Molecular-derived risk of malignancy and the related positive call rate of indeterminate thyroid cytology diagnoses as quality metrics for individual cytopathologists.

BACKGROUND: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow-up studies. However, traditional cytologic-histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular-derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. METHODS: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2-year period with at least 3 years of follow-up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic-type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic-histologic correlation outcomes. RESULTS: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%-20.8%), 28.1% (range, 22.1%-36.7%), and 27.0% (range, 19.5%-41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p = .06), the AUS PCRs were quite different (p = .002). By cytologic-histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false-positive cases. CONCLUSIONS: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement.

Cystic fibrosis related liver disease and endocrine considerations.

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

Treatment of cystic fibrosis related bone disease.

The advent of highly effective CFTR modulator therapies has slowed the progression of pulmonary complications in people with cystic fibrosis. There is increased interest in cystic fibrosis bone disease (CFBD) due to the increasing longevity of people with cystic fibrosis. CFBD is a complex and multifactorial disease. CFBD is a result of hypomineralized bone leading to poor strength, structure and quality leading to susceptibility to fractures. The development of CFBD spans different age groups. The management must be tailored to each group with nuance and based on available guidelines while balancing therapeutic benefits to risks of long-term use of bone-active medication. For now, the mainstay of treatment includes bisphosphonates. However, the long-term effects of bisphosphonate treatment in people with CF are not fully understood. We describe newer agents available for osteoporosis treatment. Still, the lack of data behooves trials of monoclonal antibodies treatments such as Denosumab and Romozosumab and anabolic bone therapy such as teriparatide and Abaloparatide. In this review, we also summarize screening and non-pharmacologic treatment of CFBD and describe the various options available for the pharmacotherapy of CFBD. We address the prospect of CFTR modulators on bone health while awaiting long-term trials to describe the effects of these medications on bone health.

Gestational and pregestational diabetes in pregnant women with cystic fibrosis.

As cystic fibrosis transmembrane regulator (CFTR) modulator therapies offer greater longevity and improved health quality, women living with cystic fibrosis (CF) are increasingly pursuing pregnancy. Maternal risks for pregnant women with CF largely depend on a woman's baseline pulmonary and pancreatic function, and the majority of CF pregnancies will successfully end in live births. Diabetes, either gestational or pre-existing cystic fibrosis-related diabetes (CFRD), is highly prevalent in women with CF, affecting 18 to 62% of pregnancies in recent CF center reports. In addition to the rising incidence of CFRD with age, gestational diabetes is also more common in women with CF due to lower insulin secretion, higher insulin resistance, and increased hepatic glucose production as compared to pregnant women without CF. Diabetes occurring during pregnancy has important implications for maternal and fetal health. It is well established in women without CF that glycemic control is directly associated with risks of fetal malformation, neonatal-perinatal mortality, cesarean delivery and need for neonatal intensive care. Small studies in women with CF suggest that pregnancies affected by diabetes have an increased risk of preterm delivery, lower gestational age, and lower fetal birth weight compared to those without diabetes. Women with CF preparing for pregnancy should be counseled on the risks of diabetes and should undergo routine screening for CFRD with oral glucose tolerance testing (OGTT) if not already completed in the past six months. Glycemic control in those with pre-gestational CFRD should be optimized prior to conception. Insulin is preferred for the management of diabetes in pregnant women with CF via multiple daily injections or insulin pump therapy, and continuous glucose monitors (CGM) can be useful in mitigating hypoglycemia risks. Women with CF face many unique challenges impacting diabetes care during pregnancy and would benefit from support by a multidisciplinary care team, including nutrition and endocrinology, to ensure healthy pregnancies.

Subcutaneous Insulin Dosing Calculators for Inpatient Glucose Control.

PURPOSE OF REVIEW: The goal of this review is to summarize information about insulin dosing software and calculators used as computerized decision support systems or electronic glucose management systems (eGMS). These are used for hospitalized, insulin-treated patients with diabetes. We describe the advantages and disadvantages and the rationale for their use. RECENT FINDINGS: We compared commercially available insulin dosing software, namely, Glucommander™, EndoTool®, GlucoStabilizer®, and GlucoTab®, in addition to computerized order entry systems that are available in electronic health records. The common feature among these eGMS is their ability to limit occurrences of hypoglycemia while achieving and maintaining patients at target blood glucose level. More research needs to be done examining the efficacy of eGMS in disease-specific states and their benefits and utility in preventing adverse outcomes. Their long-term benefits to health care systems are beginning to emerge in cost-saving benefits and prevention of readmissions.

