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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.

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.

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.

Most continuous glucose monitors (CGM) provide interstitial fluid glucose trends, which reflect blood glucose trends with alarms and alerts to prevent hypoglycemia and provide better glycemic control. CGM used in conjunction with insulin pumps has changed the management of patients with insulin-dependent diabetes, mainly type 1 diabetes. CGM technology prevents the need for frequent blood glucose testing, which is often cumbersome for patients, providing them with a better alternative. CGM technology is underprescribed and therefore advantage should be taken of this technology to provide better hemoglobin A1c (HbA1c) control and decrease incidence of diabetic complications. CGM is particularly useful in patients with hypoglycemia unawareness and nocturnal hypoglycemia. CGM is currently not approved in pregnant patients, in critically ill patients and patients on dialysis. Research suggests that the benefits certainly outweigh the limitations of this technology. This review article focuses on the technical and clinical use of continuous glucose monitoring and sensor-integrated pump technology.

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.

Transition of care from a child-centered care environment to an adult-centered care environment for pediatric patients with diabetes is needed to ensure continued diabetes care. The transition process should start early and be tailored to the developmental stage of the patient. The typical challenges of adolescence and young adulthood including pubertal changes, parent-child conflict and the potential for high-risk behavior complicate the transition process. Methods of transfer of care are variable and less than optimal. Ongoing study and continued efforts are needed to improve the transition process so that young patients with diabetes receive high quality uninterrupted care.

Obesity is a world-wide epidemic associated with significant morbidity and mortality which costs billions of dollars per year. The associated related conditions are many and include heart disease, stroke, type II diabetes mellitus, sleep apnea and certain types of cancer. Given that it is a multifactorial problem, the treatments must also address the numerous causes associated with the development of obesity. The neurohormonal regulation of feeding and energy is a complex system often necessitating modification through more than 1 pathway to achieve weight loss. Therefore, in addition to lifestyle changes, attenuation of caloric intake and increase in caloric expenditure, pharmacotherapies, including combination medications, may prove beneficial in its treatment. Adding to the current available pharmacotherapies for obesity, the Food and Drug Administration has recently approved 2 new combination medications known as lorcaserin (Belviq) and phentermine-topiramate (Qsymia). As with these and other medications used for weight loss, clinical cautions, side effects, precise review of patients’ medical history and selecting the appropriate medication are imperative. Additionally, close follow-up is necessary in patients undergoing treatment for weight loss. As weight loss progresses, patients who are currently undergoing concomitant treatment for comorbid diabetes and hypertension need to be monitored for appropriate changes in medications used to treat those conditions. Weight loss is often accompanied by improvement in blood pressure and glucose levels and therefore resting blood pressure and fasting and/or postprandial plasma glucose levels should be monitored at follow-up. Although unique to each individual, the benefits of weight loss are substantial and can improve well-being and physical health.

Diabetes affects 25.8 million persons in the United States, and these persons make more than 35 million ambulatory care visits annually. Yet, less than half of persons with diabetes meet the recommended levels of A1C, blood pressure and lipid control. One innovative approach is to use mobile health technologies to help patients better manage their diabetes and related conditions, and 85% to 90% of patients have access to mobile health technology. A brief review of the guidelines for diabetes care and mobile health technology that can support the guidelines are reported related to (1) glycemic control and self-monitoring of blood glucose, (2) pharmacological approaches and medication management, (3) medical nutrition therapy, (4) physical activity and resistance training, (5) weight loss, (6) diabetes self-management education and (7) blood pressure control and hypertension. The patient and provider are encouraged to explore possibilities for mobile health technologies that can support behavior change.

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.

