined by four parameters: R13VPDB, R17VSMOW, R18VSMOW, and λ) impact calculated Δ47 values. Here, we investigate whether use of updated and more accurate values for these parameters can remove observed interlaboratory differences in the measured T‐Δ47 relationship. Using the updated parameters, we reprocess 14 published calibration data sets measured in 11 different laboratories, representing many mineralogies, bulk compositions, sample types, reaction temperatures, and sample preparation and analysis methods. Exploiting this large composite data set (n = 1,253 sample replicates), we investigate the possibility for a “universal” clumped isotope calibration. We find that applying updated parameters improves the T‐Δ47 relationship (reduces residuals) within most labs and improves overall agreement but does not eliminate all interlaboratory differences. We reaffirm earlier findings that different mineralogies do not require different calibration equations and that cleaning procedures, method of pressure baseline correction, and mass spectrometer type do not affect interlaboratory agreement. We also present new estimates of the temperature dependence of the acid digestion fractionation for Δ47 (Δ*25‐X), based on combining reprocessed data from four studies, and new theoretical equilibrium values to be used in calculation of the empirical transfer function. Overall, we have ruled out a number of possible causes of interlaboratory disagreement in the T‐Δ47 relationship, but many more remain to be investigated.
Plain Language Summary
Measured stable and clumped isotope values are fundamentally tied to established compositions of international standard materials. When these standard compositions are updated, it impacts previously published isotope measurements such as those used to define the clumped isotope calibration relationship (the foundation for use of this isotopic proxy as a paleothermometer, recorder of burial history or past diagenetic conditions). Here we reprocess 14 published clumped isotope calibration studies using updated international standard compositions and identical data processing procedures to see if these changes would eliminate previously observed interlaboratory discrepancies in clumped isotope calibration relationships. We find that this update tightens the clumped isotope calibration relationship within most laboratories and improves overall agreement between laboratories but does not eliminate all interlaboratory differences. We also propose “best practices” for data processing and dissemination going forward. This study makes progress toward resolving discrepancies in clumped isotope calibration relationships between laboratories by eliminating a number of possible causes and moves the clumped isotope community closer toward our ultimate goal of applying this powerful new proxy routinely to exciting science questions.
Key Points
Updates to 17O correction parameters and international standard compositions affect clumped isotopic compositions
Reprocessing published calibration data using new parameters and consistent methodology slightly improves interlaboratory agreement
There is no evidence (within error) for mineral‐specific offsets in calibration equation or temperature dependence of acid digestion fractionation
The synthesis of a range of brominated-B
n
-containing (
n
= 1, 2) polycyclic aromatic hydrocarbons (PAHs) is achieved simply by reacting BBr
3
with appropriately substituted alkynes
via
a ...bromoboration/electrophilic C-H borylation sequence. The brominated-B
n
-PAHs were isolated as either the borinic acids or B-mesityl-protected derivatives, with the latter having extremely deep LUMOs for the B
2
-doped PAHs (with one example having a reduction potential of
E
1/2
= −0.96 V
versus
Fc
+
/Fc, Fc = ferrocene). Mechanistic studies revealed the reaction sequence proceeds by initial alkyne 1,1-bromoboration. 1,1-Bromoboration also was applied to access a number of unprecedented 1-bromo-2,2-diaryl substituted vinylboronate esters directly from internal alkynes. Bromoboration/C-H borylation installs useful C-Br units onto the B
n
-PAHs, which were utilised in Negishi coupling reactions, including for the installation of two triarylamine donor (D) groups onto a B
2
-PAH. The resultant D-A-D molecule has a low optical gap with an absorption onset at 750 nm and emission centered at 810 nm in the solid state.
The synthesis of a range of brominated-B
n
-containing (
n
= 1, 2) polycyclic aromatic hydrocarbons (PAHs) is achieved simply by reacting BBr
3
with appropriately substituted alkynes
via
a bromoboration/electrophilic C-H borylation sequence.
