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Background:There is discontent and turnover among faculty at US academic health centers because of the challenges in balancing clinical, research, teaching, and work–life responsibilities in the current healthcare environment. One potential strategy to improve faculty satisfaction and limit turnover is through faculty mentoring programs.Methods:A Mentor Leadership Council was formed to design and implement an institution-wide faculty mentoring program across all colleges at an academic health center. The authors conducted an experimental study of the impact of the mentoring program using pre-intervention (2011) and 6-year (2017) post-intervention faculty surveys that measured the long-term effectiveness of the program.Results:The percent of faculty who responded to the surveys was 45.9% (656/1428) in 2011 and 40.2% (706/1756) in 2017. For faculty below the rank of full professor, percent of faculty with a mentor (45.3% vs. 67.1%, P < 0.001), familiarity with promotion criteria (81.7% vs. 90.0%, P = 0.001), and satisfaction with department’s support of career (75.6% vs. 84.7%, P = 0.002) improved. The percent of full professors serving as mentors also increased from 50.3% in 2011 to 68.0% in 2017 (P = 0.002). However, the percent of non-retiring faculty considering leaving the institution over the next 2 years increased from 18.8% in 2011 to 24.3% in 2017 (P = 0.02).Conclusions:Implementation of an institution-wide faculty mentoring program significantly improved metrics of career development and faculty satisfaction but was not associated with a reduction in the percent of faculty considering leaving the institution. This suggests the need for additional efforts to identify and limit factors driving faculty turnover.

Islet engraftment after transplantation is impaired by high rates of islet/β cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow‐derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 ± 2.6 ×106 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12‐month fasting blood glucose levels (p = .02 vs. controls), smaller C‐peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: {"type":"clinical-trial","attrs":{"text":"NCT02384018","term_id":"NCT02384018"}}NCT02384018). stem cells translational medicine 2018;7:11–19

Aims Type 2 diabetes mellitus (T2DM) can substantially decrease quality of life (QOL). This study examined the effects on QOL-relevant psychosocial measures of a widely available commercial weight loss program enhanced for individuals with T2DM. Methods A year-long multi-site randomized clinical trial compared the Weight Watchers (WW) approach, supplemented with phone and email counseling with a certified diabetes educator (CDE), to brief standard diabetes nutrition counseling and education (Standard Care; SC). Participants were 400 women and 163 men (N = 279 WW; 284 SC) with T2DM [mean (± SD) HbA1c 8.32 ± 1%; BMI = 37.1 ± 5.7 kg/m2; age = 55.1 ± 9.1 years]. Psychosocial outcomes were assessed at baseline, month 6, and month 12 using a diabetes specific psychosocial measure (Diabetes Distress Scale [DDS]), Impact of Weight on Quality of Life-Lite scale (IWQOL), a generic QOL measure (SF-36), and a depression screen (PHQ-9). Results WW participants showed significantly greater improvements than did SC participants on all DDS subscales and total score and on IWQOL total score and physical function, sex life and work domains (all ps Conclusions WW enhanced for individuals with T2DM was superior to SC in improving psychosocial outcomes most specific to T2DM and obesity. Available commercial WL programs, combined with scalable complementary program-specific diabetes counseling, may have benefits that extend to diabetes-related distress and weight-relevant QOL.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

