Aromatic nucleophilic substitution reactions of O-aryl oximes with piperidine and hexylamine in cyclohexane

1132-113

Does treating obesity stabilize chronic kidney disease?

BACKGROUND: Obesity is a growing health issue in the Western world. Obesity, as part of the metabolic syndrome adds to the morbidity and mortality. The incidence of diabetes and hypertension, two primary etiological factors for chronic renal failure, is significantly higher with obesity. We report a case with morbid obesity whose renal function was stabilized with aggressive management of his obesity. CASE REPORT: A 43-year old morbidly obese Caucasian male was referred for evaluation of his chronic renal failure. He had been hypertensive with well controlled blood pressure with a body mass index of 46 and a baseline serum creatinine of 4.3 mg/dl (estimated glomerular filtration rate of 16 ml/min). He had failed all conservative attempts at weight reduction and hence was referred for a gastric by-pass surgery. Following the bariatric surgery he had approximately 90 lbs. weight loss over 8-months and his serum creatinine stabilized to 4.0 mg/dl. CONCLUSION: Obesity appears to be an independent risk factor for renal failure. Targeting obesity is beneficial not only for better control of hypertension and diabetes, but also possibly helps stabilization of chronic kidney failure

A Multiplexed Single-Cell CRISPR Screening Platform Enables Systematic Dissection of the Unfolded Protein Response

Functional genomics efforts face tradeoffs between number of perturbations examined and complexity of phenotypes measured. We bridge this gap with Perturb-seq, which combines droplet-based single-cell RNA-seq with a strategy for barcoding CRISPR-mediated perturbations, allowing many perturbations to be profiled in pooled format. We applied Perturb-seq to dissect the mammalian unfolded protein response (UPR) using single and combinatorial CRISPR perturbations. Two genome-scale CRISPR interference (CRISPRi) screens identified genes whose repression perturbs ER homeostasis. Subjecting ∼100 hits to Perturb-seq enabled high-precision functional clustering of genes. Single-cell analyses decoupled the three UPR branches, revealed bifurcated UPR branch activation among cells subject to the same perturbation, and uncovered differential activation of the branches across hits, including an isolated feedback loop between the translocon and IRE1α. These studies provide insight into how the three sensors of ER homeostasis monitor distinct types of stress and highlight the ability of Perturb-seq to dissect complex cellular responses.National Human Genome Research Institute (U.S.) (Grant P50HG006193

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

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 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 m 2), 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

DESIGN, FABRICATION, TESTING, AND FUZZY MODELING OF A LARGE MAGNETORHEOLOGICAL DAMPER FOR VIBRATION CONTROL IN A RAILCAR

ABSTRACT This paper presents the procedure used for design, fabrication, testing, and numerical modeling of a magnetorheological (MR) damper that is to be applied for vibration control in a 70-ton railcar. MR dampers are semiactive vibration control devices whose damping characteristics can be modified in real time by varying an applied current. Design parameters for the MR damper are estimated from those exhibited by a linear viscous damper that exerts the necessary force required to limit vertical vibrations of the rail truck within acceptable limits. An MR damper is fabricated by modifying the piston of a standard hydraulic damper to function as a solenoid. The assembled MR damper is tested in a uniaxial testing machine by subjecting it to sinusoidal and random displacements while simultaneously varying the current flowing in the solenoid. A variable magnetic field is applied to the MR fluid that fills the damper cavity and the resisting force exerted by the damper is recorded. Data collected in the laboratory are used to train a fuzzy model of the MR damper that characterizes its behavior. Results indicate that a fuzzy model of the MR damper can predict its behavior with a sufficient degree of accuracy while requiring minimal computational time

Correction: Anastopoulos et al. Multi-Drug Featurization and Deep Learning Improve Patient-Specific Predictions of Adverse Events. Int. J. Environ. Res. Public Health 2021, 18, 2600

In the original publication [...

Outcomes of Cephalic Arch Stenosis With and Without Stent Placement after Percutaneous Balloon Angioplasty in Hemodialysis Patients

Cephalic arch stenosis is a common complication in maintenance hemodialysis (MHD) patients with brachial artery-cephalic vein fistulas and frequently leads to loss of the functioning brachial artery-cephalic vein fistula. There is paucity of conclusive data to guide appropriate management. We examined the risk of recurrence of cephalic arch stenosis after angioplasty compared to angioplasty after stent placement determined by angiography of the involved upper extremity over time in a contemporary cohort of MHD patients treated in two interventional nephrology practices from March 2008 through May 2011. We retrospectively identified 45 MHD patients with evidence of cephalic arch stenosis (age 60&nbsp;±&nbsp;30&nbsp;years, 45% men) on elective angiograms. The median number of days until another angioplasty was required decreased, starting with a median of 91.5&nbsp;days after the first, 70.5&nbsp;days after the second, 85&nbsp;days after the third, and 56&nbsp;days after the fourth. Angioplasty is associated with a faster rate of recurrence of cephalic arch stenosis. The placement of intravascular stent seems to prolong the patency compared to angioplasty alone. Clinical trials with a larger sample size will better elucidate the value and timing of angioplasty versus stent placement in cephalic arch stenosis