Climate change projections for the Australian monsoon have been highly uncertain in previous generations of coupled climate models. The new Coupled Model Intercomparison Project Phase 6 (CMIP6) ...ensemble provides an opportunity to address the uncertainty in future projections for northern Australia. We find that the range in Australian monsoon projections from the available CMIP6 ensemble is substantially reduced compared to CMIP5, although models continue to disagree on the magnitude and direction of change. While previous CMIP5 studies identified warming in the western equatorial Pacific as important for Australian monsoon projections, here we show that the western Pacific is not strongly connected to northern Australian precipitation changes in the CMIP6 models. By comparing groups of models based on their future projections, we note that the model‐to‐model differences in Australian monsoon projections are congruent with the zonally averaged precipitation response in the Southern Hemisphere tropics within each model.
Key Points
Australian monsoon changes are smaller in the available CMIP6 ensemble than the CMIP5 ensemble
CMIP6 models still disagree on changes to Australian monsoon precipitation in a warmer world
Australian monsoon changes are congruent with the zonal mean precipitation change, more evident in CMIP6 than CMIP5
Sarcopenia, the loss of muscle mass with normal aging, devastates quality of life—and related healthcare expenditures are enormous. The prevention or attenuation of sarcopenia would be an important ...medical advance. Dietary restriction (DR) is the only dietary intervention that consistently extends median and maximum life span, as well as health span in rodents. Evidence suggests that DR will have a similar effect in primates. Furthermore, DR opposes sarcopenia in rodents. We tested the hypothesis that DR will reduce age-related sarcopenia in a nonhuman primate. Thirty adult male rhesus monkeys, half fed a normal calorie intake and half reduced by 30% in caloric intake, were examined over 17 years for changes in dual-energy X-ray absorptiometry-estimated skeletal muscle mass. Body weight-adjusted skeletal muscle mass declined somewhat in both groups but was far more rapid in the control group. We have shown that moderate, adult-onset DR can attenuate sarcopenia in a nonhuman primate model.
Introduction: Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with polycystic ovary syndrome (PCOS) women. Early gestation exposure (E) results in insulin ...resistance, impaired pancreatic beta-cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI). Objective: To determine whether PA females have altered body fat distribution. Design: Five early-treated PA (EPA), five late-treated PA (LPA) and five control adult female monkeys underwent somatometrics, dual-X-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and five EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation. Results: There were no differences in age, weight, BMI or somatometrics. LPA females had approximately 20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females (P less than or equal to 0.05). LPA females also had approximately 40% more CT-determined non-visceral abdominal fat than EPA or control females (P less than or equal to 0.05). The volume of visceral fat was similar among the three groups. EPA (R2=0.94, P less than or equal to 0.01) and LPA (R2=0.53, P=0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI (R2=0.98, P less than or equal to 0.001). There was a positive relationship between basal insulin and total body (R2=0.95, P less than or equal to 0.007), total abdominal (R2=0.81, P less than or equal to 0.04) and visceral (R2=0.82, P less than or equal to 0.03) fat quantities in EPA, but not control females. Conclusions: Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women.
