Aim
This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic ...kidney disease (CKD; estimated glomerular filtration rate eGFR ≥30 and <50 ml/min/1.73 m2).
Methods
In this 52‐week, randomized, double‐blind, placebo‐controlled study, patients (N = 269; mean eGFR, 39.4 ml/min/1.73 m2) received canagliflozin 100 or 300 mg and placebo once daily. Efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and systolic blood pressure (BP); adverse events (AEs) were also recorded.
Results
At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (−0.19, −0.33 and 0.07%, respectively); placebo‐subtracted differences (95% confidence interval) were −0.27% (−0.53, 0.001) and −0.41% (−0.68, −0.14). Canagliflozin also lowered FPG, body weight and BP versus placebo. Overall AE incidence was 85.6, 80.9, and 86.7% with canagliflozin 100 and 300 mg and placebo, respectively. Osmotic diuresis–related AEs were more common with both canagliflozin doses, and incidences of urinary tract infections and volume depletion–related AEs were higher with canagliflozin 300 mg versus placebo. Decreases in eGFR (−2.1, −4.0 and −1.6 ml/min/1.73 m2) were seen with canagliflozin 100 and 300 mg compared with placebo. Canagliflozin 100 and 300 mg provided median percent reductions in urine albumin to creatinine ratio versus placebo (−16.4, −28.0 and 19.7%).
Conclusions
Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks.
Aims
Canagliflozin is a sodium glucose co‐transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in ...subjects with T2DM and stage 3 chronic kidney disease CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2.
Methods
In this randomized, double‐blind, placebo‐controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated.
Results
Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin.
Conclusion
Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.
New particle formation (NPF) events have been recognized as an important process contributing to the cloud condensation nuclei (CCN) formation. In this study, measurement of NPF and predicted number ...concentrations of CCN using κ-Köhler theory were analyzed to assess the contribution of NPF to possible CCN. The particle growth rates of NPF events were categorized to two types: sulfur-rich (condensation and neutralization of sulfuric acid dominating net growth rate) and sulfur-poor cases. The growth rates for the sulfur-poor events were about 80% larger than those of the sulfur-rich cases on average. NPF events increased the CCN number concentrations by 0.4–6 times in the megacity area of Beijing. The enhancement ratios (the ratio of CCN number concentrations when obvious particle growth ended to that when it started during NPF events) were high for large supersaturation (
S). For example, it was about 30–50% higher under
S = 0.86% than under
S = 0.07%. The enhancement ratios exhibited similar seasonal variation as the growth rates with a larger value in summer than other seasons, which suggested that growth rate was a key factor in the conversion of NPF to possible CCN. The enhancement ratios were higher during the sulfur-poor NPF events with larger growth rates mainly contributed by organic species, indicating that organic species were the dominant chemical contributor in facilitating the conversion of newly formed particles to possible CCN in the Beijing Megacity.
► New particle formation (NPF) and fine particle chemical composition were measured. ► CCN number concentrations were predicted using κ-Köhler theory. ► NPF events increase the CCN number concentrations by 0.4–6 times. ► Growth rate is the key factor in the conversion of NPF to possible CCN. ► Organic species are implicated as the dominant contributor in the CCN conversion.
Background and purpose
Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against ...acetylcholine receptor (AChR) and muscle‐specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients.
Methods
Plasma from 81 Chinese MG patients previously found to be seronegative was tested by routine assays for AChR and MuSK antibodies. These samples were screened by (i) a novel, highly sensitive radioimmunoassay for AChR antibodies; (ii) cell‐based assays for clustered AChR, MuSK and lipoprotein receptor‐related protein 4 (LRP4) antibodies; (iii) a radioimmunoassay for titin antibodies.
Results
Antibodies to AChR, MuSK, LRP4 and titin were found in 25% (20/81), 4% (3/81), 7% (6/81) and 6% (5/78) of SNMG patients, respectively. In total, 37% of SNMG patients were found to be positive for at least one of the tested antibodies. AChR antibody positive patients had more severe disease (P = 0.008) and a trend towards fewer remissions/minimal manifestations than AChR antibody negative patients. The four patients with coexistence of antibodies had more severe disease, whilst the seronegative patients had milder MG (P = 0.015).
Conclusions
Detection of multiple muscle antibodies by more sensitive assays provides additional information in diagnosing and subgrouping of MG and may guide MG treatment.
The limitation of suitable anomalous valley Hall effect (AVHE) materials has seriously hindered the booming development and the widespread application of valleytronics. Here, through the ...first-principles calculations, we propose a MXene monolayer Y3N2O2 with spontaneous valley polarization (VP) of 21.3 meV, which induces intrinsic AVHE. The VP can be modulated linearly, which provides a route of effective control of the valley signals. Importantly, VP can be enhanced by adjusting up the spin–orbit coupling (SOC) based on a SOC Hamiltonian model and the first-principles calculations. From this physics underlying, we substitute the Y atom with the La atom and further propose the monolayer La3N2O2, in which the heavy atom La will provide stronger SOC than Y atom. The spontaneous VP in La3N2O2 is enhanced to 100.4 meV, so AVHE can be easily achieved. Our work not only provides compelling candidates for AVHE materials but also offers a novel mindset for finding suitable valleytronic devices.