A WW (formerly Weight Watchers) program adapted for persons with type 2 diabetes mellitus (T2DM) previously was found to be more effective than standard care (SC) intervention for weight loss, improved glycemic control, and weight- and diabetes-related quality of life measures. With data from the same national trial, this study examined whether WW adapted for persons with T2DM also increased engagement in weight control behaviors and decreased hedonic hunger, each of which could contribute to improved diabetes management.Individuals with T2DM (n = 563) and overweight or obesity participated in a 12-month, 16-site, randomized trial of WW with diabetes counseling or SC. Hierarchical linear modeling (HLM) evaluated whether 12-month changes in weight control behaviors (Eating Behavior Inventory; EBI) and hedonic hunger (Power of Food Scale; PFS) differed by treatment condition. If a significant treatment effect was found, 12-month changes in EBI/PFS were regressed on 12-month changes in HbAEBI scores increased significantly over the 12-months (p 0.001), with greater improvements in WW than SC (p 0.001). PFS decreased significantly in the 12-months (p 0.001), with no differences between treatment groups (p = 0.15). HLM analyses that followed up on the significant treatment effect for 12-month change in EBI revealed no significant differences by treatment condition for the relationship between change in EBI scores and change in HbAWW with diabetes counseling produced greater engagement in weight control behaviors in those with T2DM than did SC. Across both groups, improved weight control behaviors and hedonic hunger were related to improved glycemic control and weight loss.

Amiodarone induced thyrotoxicosis (AIT) is a challenging diagnosis that affects 3-5% of patients taking amiodarone in the United States. Type I AIT is seen in patients with preexisting thyroid disease and is generally treated with thionamides while type II AIT represents a destructive thyroiditis that responds to glucocorticoids. A mixed type exists and is associated with higher mortality, especially in older adults with cardiovascular disease. Thyroidectomy is considered a last resort option for patients intolerant or refractory to medical treatment. A 70 year-old male with a history of coronary artery disease, ventricular tachycardia (VT), and heart failure was referred to the endocrine clinic for abnormal thyroid function tests that showed TSH 5.0 ng/dL, FT3 4.61 pg/mL). Thyroid RAIU showed severely decreased uptake secondary to the high iodine content of amiodarone. He remained thyrotoxic despite using higher doses of prednisone (60 mg daily) and methimazole (90 mg daily). He was changed to PTU (900 mg daily) and started on cholestyramine, with no improvement in overall status. Several weeks after admission, a total thyroidectomy was performed. His postoperative course was unremarkable except for hypoparathyroidism. He was clinically and biochemically euthyroid one week after his procedure. At 6 months follow up, he remained stable on levothyroxine 100 mcg/day but continued to require calcitriol and calcium supplementation. We present an interesting case of mixed type AIT refractory to medical therapy associated with cardiovascular compromise. This case highlights the challenges in the diagnosis and management of such patients. Thyroid autoantibodies, thyroid ultrasound and RAIU were more indicative of Type II AIT, however, lack of response to high dose steroids was inconsistent with the diagnosis. While receiving the treatment for both Type I and II AIT, our patient had persistent clinical and biochemical thyrotoxicosis and required thyroidectomy. Although most AIT patients are treated medically, thyroidectomy is reserved for those most severe and refractory cases and is considered a viable option in such patients.

Introduction: Preeclampsia is a complication of pregnancy defined by new onset hypertension after 20 weeks with proteinuria or new onset thrombocytopenia, renal or liver dysfunction, pulmonary edema or cerebral/visual symptoms. Hyperthyroidism in pregnancy is usually due to Graves’ disease, and if poorly controlled can increase the risk of preeclampsia and thyroid storm. In this case report we present a case of preeclampsia with impending thyroid storm treated successfully with medical therapy, delivery, and plasmapheresis. Case Description: A 40-year-old female who is 31 6/7 weeks pregnant presents with cough and dyspnea. She has no known thyroid disease. Her systolic blood pressure at presentation is >160 mmHg. She is diagnosed with preeclampsia based on elevated spot protein/creatinine ratio (1.4 g/g) and persistent hypertension. A brain natriuretic peptide is elevated to 847 (reference range 4 (non-pregnancy reference range 0.70-1.48 ng/dL). She is started on therapy for impending thyroid storm, including maximum doses of propranolol, propylthiouracil, hydrocortisone and saturated solution of potassium iodide. Her thyroid stimulating immunoglobulin is > 500 (reference range 40 (reference range

