Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Is it feasible to use smartphone images to perform telediagnosis of different stages of occlusal caries lesions?

The purpose of this study was to compare the performance of two different models of smartphone and a conventional camera with that of direct clinical examination in detecting caries lesions at different stages of progression in deciduous molars. The photographic equipment consisted of two smartphones (iPhone and Nexus 4) and a conventional macro camera setup. First, in the laboratory phase of the study, we compared the images of 20 exfoliated primary teeth having caries lesions at different stages. Then, in the clinical phase of the study, the images of 119 primary molars from fifteen children (3 to 6 years old) were used. All of the photographic images were taken using the previously described devices. In both groups, two examiners, blinded to the photographic equipment used, assessed the images independently on a computer screen, and classified them according to the International Caries Detection and Assessment System (ICDAS). The teeth were then examined directly by two other experienced examiners, and the consensus reached was considered the reference standard. Parameters of validity, such as percentage of correct answers, agreement with the reference standard, sensitivity, specificity and inter-examiner agreement (using the weighted kappa test) were calculated. The examiners performed similarly in both in vitro and in vivo studies. Inter-examiner reliability was approximately 0.7 for all the devices in the laboratory setting, and for the macro camera photography system in the clinical setting, but it was approximately 0.9 for the iPhone and Nexus images taken in vivo. With regard to the percentage of correct answers, the highest values were observed for sound and extensive caries lesions in both laboratory and clinical settings. The percentage of correct answers for initial and moderate lesions was particularly low in the clinical evaluation, irrespective of the camera devices used. Therefore, we concluded that photographic diagnosis using smartphone images is feasible and accurate for distinguishing sound tooth surfaces from extensive caries lesions; however, photographic images are not a good method for accurately detecting initial and moderate caries lesions

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Systematic study of flow vector decorrelation in sNN=5.02\mathbf{\sqrt{\textit{s}_{_{\bf NN}}}=5.02} TeV Pb--Pb collisions

Measurements of the $p_{\rm T}$-dependent flow vector fluctuations in Pb--Pb collisions at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ using azimuthal correlations with the ALICE experiment at the LHC are presented. A four-particle correlation approach [1] is used to quantify the effects of flow angle and magnitude fluctuations separately. This paper extends previous studies to additional centrality intervals and provides measurements of the $p_{\rm T}$-dependent flow vector fluctuations at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ with two-particle correlations. Significant $p_{\rm T}$-dependent fluctuations of the $\vec{V}_{2}$ flow vector in Pb--Pb collisions are found across different centrality ranges, with the largest fluctuations of up to $\sim$15% being present in the 5% most central collisions. In parallel, no evidence of significant $p_{\rm T}$-dependent fluctuations of $\vec{V}_{3}$ or $\vec{V}_{4}$ is found. Additionally, evidence of flow angle and magnitude fluctuations is observed with more than $5\sigma$ significance in central collisions. These observations in Pb--Pb collisions indicate where the classical picture of hydrodynamic modeling with a common symmetry plane breaks down. This has implications for hard probes at high $p_{\rm T}$, which might be biased by $p_{\rm T}$-dependent flow angle fluctuations of at least 23% in central collisions. Given the presented results, existing theoretical models should be re-examined to improve our understanding of initial conditions, quark--gluon plasma (QGP) properties, and the dynamic evolution of the created system.Measurements of the pT-dependent flow vector fluctuations in Pb–Pb collisions at sNN=5.02TeV using azimuthal correlations with the ALICE experiment at the Large Hadron Collider are presented. A four-particle correlation approach [ALICE Collaboration, Phys. Rev. C 107, L051901 (2023)] is used to quantify the effects of flow angle and magnitude fluctuations separately. This paper extends previous studies to additional centrality intervals and provides measurements of the pT-dependent flow vector fluctuations at sNN=5.02TeV with two-particle correlations. Significant pT-dependent fluctuations of the V⃗2 flow vector in Pb–Pb collisions are found across different centrality ranges, with the largest fluctuations of up to ∼15% being present in the 5% most central collisions. In parallel, no evidence of significant pT-dependent fluctuations of V⃗3 or V⃗4 is found. Additionally, evidence of flow angle and magnitude fluctuations is observed with more than 5σ significance in central collisions. These observations in Pb–Pb collisions indicate where the classical picture of hydrodynamic modeling with a common symmetry plane breaks down. This has implications for hard probes at high pT, which might be biased by pT-dependent flow angle fluctuations of at least 23% in central collisions. Given the presented results, existing theoretical models should be reexamined to improve our understanding of initial conditions, quark–gluon plasma properties, and the dynamic evolution of the created system.Measurements of the $p_{\rm T}$-dependent flow vector fluctuations in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ using azimuthal correlations with the ALICE experiment at the LHC are presented. A four-particle correlation approach [1] is used to quantify the effects of flow angle and magnitude fluctuations separately. This paper extends previous studies to additional centrality intervals and provides measurements of the $p_{\rm T}$-dependent flow vector fluctuations at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ with two-particle correlations. Significant $p_{\rm T}$-dependent fluctuations of the $\vec{V}_{2}$ flow vector in Pb-Pb collisions are found across different centrality ranges, with the largest fluctuations of up to $\sim$15% being present in the 5% most central collisions. In parallel, no evidence of significant $p_{\rm T}$-dependent fluctuations of $\vec{V}_{3}$ or $\vec{V}_{4}$ is found. Additionally, evidence of flow angle and magnitude fluctuations is observed with more than $5\sigma$ significance in central collisions. These observations in Pb-Pb collisions indicate where the classical picture of hydrodynamic modeling with a common symmetry plane breaks down. This has implications for hard probes at high $p_{\rm T}$, which might be biased by $p_{\rm T}$-dependent flow angle fluctuations of at least 23% in central collisions. Given the presented results, existing theoretical models should be re-examined to improve our understanding of initial conditions, quark--gluon plasma (QGP) properties, and the dynamic evolution of the created system