A systematic study is undertaken for projected changes in tropical Australian climate in 19 CMIP3 Coupled Models for the A2 scenario over the 21st century. While equatorial regions to the north of ...Australia are projected to have increased precipitation during austral summer (December to February) by the end of the 21st century, there is no significant change over northern Australia based on the model ensemble mean. There is a large spread in model simulations of precipitation change, with both large positive and negative anomalies. The ensemble mean change in the seasonal cycle of precipitation over tropical Australia is small, with precipitation increase during March and April, suggesting a prolonged Australian wet season. There is no model consensus on how interannual variability of tropical Australian precipitation will change in future climate, although more models simulate increased variability than decreased. Correlations between full wet season (October to April) precipitation and austral spring (September to November) NINO3.4 sea surface temperature anomalies show a slight weakening. The spread in projected precipitation seasonal cycle changes between simulations from the same model is larger than the inter‐model range, indicating that there is large internal or natural variability in tropical Australian precipitation relative to the climate change signal. Zonal wind changes indicate an intensification of austral summer low level westerlies although combined with a weakening of upper easterlies. Low level westerlies also persist for longer, consistent with a delay in the monsoon retreat. All models simulate an increase in the land‐ocean temperature contrast in austral summer, with a significant correlation between changes in land‐ocean temperature contrast in the pre‐monsoon (austral spring) and summer precipitation changes. Analysis of precipitation changes using regime‐sorting techniques shows offsetting tendencies from thermodynamic changes associated with enhanced atmospheric moisture and dynamic changes associated with a weakened atmospheric circulation.
Key Points
There is a large spread in model CMIP3 simulations of precipitation change
Zonal winds changes indicate intensification of austral summer low level winds
Regime‐sorting techniques provide insight into uncertainty of precip projections
Moderate caloric restriction (CR) without malnutrition increases healthspan in virtually every species studied, including nonhuman primates. In mice, CR exerts significant microvascular protective ...effects resulting in increased microvascular density in the heart and the brain, which likely contribute to enhanced tolerance to ischemia and improved cardiac performance and cognitive function. Yet, the underlying mechanisms by which CR confer microvascular protection remain elusive. To test the hypothesis that circulating factors triggered by CR regulate endothelial angiogenic capacity, we treated cultured human endothelial cells with sera derived from Macaca mulatta on long-term (over 10 years) CR. Cells treated with sera derived from ad-libitum-fed control monkeys served as controls. We found that factors present in CR sera upregulate vascular endothelial growth factor (VEGF) signaling and stimulate angiogenic processes, including endothelial cell proliferation and formation of capillary-like structures. Treatment with CR sera also tended to increase cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing ECIS technology) and adhesion to collagen. Collectively, we find that circulating factors induced by CR promote endothelial angiogenic processes, suggesting that increased angiogenesis may be a potential mechanism by which CR improves cardiac function and prevents vascular cognitive impairment.
•This study focuses on femoral head measurements for sex estimation.•Both dry bone- and CT-based measurements were tested for reliability and accuracy.•Only femoral measurements with acceptable ...agreement were used.•Formulae were developed by using clinical CT data as a source of osteometric data.•A population-specific sex estimation method for the Dutch population is presented.
Sex estimation techniques are frequently applied in forensic anthropological analyses of unidentified human skeletal remains. While morphological sex estimation methods are able to endure population differences, the classification accuracy of metric sex estimation methods are population-specific. No metric sex estimation method currently exists for the Dutch population. The purpose of this study is to create Dutch population specific sex estimation formulae by means of osteometric analyses of the proximal femur. Since the Netherlands lacks a representative contemporary skeletal reference population, 2D plane reconstructions, derived from clinical computed tomography (CT) data, were used as an alternative source for a representative reference sample.
The first part of this study assesses the intra- and inter-observer error, or reliability, of twelve measurements of the proximal femur. The technical error of measurement (TEM) and relative TEM (%TEM) were calculated using 26 dry adult femora. In addition, the agreement, or accuracy, between the dry bone and CT-based measurements was determined by percent agreement. Only reliable and accurate measurements were retained for the logistic regression sex estimation formulae; a training set (n=86) was used to create the models while an independent testing set (n=28) was used to validate the models. Due to high levels of multicollinearity, only single variable models were created. Cross-validated classification accuracies ranged from 86% to 92%.
The high cross-validated classification accuracies indicate that the developed formulae can contribute to the biological profile and specifically in sex estimation of unidentified human skeletal remains in the Netherlands. Furthermore, the results indicate that clinical CT data can be a valuable alternative source of data when representative skeletal collections are unavailable.
PDF