Objective:The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study is the first stroke prevention trial to include protocol-driven intensive management of multiple risk factors. In this prespecified analysis, we aimed to investigate the relationship between risk factor control during follow-up and outcome of patients in the medical arm of SAMMPRIS.Methods:Data from SAMMPRIS participants in the medical arm (n = 227) were analyzed. Risk factors were recorded at baseline, 30 days, 4 months, and then every 4 months for a mean follow-up of 32 months. For each patient, values for all risk factor measures were averaged and dichotomized as in or out of target.Results:Participants who were out of target for systolic blood pressure and physical activity, as well as those with higher mean low-density lipoprotein cholesterol and non–high-density lipoprotein, were more likely to have a recurrent vascular event (stroke, myocardial infarction, or vascular death) at 3 years compared to those who had good risk factor control. In the multivariable analysis, greater physical activity decreased the likelihood of a recurrent stroke, myocardial infarction, or vascular death (odds ratio 0.6, confidence interval 0.4–0.8).Conclusions:Raised blood pressure, cholesterol, and physical inactivity should be aggressively treated in patients with intracranial atherosclerosis to prevent future vascular events. Physical activity, which has not received attention in stroke prevention trials, was the strongest predictor of a good outcome in the medical arm in SAMMPRIS.ClinicalTrials.gov identifier:NCT00576693.

Objective Modest weight loss from clinical interventions improves glycemic control in type 2 diabetes (T2DM). Data are sparse on the effects of weight loss via commercial weight loss programs. This study examined the effects on glycemic control and weight loss of the standard Weight Watchers program, combined with telephone and email consultations with a certified diabetes educator (WW), compared with standard diabetes nutrition counseling and education (standard care, SC). Methods In a 12-month randomized controlled trial at 16 U.S. research centers, 563 adults with T2DM (HbA1c 7–11%; BMI 27–50 kg/m2) were assigned to either the commercially available WW program (regular community meetings, online tools), plus telephone and email counseling from a certified diabetes educator, or to SC (initial in-person diabetes nutrition counseling/education, with follow-up informational materials). Results Follow-up rate was 86%. Twelve-month HbA1c changes for WW and SC were −0.32 and +0.16, respectively; 24% of WW versus 14% of SC achieved HbA1c

The pathophysiology of type 2 diabetes mellitus involves several biologic mechanisms and no single medication addresses them all. Most patients require more than one medication to adequately treat their diabetes, needing drugs with unique and complementary mechanisms of action to address and balance insulin and glucagon levels. In the past decade, several therapeutic drug classes have been developed for type 2 diabetes mellitus. Each provides therapeutic options with novel mechanisms of action to help clinicians achieve the goal of glucose homeostasis while controlling adverse events, especially reducing the risk of hypoglycemia.

Outcomes from intensive glycemic control postrenal transplant have not been studied.Our objective was to observe the optimal management of hyperglycemia in patients with diabetes or impaired glucose tolerance receiving renal transplantation.We conducted a randomized controlled trial with patients undergoing renal transplantation randomized to either i.v. insulin therapy (intensive) or standard s.c. insulin therapy while the patients were admitted to the hospital.The study consisted of a 3-day postrenal transplant group treated with intensive i.v. insulin [blood glucose (BG) = 70-110 mg/dl] or a control group treated with s.c. insulin (BG = 70-180 mg/dl).The primary endpoint was delayed graft function (DGF). Secondary endpoints were glycemic control, graft survival, and acute rejection episodes.A total of 104 patients were screened and randomized to either the intensive or control condition; however, the intention-to-treat analysis set consisted of only the 93 participants (n = 44 intensive, n = 49 control) that underwent a renal transplant. DGF was present in 18% (eight of 44) of the intensive group and 24% (12 of 49) of the control group (P = 0.46). The occurrence of severe hypoglycemia (BG40 mg/dl) and severe hyperglycemia (BG350 mg/dl) were the primary safety outcome measures. There were nine participants with hypoglycemia identified, seven of which (78%) were in the intensive treatment group (P = 0.08). There were 30 instances of hyperglycemia with five participants (11%) in the intensive group and 12 participants (24%) in the control group having at least one hyperglycemic event (P = 0.10). For the 11 rejection episodes, nine were in the intensive treatment group (P = 0.013).The primary outcome measure of DGF was not statistically different for the two treatment groups. Regarding longer-term rejection and graft survival, the intensively treated participants were at higher risk for a rejection episode.