Comparison of Computer-Guided Versus Standard Insulin Infusion Regimens in Patients With Diabetic Ketoacidosis.

BACKGROUND: This study was performed to investigate the efficacy of Glucommander (GM) (Glytec®), a computer-based algorithm versus standard (paper form-based) continuous insulin infusion (CII) in the treatment of patients with diabetic ketoacidosis (DKA). METHODS: This was a retrospective multicenter study involving 2665 patients with DKA treated with either GM (n = 1750) or standard protocols (n = 915) across 34 institutions in the United States. GM estimates the rate of CII using an insulin sensitivity factor referred to as a "multiplier" that ranges between 0.01 and 0.03. Outcomes of interest were differences in time to resolve DKA (blood glucose [BG] <200 mg/dL and bicarbonate < 18 mmol/L) and number of hypoglycemic events defined as a BG <70 mg/dl. RESULTS: Treatment with GM was associated with lower rates of hypoglycemia during the time of the insulin drip (12.9% vs 35%, P = .001), faster time to normalization of blood glucose (9.7 ± 8.9 vs 10.97 ± 10.2 hours, P = .0001) and resolution of metabolic acidosis (13.6 ± 11.8 vs 17.3 ± 19.6 hours, P = .0001), and shorter hospital length of stay (3.2 ± 2.9 vs 4.5 ± 4.8 days, P = .01) compared to standard care. Best treatment outcomes were achieved with an initial multiplier of 0.01 and a glucose target range between 120 and 180 mg/dl. CONCLUSION: The GM algorithm in DKA treatment resulted in lower rates of hypoglycemia and faster DKA resolution over standard paper-based algorithms. Prospective randomized clinical trials comparing the efficacy and cost of computer-based algorithms versus standard CII regimens are warranted.

Comparison of an Electronic Glycemic Management System Versus Provider-Managed Subcutaneous Basal Bolus Insulin Therapy in the Hospital Setting.

BACKGROUND: American Diabetes Association (ADA) guidelines recommend a basal bolus correction insulin regimen as the preferred method of treatment for non-critically ill hospitalized patients. However, achieving ADA glucose targets safely, without hypoglycemia, is challenging. In this study we evaluated the safety and efficacy of basal bolus subcutaneous (SubQ) insulin therapy managed by providers compared to a nurse-directed Electronic Glycemic Management System (eGMS). METHOD: This retrospective crossover study evaluated 993 non-ICU patients treated with subcutaneous basal bolus insulin therapy managed by a provider compared to an eGMS. Analysis compared therapy outcomes before Glucommander (BGM), during Glucommander (DGM), and after Glucommander (AGM) for all patients. The blood glucose (BG) target was set at 140-180 mg/dL for all groups. The safety of each was evaluated by the following: (1) BG averages, (2) hypoglycemic events <40 and <70 mg/dL, and (3) percentage of BG in target. RESULT: Percentage of BG in target was BGM 47%, DGM 62%, and AGM 36%. Patients' BGM BG average was 195 mg/dL, DGM BG average was 169 mg/dL, and AGM BG average was 174 mg/dL. Percentage of hypoglycemic events <70 mg/dL was 2.6% BGM, 1.9% DGM, and 2.8% AGM treatment. CONCLUSION: Patients using eGMS in the DGM group achieved improved glycemic control with lower incidence of hypoglycemia (<40 mg/dL and <70 mg/dl) compared to both BGM and AGM management with standard treatment. These results suggest that an eGMS can safely maintain glucose control with less hypoglycemia than basal bolus treatment managed by a provider.

Use of a Computer-Based Insulin Infusion Algorithm to Treat Diabetic Ketoacidosis in the Emergency Department.

