Design ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes. Methods Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment. Results A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch. Conclusions Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.

ObjectivesTo deliver an estimate of bullying among residents and fellows in the United States graduate medical education system and to explore its prevalence within unique subgroups.Design/Setting/ParticipantsA national cross-sectional survey from a sample of residents and fellows who completed an online bullying survey conducted in June 2015. The survey was distributed using a chain sampling method that relied on electronic referrals from 4,055 training programs, with 1,791 residents and fellows completing the survey in its entirety. Survey respondents completed basic demographic and programmatic information plus four general bullying and 20 specific bullying behavior questions. Between-group differences were compared for demographic and programmatic stratifications.Main Outcomes/MeasuresSelf-reported subjected to workplace bullying from peers, attendings, nurses, ancillary staff, or patients in the past 12 months.ResultsAlmost half of the respondents (48%) reported being subjected to bullying although both those subjected and not subjected reported experiencing ≥ 1 bullying behaviors (95% and 39% respectively). Attendings (29%) and nurses (27%) were the most frequently identified source of bullying, followed by patients, peers, consultants and staff. Attempts to belittle and undermine work and unjustified criticism and monitoring of work were the most frequently reported bullying behaviors (44% each), followed by destructive innuendo and sarcasm (37%) and attempts to humiliate (32%). Specific bullying behaviors were more frequently reported by female, non-white, shorter than < 5’8 and BMI ≥ 25 individuals.Conclusions/RelevanceMany trainees report experiencing bullying in the United States graduate medical education programs. Including specific questions on bullying in the Accreditation Council for Graduate Medical Education annual resident/fellow survey, implementation of anti-bullying policies, and a multidisciplinary approach engaging all stakeholders may be of great value to eliminate these pervasive behaviors in the field of healthcare.

Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor K K. When cells were pre-treated with glutathione, a proposed cellular regulator of neutral sphingomyelinase, inhibition of ceramide accumulation at early time points was achieved with attenuation of cell death. Inhibition of both pathways achieved near-complete inhibition of ceramide accumulation and cell death indicating that both pathways of ceramide generation are stimulated. This illustrates the complexity of ceramide generation in cytokine action. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Diabetic nephropathy (DN) is a well-described complication of diabetes mellitus and the leading cause of end stage renal disease (ESRD). Although increased albuminuria has been the gold standard for screening, data suggests that renal damage starts long before the onset of clinically apparent increases in macro and even micro-albuminuria. Clinical practice guidelines for the prevention of DN have been traditionally focused on the control of serum glucose, blood pressure and dyslipidemia, with some focus on the renin-angiotensin-aldosterone system (RAAS) as a main target for successful therapy. Recent evidence has led to a better understanding of the underlying mechanisms of the pathophysiology of this disease and suggests that various novels pathways can be targeted to delay and even prevent the progression of DN. Hence a more comprehensive therapeutic approach to therapy is on the horizon, carrying the promise for a more successful and impactful management. This review will highlight new insights into the pathophysiology, clinical aspects and future diagnostic and therapeutic modalities for DN.