Many insulin infusion protocols are available for clinical use. We developed a Web-based, online intravenous insulin infusion calculator (IVIIC) for use in our intensive care and medical-surgical units.In September 2006, we implemented a quality improvement project: an online survey to evaluate the acceptance of this protocol by the nursing staff. Of the 103 registered nurses (RNs) who participated, there was no difference among experience levels of the RNs (/= or5 years) or among durations that RNs had been working within their unit (/= or2 years).The nurses were surveyed regarding the use and interpretation of the protocol, their comfort with, confidence in, and experience in using the protocol. More than 80% of the RNs found the protocol easy to implement, easy to interpret, and successful in controlling the blood glucose levels. Approximately 71% (+/-9%) of the RNs were comfortable with the tight blood glucose levels of the protocol. The nurses' confidence with the protocol was 82% (+/-8%), likely because 70% (+/-9%) of the nurses believed the training to be adequate. Significantly less than 25% of the RNs (18 +/- 7%) believed it was necessary to deviate from the protocol. More than 85% of the RNs appreciated the ability to make changes at their level of practice (92 +/- 5%).In summary, the IVIIC is well accepted by RNs for care of hyperglycemia in a hospital setting.

Modest weight loss from clinical interventions improves glycemic control in type 2 diabetes (T2DM). Data are sparse on the effects of weight loss via commercial weight loss programs. This study examined the effects on glycemic control and weight loss of the standard Weight Watchers program, combined with telephone and email consultations with a certified diabetes educator (WW), compared with standard diabetes nutrition counseling and education (standard care, SC).In a 12-month randomized controlled trial at 16 U.S. research centers, 563 adults with T2DM (HbAFollow-up rate was 86%. Twelve-month HbAWidely available commercial weight loss programs with community and online components, combined with scalable complementary diabetes education, may represent accessible and effective components of management plans for adults with overweight/obesity and T2DM.

Diabetes affects over 25 million people in the United States, most of whom are over the age of 16 and many of whom are licensed to drive a motor vehicle. Safe operation of a motor vehicle requires complex interactions of cognitive and motor functions and medical conditions that affect these functions often will increase the risk of motor vehicle accidents (MVA). In the case of diabetes, hypoglycemia is the most common factor that has been shown to increase MVA rates. When people with diabetes are compared with nondiabetic controls, systematic analyses show that the relative risk of MVA is increased by between 12% and 19% (Relative Risk Ratio 1.12-1.19). In comparison, the RRR for attention deficit hyperactivity disorder is 4.4 and for sleep apnea is 2.4. Epidemiologic research suggests that patients at risk for hypoglycemia-related MVAs may have some characteristics in common, including a history of severe hypoglycemia or of hypoglycemia-related driving mishaps. Experimental studies also have shown that people with a history of hypoglycemia-related driving mishaps have abnormal counter-regulatory responses to hypoglycemia and greater cognitive impairments during moderate hypoglycemia.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

OBJECTIVE Effective treatment algorithms are needed to guide diabetes care at hospital discharge in general medicine and surgery patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a prospective, multicenter open-label study aimed to determine the safety and efficacy of a hospital discharge algorithm based on admission HbA1c. Patients with HbA1c 9% were discharged on oral antidiabetes agents (OADs) plus glargine or basal bolus regimen at 80% of inpatient dose. The primary outcome was HbA1c concentration at 12 weeks after hospital discharge. RESULTS A total of 224 patients were discharged on OAD (36%), combination of OAD and glargine (27%), basal bolus (24%), glargine alone (9%), and diet (4%). The admission HbA1c was 8.7 ± 2.5% (71.6 mmol/mol) and decreased to 7.3 ± 1.5% (56 mmol/mol) at 12 weeks of follow-up (P < 0.001). The change of HbA1c from baseline at 12 weeks after discharge was −0.1 ± 0.6, −0.8 ± 1.0, and −3.2 ± 2.4 in patients with HbA1c 9%, respectively (P < 0.001). Hypoglycemia (7% (31%, P = 0.54). CONCLUSIONS Measurement of HbA1c on admission is beneficial in tailoring treatment regimens at discharge in general medicine and surgery patients with type 2 diabetes.

IN BRIEF Ward management of diabetic ketoacidosis (DKA) using subcutaneous insulin in specific patient populations is safe and effective, but insulin administered by continuous infusion has not been analyzed in this setting. This retrospective cohort study utilizing a nursing-driven, continuous infusion insulin calculator demonstrated safe and effective treatment of patients with DKA on medicine wards.

To determine differences in inpatient glycemic control and response to two different glargine-based insulin regimens in general medicine and surgery patients with type 2 diabetes (T2D).This is a post-hoc analysis of a prospective, multicenter, randomized trial of 298 non-ICU medicine and surgery patients with T2D treated with Basal Bolus regimen with glargine once daily and glulisine before meals and with Basal Plus regimen with glargine once daily and supplemental doses of glulisine before meals for blood glucose (BG)140mg/dl. Major study outcomes included differences in mean daily BG, frequency of treatment failures (defined as2 consecutive BG240mg/dl or a mean daily BG240mg/dl), and hypoglycemia between the medicine and surgery cohorts.Patients treated with Basal Bolus or with Basal Plus experienced similar improvement in mean daily BG after 1st day of therapy (p=0.16), number of treatment failures (p=0.11) and hypoglycemic events (p=0.50). Compared to surgery patients (n=130), medicine patients (n=168) had higher admission BG (p=0.01) and HbA1c levels (p0.01); however, they had similar response to either treatment regimen without differences in mean daily BG after 1st day of therapy (p=0.18), number of treatment failures (p=0.58), daily insulin requirements (p=0.36), or in the frequency of hypoglycemia (p=0.79).The Basal Plus regimen with glargine once daily and correction doses with glulisine before meals resulted in similar glycemic control to basal bolus regimen. We observed no differences in response to either basal insulin regimen between medicine and surgery patients with type 2 diabetes.

OBJECTIVE Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG CONCLUSIONS The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.

The value of comprehensive intensive atherosclerotic risk factor control in patients with coronary artery disease is well established. In 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial demonstrated that among patients with stable coronary disease, intensive management of vascular risk factors was as good as endovascular intervention plus intensive medical management for preventing cardiac ischemic events.1 Yet, despite the fact that atherosclerotic risk factor control in patients with stroke or transient ischemic attack is recommended by guidelines,2 a multimodal approach to prevention has not previously been tested in patients with atherosclerotic stroke. Older atherosclerotic stroke prevention trials comparing carotid revascularization with medical therapy, such as North American Symptomatic Carotid Endarterectomy Trial (NASCET)3 and Asymptomatic Carotid Atherosclerosis Study (ACAS),4 were performed in an era before statins and angiotensin converting enzyme inhibitors became standard of care, and therefore risk factor control was not adequate by today’s standards. Even recent trials comparing carotid revascularization procedures5,6 had little emphasis on risk factor control in their design and therefore had little impact on blood pressure and cholesterol measures at 1 year.7,8 Among stroke prevention trials in patients with heterogeneous causes of stroke, several trials have studied the effects of specific risk factor medications9–11 or of intensive control of a particular risk factor, such as blood pressure,12 but no stroke prevention trials have used a mutimodal aggressive risk factor approach. Among patients with intracranial atherosclerosis, which may be the most common cause of stroke worldwide,13 risk factor control is also believed to be important for stroke prevention. The Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, in which patients with symptomatic intracranial stenosis were managed with either warfarin or aspirin and usual risk factor management,14 showed that …

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.