This study was aimed at investigating the bioefficacy of organic compared with inorganic manganese (Mn) for eggshell quality. An amino acid-Mn complex or Mn sulfate monohydrate was used as the ...organic or inorganic Mn source. A total of six hundred forty-eight 50-wk-old layers (Hy-Line Brown) were divided into 9 groups; each group consisted of 6 replicates with 12 layers each. The feeding trial lasted 12 wk. During the first 4 wk of the feeding trial, the groups were fed a basal diet, which met the nutrient requirements of the layers, except for Mn. During the following 8 wk, 9 levels of Mn (inorganic Mn: 0, 25, 50, 100, and 200 mg/kg; organic Mn: 25, 50, 100, and 200 mg/kg) were used to supplement, respectively, in the basal diet on an equimolar basis. An exponential regression model was applied to calculate the bioefficacy of organic Mn compared with the inorganic Mn. Dietary supplementation with either organic or inorganic Mn did not influence egg production and feed efficiency of (P > 0.05), and eggshell quality did not exhibit a significant response to dietary supplementation with Mn sources at 56 and 58 wk (P > 0.05). Dietary supplementation with either organic Mn or inorganic Mn significantly enhanced the thickness, breaking strength, and elastic modulus of the eggshells compared with the control group at the end of 62 wk (P < 0.05). At the end of 62 wk, the bioefficacy of organic Mn was 357% (shell thickness), 406% (breaking strength), 458% (elastic modulus), and 470% (eggshell Mn), as efficacious as inorganic Mn at equimolar levels. This study suggests that organic Mn enhances eggshell quality in aged laying hens compared with inorganic Mn.
Measurements of OH, HO2, complex RO2 (alkene- and aromatic-related RO2) and total RO2 radicals taken during the integrated Study of AIR Pollution PROcesses in Beijing (AIRPRO) campaign in central ...Beijing in the summer of 2017, alongside observations of OH reactivity, are presented. The concentrations of radicals were elevated, with OH reaching up to 2.8×107moleculecm-3, HO2 peaking at 1×109moleculecm-3 and the total RO2 concentration reaching 5.5×109moleculecm-3. OH reactivity (k(OH)) peaked at 89 s-1 during the night, with a minimum during the afternoon of ≈22s-1 on average. An experimental budget analysis, in which the rates of production and destruction of the radicals are compared, highlighted that although the sources and sinks of OH were balanced under high NO concentrations, the OH sinks exceeded the known sources (by 15 ppbvh-1) under the very low NO conditions (<0.5ppbv) experienced in the afternoons, demonstrating a missing OH source consistent with previous studies under high volatile organic compound (VOC) emissions and low NO loadings. Under the highest NO mixing ratios (104 ppbv), the HO2 production rate exceeded the rate of destruction by ≈50ppbvh-1, whilst the rate of destruction of total RO2 exceeded the production by the same rate, indicating that the net propagation rate of RO2 to HO2 may be substantially slower than assumed. If just 10 % of the RO2 radicals propagate to HO2 upon reaction with NO, the HO2 and RO2 budgets could be closed at high NO, but at low NO this lower RO2 to HO2 propagation rate revealed a missing RO2 sink that was similar in magnitude to the missing OH source. A detailed box model that incorporated the latest Master Chemical Mechanism (MCM3.3.1) reproduced the observed OH concentrations well but over-predicted the observed HO2 under low concentrations of NO (<1ppbv) and under-predicted RO2 (both the complex RO2 fraction and other RO2 types which we classify as simple RO2) most significantly at the highest NO concentrations. The model also under-predicted the observed k(OH) consistently by ≈10s-1 across all NOx levels, highlighting that the good agreement for OH was fortuitous due to a cancellation of missing OH source and sink terms in its budget. Including heterogeneous loss of HO2 to aerosol surfaces did reduce the modelled HO2 concentrations in line with the observations but only at NO mixing ratios <0.3ppbv. The inclusion of Cl atoms, formed from the photolysis of nitryl chloride, enhanced the modelled RO2 concentration on several mornings when the Cl atom concentration was calculated to exceed 1×104atomscm-3 and could reconcile the modelled and measured RO2 concentrations at these times. However, on other mornings, when the Cl atom concentration was lower, large under-predictions in total RO2 remained. Furthermore, the inclusion of Cl atom chemistry did not enhance the modelled RO2 beyond the first few hours after sunrise and so was unable to resolve the modelled under-prediction in RO2 observed at other times of the day. Model scenarios, in which missing VOC reactivity was included as an additional reaction that converted OH to RO2, highlighted that the modelled OH, HO2 and RO2 concentrations were sensitive to the choice of RO2 product. The level of modelled to measured agreement for HO2 and RO2 (both complex and simple) could be improved if the missing OH reactivity formed a larger RO2 species that was able to undergo reaction with NO, followed by isomerisation reactions reforming other RO2 species, before eventually generating HO2. In this work an α-pinene-derived RO2 species was used as an example. In this simulation, consistent with the experimental budget analysis, the model underestimated the observed OH, indicating a missing OH source. The model uncertainty, with regards to the types of RO2 species present and the radicals they form upon reaction with NO (HO2 directly or another RO2 species), leads to over an order of magnitude less O3 production calculated from the predicted peroxy radicals than calculated from the observed peroxy radicals at the highest NO concentrations. This demonstrates the rate at which the larger RO2 species propagate to HO2, to another RO2 or indeed to OH needs to be understood to accurately simulate the rate of ozone production in environments such as Beijing, where large multifunctional VOCs are likely present.
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