Maintaining blood glucose concentration within an acceptable range is a goal for patients with diabetes mellitus. Point-of-care glucose meters initially designed for home self-monitoring in patients with diabetes have been widely used in the hospital settings because of ease of use and quick reporting of blood glucose information. They are not only utilized for the general inpatient population but also for critically ill patients. Many factors affect the accuracy of point-of-care glucose testing, particularly in critical care settings. Inaccurate blood glucose information can result in unsafe insulin delivery which causes poor glucose control and can be fatal. Healthcare professionals should be aware of the limitations of point-of-care glucose testing. This chapter will first introduce glucose regulation in diabetes mellitus, hyperglycemia/hypoglycemia in the intensive care unit, importance of glucose control in critical care patients, and pathophysiological variables of critically ill patients that affect the accuracy of point-of-care glucose testing. Then, we will discuss currently available point-of-care glucose meters and preanalytical, analytical, and postanalytical sources of variation and error in point-of-care glucose testing.

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.

Glucose control in the hospital setting is very important. There is a high incidence of hyperglycemia, hypoglycemia, and glycemic variability in hospitalized patients. Safe insulin delivery and glucose control is dependent on reliable glucose meters and monitoring systems in the hospital. Different glucose monitoring systems use arterial, venous, central venous, and capillary blood samples. It is important for clinicians to be aware that there are limitations of specific point-of-care (POC) glucose meters and that situations exist whereby POC glucose meters as the sole measurement device should be avoided. POC meter devices are not approved by the Food and Drug Administration for use in critical care, although POC meter devices are commonly used in critical care settings and elsewhere. This review focuses on glucose assay principles, instrument technology, influences on glucose measurement, standards for glucose measurement, and an evaluation of different methods to measure blood glucose in the hospital setting.

Hyperglycemia in critical care patients is a common and costly problem with serious medical consequences. There is a complex host of endocrinologic features associated with critical illness. Insulin resistance in the liver, skeletal muscle, and heart causes stress-induced hyperglycemia. The optimal means for achieving tight glycemic control in a critical care setting is with insulin therapy, preferably intravenous insulin. There are studies that indicate that morbidity, mortality, clinical outcomes and cost can be improved in certain patients in the critical care setting. Some of the benefits from intensive insulin therapy are associated with improvements in inflammation and immunity. The benefits of insulin treatment are associated with blood glucose (BG) control and the glucose-independent mechanisms of insulin therapy. It appears that insulin infusion linked to glucose lowering must occur to show beneficial outcomes. The importance of good glycemic control has been demonstrated in medical and surgical patients, acute myocardial infarction, cardiac surgery, infection, and patients in the medical-surgical intensive care unit (ICU). This article reviews data which are supportive of intensive glycemic control in the ICU, discusses recommendations from national guidelines concerning tight glycemic control, and provides examples of different protocols to achieve good metabolic control in an ICU setting.

Thyroid storm is a complication of thyrotoxicosis with a 20% to 30% mortality rate characterized by hyperthermia, tachycardia and altered mental status. Rarely, thyroid storm may have an apathetic presentation. The authors present a 63-year-old woman with apathetic thyrotoxicosis and hypercalcemia. The action of thyroid hormones stimulating bone resorption more than bone formation is thought to cause increased bone demineralization and, occasionally, hypercalcemia. This occurs in the absence of malignancy, prolonged immobility, hypervitaminosis D and primary hyperparathyroidism. Her thyroid storm was medically managed and her hypercalcemia was treated with intravenous fluids, calcitonin and a bisphosphonate. This case describes the presence of hypercalcemia in a patient with apathetic thyroid storm with no other factors contributing to the hypercalcemia. In addition, this patient had significant elevation in serum calcium, which possibly contributed to her symptomatology. The calcium remained normal after the thyrotoxicosis resolved, which is typical of the hypercalcemia of thyrotoxicosis.

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.

Background Diabetes is a major public health problem in South Carolina; however, the Diabetes Initiative of South Carolina (DSC) provides a realistic mechanism to address issues on a statewide basis. Methods The Diabetes Center of Excellence in the DSC provides oversight for developing and supervising professional education programs for health care workers of all types in South Carolina to increase their knowledge and ability to care for people with diabetes. The DSC has developed many programs for the education of a variety of health professionals about diabetes and its complications. Results The DSC has sponsored 21 Annual Diabetes Fall Symposia for primary health care professionals featuring education regarding many aspects of diabetes mellitus. The intent of the program is to enhance the lifelong learning process of physicians, advanced practice providers, nurses, pharmacists, dietitians, laboratorians and other health care professionals, by providing educational opportunities and to advance the quality and safety of patient care. The symposium is an annual 2-day statewide program that supplies both a comprehensive diabetes management update to all primary care professionals and an opportunity for attendees to obtain continuing education credits at a low cost. Conclusion The overarching goal of the DSC is that the programs it sponsors and the development of new targeted initiatives will lead to continuous improvements in the care of people at risk and with diabetes along with a decrease in morbidity, mortality and costs of diabetes and its complications in South Carolina and elsewhere.

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.

BACKGROUND We previously reported that compared to standard glycemic control [blood glucose (BG): 70-180 mg/dL], patients randomized to intensive glycemic control (BG: 70-110 mg/dL) were at increased risk of graft rejection in renal transplantation. However, the underlying mechanisms that associate the effect of intensive glycemic control with renal transplant outcomes have not been identified. METHODS A secondary data analysis of 93 participants (n=44 intensive, n=49 control) was conducted using data from a previous randomized controlled clinical trial. We examined inflammatory biomarkers, glycemic variability, hypoglycemia, and hyperglycemia as potential contributing etiologies by assessing the effect of intensive glycemic control on these characteristics, and evaluate the association of these variables with graft rejection. RESULTS Intensive glycemic control had no appreciable effect on highly sensitive C-reactive protein, interleukin (IL)-6, tumor necrosis factor alpha, IL-1β, or IL-10 levels at all time points after transplantation. Moreover, neither inflammatory biomarkers nor increased glycemic variability were associated with graft rejection. However, intensive treatment increased the risk of hypoglycemia (BG

Objectives Provide treatment guidelines for glucocorticoid-induced hyperglycemia and to understand the clinical implications of glucocorticoid-induced hyperglycemia. Methods The authors analyzed an electronic search (Medline) and a literature review of the pertinent articles published from 1980 to September 2012. Results In patients treated with glucocorticoids, the odds ratio for development of new-onset diabetes mellitus has been reported to be 1.36 to 2.31. The prevalence of abnormal glucose metabolism in post renal transplant patients taking glucocorticoids has been reported to be 17% to 32%. Sustained glucocorticoid treatment increases the potential for future cardiovascular disease through multiple pathways, resulting in a trade-off between benefit and harm. Complications related to glucocorticoid treatments are associated with the total glucocorticoid dose and duration of therapy. Other risk factors include age and body mass index. Understanding the pharmacodynamics and clinical implications of glucocorticoid-induced hyperglycemia can promote recognition and improvement of its treatment. Conclusions Glucocorticoid-induced hyperglycemia has significant clinical implications in patients with diabetes mellitus and without diabetes mellitus. Early recognition and proper proactive management of glucocorticoid-induced hyperglycemia should enhance care for patients receiving glucocorticoid treatment. Furthermore, treatment has been effective for both the inpatient and the outpatient settings.

Background There is a huge economic burden of diabetes in South Carolina. Methods The South Carolina Guidelines for Diabetes Care were based on the 2013 Standards of Medical Care from the American Diabetes Association. Results From a review of the Diabetes Quality Indicators in South Carolina 2007, Medicare claims data show: 65% of South Carolinians with diabetes insured by Medicare received 2 A1C test per year, 54% received an eye examination and 78% received a lipid panel. Only 42% of these individuals with diabetes had all 3 tests in the same year. In addition, only 50% of individuals with diabetes in South Carolina attended a diabetes self-management class. To improve the statistics and outcomes, the Diabetes Advisory Council provided the evidence-based South Carolina Guidelines for Diabetes Care. They are based on the 2013 Standards of Medical Care from the American Diabetes Association. These guidelines have been promoted at the continuing education programs sponsored by the Diabetes Initiative of South Carolina and the South Carolina Division of Diabetes Prevention and Control and distributed in the community sites by the Racial and Ethnic Approaches to Community Health coalition. Conclusions The South Carolina Guidelines for Diabetes will provide evidence-based therapy and monitoring to minimize complications from diabetes and promote a higher quality of life for those with diabetes.

The Diabetes Initiative of South Carolina (DSC) is charged with the development of guidelines for the management of diabetes and supporting adherence to evidence-based standards for education and care. The DSC is committed to lowering the burden of diabetes in the state through translation of evidence-based standards of clinical practice, and patient and community education centered on blood glucose control, blood pressure control, healthy eating, physical activity, and foot care. The DSC has developed many programs for the education of a variety of health professionals about diabetes and its complications. DSC has sponsored 18 Annual Diabetes Fall Symposia for primary health care professionals featuring education on all aspects of diabetes mellitus. The intent of the program is to enhance the lifelong learning process of physicians, nurses, pharmacists, dietitians and other health care professionals by providing educational opportunities and to advance the quality and safety of patient care.

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.

BACKGROUND: Great emphasis is placed on optimizing treatment of hospitalized patients with diabetes and hyperglycemia. OBJECTIVE: This study was conducted to determine if the application of hospital-wide insulin order sets improved inpatient safety by reducing the number of actual hypoglycemic and hyperglycemic events and increasing at-target blood glucose. DESIGN: A retrospective chart review was conducted of hypoglycemic and hyperglycemic events and at-target blood glucose occurring before and after institution of the insulin order sets and blood glucose protocols. SETTING: The Medical University of South Carolina (MUSC) Medical Center is a 709-bed hospital and tertiary referral center for partnering hospitals in the southeastern United States. PATIENTS: All patients were evaluated who had a documented history of diabetes or who had at least 1 finger-stick blood glucose above 180 mg/dL who were admitted for care to the MUSC adult main hospital (minimum of 18 years-of-age; maximum 100 years-of-age) during June 2004, June 2005, June 2006, and June 2007. INTERVENTION: The intervention involved institution of hospital-wide hypoglycemia, hyperglycemia, subcutaneous insulin, and intravenous insulin treatment protocols. MEASUREMENTS: Retrospective data on hypoglycemia, hyperglycemia, and at-target blood glucose incidence and frequency were collected via a computerized repository for all inpatients. RESULTS: The percent time in range improved by 10% with no increase in the amount of severe hypoglycemic episodes for the blood glucose results. CONCLUSIONS: Implementing standardized insulin order sets including hypoglycemia and hyperglycemia treatment protocols at MUSC produced expected benefits for patient safety for this patient population. Journal of Hospital Medicine 2009;4:331–339. © 2009 Society of Hospital Medicine.

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.

The purpose of this study was to examine whether a web-based, on-line intravenous insulin (IVI) infusion calculator (IVIIC) program for the delivery of IVI therapy in coronary artery bypass graft (CABG) patients was superior to a prior IVI protocol used in the cardiothoracic intensive care unit at our institution.The study included 97 CABG patients studied from October 2004 to February 2005 pre-protocol (type 2 diabetes) and October 2005 to February 2006 post-protocol (with or without type 2 diabetes). The IVIIC was programmed to resemble an algorithm whereby any patient with type 2 diabetes or a blood glucose (BG) greater than 120 mg/dL was started on IVI with an insulin sensitivity factor, a multiplier of 0.03. The calculator used the following mathematical formula: rate of insulin infusion/hour = (current BG - 60 mg/dL) x 0.03.Pre- and post-protocol groups for patients with type 2 diabetes were similar in all demographics measured, including initial age, mean age, percentage female, and percentage African-American. Significant differences were observed between pre- and post-protocol groups in mean BG recorded over a 48-h period (P0.0001), percentage not at target within 48 h (P0.0001), mean hours to first BG between 80 to 120 mg/dL (P0.0001), mean hours to target (three consecutive BGs 80-120 mg/dL) (P0.0001), and hyperglycemic index (P0.0001). The incidence of hypoglycemia (percentage BG70 mg/dL) was not significantly increased in the post-protocol groups (P = 0.2581).We conclude that the IVIIC is a safe nurse-driven protocol with excellent BG outcomes.

Objective: Intensive insulin therapy to normalize blood glucose may improve outcome in intensive care unit patients. We prospectively evaluated the implementation of an intensive insulin protocol in medical intensive care patients to identify and overcome obstacles that this complex therapy creates. Design: This prospective, quality assessment study was designed to establish a standard protocol for glucose control in critically ill patients. Setting: The study took place in the medical intensive care unit at the Medical University of South Carolina, a tertiary care center. Patients: Patients diagnosed with sepsis and two consecutive blood glucose measurements of >120 mg/dL were included in the study. Interventions: The protocol, targeting blood glucose of 80-120 mg/dL, was a multidisciplinary initiative involving extensive education of house staff before subject enrollment. Based on predefined criteria, patients were monitored daily for glycemic control, inclusion criteria, and protocol adherence. Protocol improvements were assessed at 6 and 12 months via nursing surveys. Measurements and Main Results: Seventy patients receiving insulin infusion for >8 hrs were included in data analysis, accounting for 4,920 glucose readings. Eighty-six hypoglycemic events were recorded, with the number of events decreasing from 7.6% to 0.3% by the final version of the protocol. Average duration on protocol was 6 days, and average time to target range was 5.4 hrs. Identifiable causes of hypoglycemia and survey results led to four protocol revisions by study completion. Conclusions: In comparison to studies suggesting that normoglycemia is an easily achievable goal, our protocol often recorded glucose values

The development of type 2 diabetes is increasing in epidemic proportions. There is a significant risk for cardiovascular disease, which is the most prevalent and detrimental complication for the diabetic population. Serum lipid abnormalities are common in patients with diabetes, and due to this increased vascular risk, it is recommended to aggressively treat the hyperlipidemia. Therefore, intensive lipid-lowering therapy should be used for primary and secondary prevention against macrovascular complications for patients with type 2 diabetes. In this article some of the key studies justifying the need for lipid reduction in patients with type 2 diabetes are reviewed and practical guidelines for management of the dyslipidemia are suggested.

It has been suggested that low-density lipoprotein (LDL) modified by glycation may be more susceptible to oxidation and thus, enhance its atherogenicity. Using affinity chromatography, LDL glycated in vivo (G-LDL) and relatively nonglycated. (N-LDL) subfractions can be isolated from the same individual. The extent of and susceptibility to oxidation of N-LDL compared with G-LDL was determined in 15 type 1 diabetic patients. Total LDL was isolated and separated by boronate affinity chromatography into relatively glycated (G-) and nonglycated (N-) subfractions. The extent of glycation, glycoxidation, and lipoxidation, lipid soluble antioxidant content, susceptibility to in vitro oxidation, and nuclear magnetic resonance (NMR)-determined particle size and subclass distribution were determined for each subfraction. Glycation, (fructose-lysine) was higher in G-LDL versus N-LDL, (0.28 +/- 0.08 v 0.13 +/- 0.04 mmol/mol lysine, P < .0001). However, levels of glycoxidation/lipoxidation products and of antioxidants were similar or lower in G-LDL compared with N-LDL and were inversely correlated with fructose-lysine (FL) concentrations in G-LDL, but positively correlated in N-LDL. In vitro LDL (CuCl2) oxidation demonstrated a longer lag time for oxidation of G-LDL than N-LDL (50 +/- 0.16 v 37 +/- 0.15 min, P < .01), but there was no difference in the rate or extent of lipid oxidation, nor in any aspect of protein oxidation. Mean LDL particle size and subclass distribution did not differ between G-LDL and N-LDL. Thus, G-LDL from well-controlled type 1 diabetic patients is not more modified by oxidation, more susceptible to oxidation, or smaller than relatively N-LDL, suggesting alternative factors may contribute to the atherogenicity of LDL from type 1 diabetic patients.

Objective: To report the successful laparoscopic surgical management of a case of right unilateral adrenal hyperplasia. Methods: We present a case of unilateral adrenal hyperplasia and review the pertinent literature. The effectiveness of surgical treatment of unilateral adrenal hyperplasia is evaluated. Results: A 50-year-old man had a 7-year history of hypertension, which had been treated with antihypertensive medications. On initial assessment, he was taking long-acting diltiazem, 240 mg twice a day, and his blood pressure was 150/84 mm Hg. He was noted to have recurrent hypokalemia, low plasma renin activity, increased plasma aldosterone concentration, and high urinary aldosterone levels. Magnetic resonance imaging of the adrenal glands revealed a normal left adrenal gland and fullness of the right adrenal gland. Selective adrenal vein catheterization showed findings consistent with a right-sided adrenal gradient. Surgical removal of the right adrenal gland laparoscopically alleviated his symptoms and cured his hypertension and hypokalemia. Pathologic examination of the right adrenal gland revealed diffuse hyperplasia of the zona fasciculata and zona reticularis. Plasma aldosterone, renin, and potassium levels returned to normal postoperatively, and his blood pressure declined to 120/70 mm Hg. At 1-year follow-up, the patient remained normotensive without the need for antihypertensive agents. Conclusion: This rare type of hyperaldosteronism, known as unilateral adrenal hyperplasia, is difficult to categorize not only because it fails to typify a conventional subtype but also because it is difficult to confirm the pathologic diagnosis. Recognition of the variety of provocative, biochemical, and imaging results that may be seen in this disorder is important in making the correct diagnosis. Determining unilaterality of disease by selective adrenal vein sampling can result in a cure of hypertension and hypokalemia by surgical resection. (Endocr Pract. 2000;6:153-158)

Insulin resistance syndrome (IRS), also termed syndrome X, is a distinctive constellation of risk factors for the development of type 2 diabetes mellitus and cardiovascular disease. The syndrome's hallmarks are glucose intolerance, hyperinsulinemia, a characteristic dyslipidemia (high triglycerides; low high-density lipoprotein cholesterol, and small, dense low-density lipoprotein cholesterol), obesity, upper-body fat distribution, hypertension, and increased prothrombotic and antifibrinolytic factors. Insulin resistance, caused by a complex of genetic and environmental influences, is now recognized not just as a mechanism contributing to hyperglycemia in type 2 diabetes, but also as an early metabolic abnormality that precedes the development of overt diabetes. The clinical definition of insulin resistance is the impaired ability of insulin (either endogenous or exogenous) to lower blood glucose. In some insulin-resistant individuals, insulin secretion will begin to deteriorate under chronic stress (glucose toxicity) and overt diabetes will result. If not, individuals will remain hyperinsulinemic, with perhaps some degree of glucose intolerance, together with other hallmarks of the IRS. The statistical correlation between hypertension and impaired glucose tolerance is clear, although the mechanism is not yet fully understood. Epidemiologic evidence of insulin resistance as an independent risk factor for atherosclerosis and coronary heart disease (CHD) completed the evolving concept of IRS as the common soil for the development of both diabetes and CHD. No single laboratory test exists for diagnosis of IRS. Rather, IRS remains a clinically evident syndrome that can be suspected on the basis of physical and laboratory findings. This identifies individual patients whom the clinician should screen for associated comorbid conditions, aggressively control cardiovascular risk factors, and tailor drug therapy for optimal benefit. This article provides practical guidelines to achieve these goals and specific strategies to ameliorate cardiovascular and metabolic risk in the IRS.

Pheochromocytoma is known to increase morbidity and mortality. We describe a case of pheochromocytoma during pregnancy. A patient was transferred to our hospital during gestational week 15 with severe hypertension, acute pulmonary edema, and cardiomyopathy. One day after transfer, she had a spontaneous abortion of the fetus. One week after hospital transfer, she developed acute dyspnea, supraventricular tachycardia degenerating into ventricular tachycardia, and respiratory failure requiring mechanical ventilation. Pheochromocytoma caused by a right adrenal mass was diagnosed. The patient was treated with titrated doses of phenoxybenzamine, intravenous nicardipine, and metyrosine over a period of 3 weeks with resultant stabilization of her blood pressure. She underwent a successful right adrenalectomy 1 month after her initial presentation. Four months after surgery, all antihypertensive medications were discontinued and her blood pressure remained stable 1 year after the surgery. This case describes the maternal morbidity and fetal mortality that may be associated with pheochromocytoma during pregnancy.

Increased susceptibility of LDL to oxidation has been shown to be associated with the presence of coronary heart disease and may account for the accelerated vascular disease seen in diabetes. The response of LDL to in vitro oxidative stress has been proposed as a measure of the predisposition of LDL to the in vivo subendothelial oxidative stress. Increased susceptibility to oxidation has been demonstrated recently in diabetic patients with poorly controlled IDDM. Thus, we conducted studies to determine whether the increased susceptibility of LDL to oxidation was secondary to diabetes per se or to the level of glycemic control. Fifteen IDDM patients with good glycemic control and with no evidence of macrovascular disease or proteinuria were compared with healthy age-, sex-, race-, and BMI-matched nondiabetic subjects. Fasting blood glucose levels averaged 12.1 +/- 1.1 (mean +/- SE) vs. 4.9 +/- 0.1 mmol/l in the diabetic versus the control groups, respectively. HbA1c levels averaged 7.7 +/- 0.5 vs. 4.4 +/- 0.2%, reflecting well-controlled diabetes (P < 0.0001). Total, LDL, VLDL, and HDL cholesterol, triglyceride, and lipoprotein(a) levels did not differ between the groups. The particle size, lipid composition, fatty acid content, antioxidant content, and glycation were similar for LDL isolated from both groups. A rapid LDL preparation technique was used to compare LDL susceptibility to oxidation under the following conditions: final LDL cholesterol concentration of 100 microg/ml, 5 micromol/l of CuCl2 at 25 degrees C. There was no difference in the susceptibility to in vitro oxidation of LDL isolated from IDDM patients compared with control subjects. There was no correlation of glycemic control with any of the parameters of the in vitro oxidation of LDL. LDL from patients with well-controlled IDDM does not differ in composition or in susceptibility to in vitro oxidative stress compared with LDL from nondiabetic subjects.

In an effort to avoid the trauma and other nonolfactory effects produced by surgical sectioning of pigeons' olfactory nerves, and to avoid the interference with breathing produced by nostril plugs, a way of making pigeons anosmic by inserting plastic tubes in their nostrils was developed. A total of 16 experimental releases were conducted from unfamiliar sites to compare the homing behavior of birds wearing a tube in each nostril with controls wearing a tube in only one nostril. In five short-distance releases (less than 25 km), no convincing differences in initial orientation, vanishing intervals, or homing success were observed. In eleven releases from longer distances (more than 76 km), the experimental birds were random in three cases and the controls were random in two. In no case were the differences in the distributions of the bearings of experimental and control birds statistically significant, nor were there ever significant differences in vanishing intervals. However, experimental birds had much poorer homing success from these long-distance releases. It is concluded, in view of the anosmic pigeons' good orientation at distant unfamiliar sites, that olfaction is not necessary for homeward orientation and hence that it cannot be the basis of the birds' navigational map. Poor homing success from long distances is probably a consequence of the physical irritation and interference with breathing unfortunately produced by the nasal tubes.