Summary Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of ...canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Methods We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18–80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c ) of 7·0–9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00968812. Findings 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0·01% 95% CI −0·11 to 0·09), and canagliflozin 300 mg was superior to glimepiride (–0·12% –0·22 to −0·02). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 11% and 34 14% vs five 2%; men: 17 7% and 20 8% vs three 1%), urinary tract infections (31 6% for both canagliflozin doses vs 22 5%), and osmotic diuresis-related events (pollakiuria: 12 3% for both doses vs one <1%; polyuria: four <1% for both doses vs two <1%). Interpretation Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. Funding Janssen Research & Development, LLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To determine the sex- and ethnicity-specific prevalence of color vision deficiency (CVD) in black, Asian, Hispanic, and non-Hispanic white preschool children.
Population-based, cross-sectional study.
...The Multi-Ethnic Pediatric Eye Disease Study is a population-based evaluation of the prevalence of vision disorders in children in Southern California. A total of 5960 subjects 30 to 72 months of age were recruited for the study, of whom 4177 were able to complete color vision testing (1265 black, 812 Asian, 1280 Hispanic, and 820 non-Hispanic white).
Color vision testing was performed using Color Vision Testing Made Easy color plates (Home Vision Care, Gulf Breeze, FL), and diagnostic confirmatory testing was performed using the Waggoner HRR Diagnostic Test color plates (Home Vision Care).
Testability of color vision in preschool children between 30 and 72 months of age and prevalence of CVD stratified by age, sex, and ethnicity.
Testability was 17% in children younger than 37 months of age, increasing to 57% in children 37 to 48 months of age, 89% in children 49 to 60 months of age, and 98% in children 61 to 72 months of age. The prevalence of CVD among boys was 1.4% for black, 3.1% for Asian, 2.6% for Hispanic, and 5.6% for non-Hispanic white children; the prevalence in girls was 0.0% to 0.5% for all ethnicities. The ethnic difference in CVD was statistically significant between black and non-Hispanic white children (P = 0.0003) and between Hispanic and non-Hispanic white children (P = 0.02). In boys, most CVD cases were either deutan (51%) or protan (34%); 32% were classified as mild, 15% as moderate, and 41% as severe.
Testability for CVD in preschool children is high by 4 years of age. The prevalence of CVD in preschool boys varies by ethnicity, with the highest prevalence in non-Hispanic white and lowest in black children.
The geometric structures, stabilization energies, dipole moments, and vibrational frequencies of the neutral water clusters (H
2
O)
n
, with
n
= 1–10, were investigated using density functional ...theory along with a variety of exchange-correlation functionals (LDA with SVWN5 parameterization, GGA with BLYP, PW91, PBE, B3LYP, X3LYP, PBE0, PBE1W, M05-2X, M06-2X and M06-L parameterizations) as well as high-level ab initio MP2 and CCSD(T) methods. Using the MP2 and CCSD(T) results as benchmarks, the effects of exchange-correlation functionals and basis sets were carefully examined. Each functional has its advantage in certain aspects; for example, M05-2X and X3LYP yield better geometries, and the capability of these two functionals to distinguish the relative energies between isomers are more similar to MP2. The size of the split-valence basis set (6-31G or larger), diffuse functions on the oxygen atom, and d(p) polarization on the oxygen (hydrogen) atom are crucial for an accurate description of intermolecular interaction in water clusters. The 6-31+G(2d,p) basis set is thus recommended as a compromise between computational efficiency and accuracy for structural description. We further demonstrated that the numerical basis set, TNP, performs satisfactorily in describing structural parameters of water clusters.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemical doping of carbon nanotubes provides a variety of opportunities for tailoring the physical properties of carbon nanotubes. In this review, we discussed the optical properties of doped carbon ...nanotubes and the related applications as nanoscale photonic devices. The fundamental optical properties of carbon nanotubes with various chemical doping have been summarized. Novel optoelectronic and photonic devices based on doped carbon nanotubes, such as optical nonlinear materials, optical limiting devices, photovoltaic devices, etc., have been discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
“Accelerated” chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to ...the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Retinal activation via transcorneal electrical stimulation (TcES) in normal humans was investigated by comparing subject perception, model predictions, and brain activation patterns. The preferential ...location of retinal stimulation was predicted from 3-D admittance modeling. Visual cortex activation was measured using positron emission tomography (PET) and 18 F-fluorodeoxyglucose (FDG). Two different corneal electrodes were investigated: DTL-Plus and ERG-Jet. Modeling results predicted preferential stimulation of the peripheral, inferior, nasal retina during right eye TcES using DTL-Plus, but more extensive activation of peripheral, nasal hemiretina using ERG-Jet. The results from human FDG PET study using both corneal electrodes showed areas of visual cortex activation that consistently corresponded with the reported phosphene percept and modeling predictions. ERG-Jet was able to generate brighter phosphene percept than DTL-Plus and elicited retinotopically mapped primary visual cortex activation. This study demonstrates that admittance modeling and PET imaging consistently predict the perceived location of electrically elicited phosphenes produced during TcES.
Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma subtype. Primary adrenal and renal lymphomas (PARL) ...exhibit a high predilection for the central nervous system (CNS). Therefore, current guidelines support the use of CNS prophylaxis in PARL, particularly in cases of high-risk Central Nervous System International Prognostic Index (CNS-IPI). However, the route of administration (i.e. systemic vs. intrathecal chemotherapy) has not been clearly elucidated. With this in mind, we initiated an international collaboration and literature review to analyze 50 patient cases, 20 of whome received CNS prophylaxis. Based on our analysis, we conclude that PARL may indicate a need for CNS chemo-prophylaxis in the form of systemic high-dose methotrexate (HD-MTX) over intrathecal methotrexate (IT-MTX), although IT-MTX may still have utility in certain cases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from India. ...Methods: Changes from baseline in HbA1c, fasting plasma glucose (FPG), body weight, and blood pressure (BP) with canagliflozin 100 and 300 mg were evaluated in a subgroup of patients from India (n = 124) from 4 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 2313; Population 1). Safety was assessed based on adverse event (AE) reports in these patients and in a broader subgroup of patients from India (n = 1038) from 8 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2). Results: Reductions in HbA1cwith canagliflozin 100 and 300 mg were −0.74% and −0.88%, respectively, in patients from India, and −0.81% and −1.00%, respectively, in the 4 pooled Phase 3 studies. In the Indian subgroup, both canagliflozin doses provided reductions in FPG, body weight, and BP that were consistent with findings in the overall population. The incidence of overall AEs in patients from India was generally similar with canagliflozin 100 and 300 mg and noncanagliflozin. The AE profile in patients from India was generally similar to the overall population, with higher rates of genital mycotic infections and osmotic diuresis-related and volume depletion-related AEs with canagliflozin versus noncanagliflozin. Conclusion: Canagliflozin provided glycemic control, body weight reduction, and was generally well tolerated in patients with T2DM from India.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. This review ...provides a comprehensive summary of preclinical and clinical data on the effects of the SGLT2 inhibitor canagliflozin on mineral balance and bone.
Methods: Published articles and internal study reports through November 2015 were included.
Results: In clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, parathyroid hormone, or vitamin D. Canagliflozin was associated with increases in serum magnesium and phosphate without changes in their urinary excretion. Increases in serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker, were observed with canagliflozin. Decreases in total hip bone mineral density (BMD) of up to 1.2% were seen with canagliflozin after 2 years; no changes in BMD were seen at other skeletal sites. Changes in total hip BMD and serum beta-CTX with canagliflozin correlated with decreases in body weight. In a clinical program-wide analysis, canagliflozin was associated with increased fracture risk that was driven by a higher incidence in the cardiovascular safety study (CANVAS), with no fracture imbalance seen in pooled data from other Phase 3 studies. The fracture imbalance occurred within 12 weeks after initiating treatment, most frequently in the distal portion of the upper and lower extremities.
Conclusions: Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. Increases in bone turnover markers and decreases in BMD at the total hip, but not at other sites, that correlated with weight loss were seen with canagliflozin. Canagliflozin was associated with a higher fracture incidence within 12 weeks, primarily in distal extremities. Data from ongoing canagliflozin studies will provide additional information on fracture risk.
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