BACKGROUND: Efforts at improving quality metrics in diabetes focus on minimizing adverse events and avoiding re-admissions to the hospital. Our experience with Glucommander™ (Glytec, Greenville, SC), a cloud-based insulin management software system, suggested that its use in the emergency department (ED) would be useful in treating patients with mild diabetic ketoacidosis (DKA). MATERIALS AND METHODS: Thirty-five patients seen in the ED with hyperglycemic crises and diagnosed with DKA during one calendar year were reviewed. A retrospective chart review was performed on patients who were placed on Glucommander™ for DKA management. We excluded patients with significant acidosis or concomitant medical illnesses. RESULTS: Initial average capillary glucose level was 487 ± 68 mg/dL, average time to target glucose was 5 h 11 min, and rate of hypoglycemia (blood glucose level <70 mg/dL) was less than 0.3%. Sixteen patients treated with the protocol were discharged from the ED directly, and 19 were admitted. Patients were maintained for an average of 14 ± 1 h on the Glucommander™ protocol. There was a significantly higher anion gap (P = 0.002) and lower serum bicarbonate level (P = 0.006) in the admitted group. We found very low evidence of re-admission (6%) within 30 days of discharge from the ED for DKA patients. No significant glucose-related adverse events were noted. CONCLUSIONS: Use of Glucommander™ for guiding the insulin treatment of mild DKA in the ED can decrease admissions to the hospital for DKA by 45%. Low rates of hypoglycemia make this an option to improve efficiency of utilization of inpatient hospital beds. The cost savings for nonadmissions were estimated at $78,000 over the 12 months of the study. Our results suggest that Glucommander™ is a safe and efficient tool for use in the ED to manage mild to moderate DKA.

Improvement in inpatient glycemic care: pathways to quality.

The management of inpatient hyperglycemia is a focus of quality improvement projects across many hospital systems while remaining a point of controversy among clinicians. The association of inpatient hyperglycemia with suboptimal hospital outcomes is accepted by clinical care teams; however, the clear benefits of targeting hyperglycemia as a mechanism to improve hospital outcomes remain contentious. Glycemic management is also frequently confused with efforts aimed at intensive glucose control, further adding to the confusion. Nonetheless, several regulatory agencies assign quality rankings based on attaining specified glycemic targets for selected groups of patients (Surgical Care Improvement Project (SCIP) measures). The current paper reviews the data supporting the benefits associated with inpatient glycemic control projects, the components of a successful glycemic control intervention, and utilization of the electronic medical record in implementing an inpatient glycemic control project.

A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet.

This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia.

Reversal of phrenic nerve palsy with topiramate.

A 57-year-old Caucasian man presented with diaphragmatic paralysis and type 2 diabetes. He had severe orthopnea that remained unchanged for 1 year. He was later diagnosed with distal symmetric polyneuropathy and was started on topiramate. Within 26 weeks of treatment, the patient showed improvement in diaphragmatic function and regrowth of intraepidermal nerve fibers, accompanied by improvement in respiratory and peripheral neuropathy symptoms. Topiramate may prove to be an effective agent in the treatment of nonremitting diaphragmatic paralysis and regrowth of intraepidermal nerve fibers.

Diabetic neuropathies: clinical manifestations and current treatment options.

Diabetic neuropathies are a heterogeneous group of disorders that include a wide range of abnormalities. They can be focal or diffuse, proximal or distal, affecting both peripheral and autonomic nervous systems, causing morbidity with significant impact on the quality of life of the person with diabetes, and can result in early death. Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, usually involves small and large nerve fibers. Small-nerve-fiber neuropathy often presents with pain but without objective signs or electrophysiologic evidence of nerve damage, and is recognized as a component of the impaired glucose tolerance and metabolic syndromes. The greatest risk resulting from small-fiber neuropathy is foot ulceration and subsequent gangrene and amputation. Large-nerve-fiber neuropathies produce numbness, ataxia and uncoordination, impairing activities of daily living and causing falls and fractures. A careful history and detailed physical examination are essential for the diagnosis. Symptomatic therapy has become available and newer and better treatment modalities, based on etiologic factors, are being explored with potential for significant impact on morbidity and mortality. Preventive strategies and patient education still remain key factors in reducing complication rates and mortality.

The role of PPARs in the microvascular dysfunction in diabetes.

There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.

Pioglitazone treatment improves nitrosative stress in type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a randomized, parallel, cross-over, double-blind, within- and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 +/- 30.8 years, HbA(1c) 7.9 +/- 00.4%, BMI 31.3 +/- 1.2 kg/m(2)). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks. RESULTS: The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 +/- 1.0 vs. 2.8 +/- 0.8, P < 0.01), after local heat stimulation at 40 degrees C (12.9 +/- 2.2 vs. 5.7 +/- 1.7, P < 0.01), and after nociceptor stimulated flow with local heating at 44 degrees C (36.4 +/- 6.3 vs. 16.6 +/- 3.4). Differences were not significant in the placebo-treated group. CONCLUSIONS: Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation.