Vasoactive mediators of hypertension in obesity.

Obesity is associated with hypertension. However, the mechanisms involved are not fully understood. Therefore, we investigated the relationship between obesity and vasoactive mediators. In this cross-sectional study, blood pressure (BP) and vasoactive mediators of hypertension are compared among 135 adults in the nonobese, obese, and morbidly obese body mass index (BMI) ranges (BMI ≤27, 30-40, and >40 kg/m2, respectively). Angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1 (ET-1), neprilysin, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) levels were measured and their relationship to BP, BMI, race, and gender were investigated. Systolic and diastolic BP (SBP and DSP) were significantly higher in subjects with obesity and morbid obesity compared with nonobese. Angiotensin II, ET-1, and neprilysin were significantly higher in subjects with morbid obesity while BNP was lower. Levels of angiotensinogen, renin, aldosterone, ANP, cGMP, and cAMP did not differ between the groups. BMI was positively related to SBP, DBP, angiotensin II, ET-1, and neprilysin, and inversely related to cGMP and BNP. Age, male gender, and African-American race were associated with higher SBP. SBP was positively related to angiotensin II and ET-1 and inversely related to aldosterone, renin, and cGMP. On multivariate analyses, age, BMI, gender, and race were the main determinants of SBP, and excluding these variables, angiotensin II, aldosterone, renin, and ET-1 accounted for 21.1% ability to predict SBP. Obesity, especially morbid obesity, is associated with higher BP, higher angiotensin II and ET-1 (vasoconstrictors), and lower levels BNP and cGMP (vasodilators). SBP variability can be partly explained by angiotensin II, aldosterone, renin, and ET-1.NEW & NOTEWORTHY Our data show that obesity, especially morbid obesity, is associated with higher blood pressure levels and increases angiotensin II and endotherlin-1 (ET-1) (vasoconstrictors) and lower levels BNP and cGMP (vasodilators) and that systolic blood pressure variability can be partly explained by levels of angiotensin II, aldosterone, renin, and ET-1. The effect of these mediators on blood pressure is in addition to the effects of other known factors related to age, male gender, and AA race.

Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP-1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard-of-care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes-related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose-lowering medications from the dipeptidyl peptidase-4 inhibitor (sitagliptin) and sodium-glucose co-transporter-2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP-1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP-1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1RA treatment in the paradigm of T2D management.

Association of Malignancy Prevalence With Test Properties and Performance of the Gene Expression Classifier in Indeterminate Thyroid Nodules.

Importance: It is crucial for clinicians to know the malignancy prevalence within each indeterminate cytologic category to estimate the performance of the gene expression classifier (GEC). Objective: To examine the variability in the performance of the GEC. Design, Setting, and Participants: This retrospective cohort study of patients with Bethesda category III and IV thyroid nodules used single-institution data from January 1, 2013, through February 29, 2016. Expected negative predictive value (NPV) was calculated by adopting published sensitivity and specificity. Observed NPV was calculated based on the true-negative rate. Outcomes were compared with pooled data from 11 studies published January 1, 2010, to January 31, 2016. Results: A total of 145 patients with 154 thyroid nodules were included in the study (mean [SD] age, 56.0 [16.2] years; 106 females [73.1%]). Malignancy prevalence was 45%. On the basis of this prevalence, the expected NPV is 85% and the observed NPV is 69%. If the prevalence is assumed to be 25%, the expected NPV would be 94%, whereas the observed NPV would be 85%. Pooled data analysis of 11 studies comprising 1303 participants revealed a malignancy prevalence of 31% (95% CI, 29%-34%) and a pooled NPV of 92% (95% CI, 87%-96%). Conclusions and Relevance: In this study, variability in the performance of the GEC was not solely a function of malignancy prevalence and may have been attributable to intrinsic variability of the test sensitivity and specificity. The utility of the GEC in practice is elusive because of this variability. A better definition of the GEC's intrinsic properties is needed.

Optimal timing for a repeat fine-needle aspiration biopsy of thyroid nodule following an initial nondiagnostic fine-needle aspiration.

BACKGROUND: In the case of a nondiagnostic thyroid fine-needle aspiration (FNA) biopsy result, recent guidelines from the Bethesda system recommend repeat thyroid FNA after 3 months to prevent false-positive results. We aimed to examine our institutional data to determine whether the 3-month period affects the diagnostic yield of repeat biopsies. METHODS: A retrospective review of patient records over a 5-year period at our institution was performed. Patients who required repeat FNA due to nondiagnostic results were included. The time between the FNA biopsies, adequacy of the FNA specimens, as well as the surgical pathology diagnosis were analyzed. RESULTS: We identified 317 patients who required a repeat FNA. Of these, 96 (30.3%) patients had repeat FNAs less than 3 months after initial biopsy, while 221 (69.7%) patients had repeat FNAs in greater than 3 months. One hundred five patients were referred to our clinic with an initial nondiagnostic biopsy from an outside institution. Repeat FNA was nondiagnostic in 35 patients (11.04%) in the total study population. There was no difference in satisfactory diagnostic yield between repeat FNAs performed greater than 3 months (201 patients, 90.95%) or less than 3 months (81 patients, 84.38%) after the initial biopsy (P = .117). Of the 35 patients with repeat nondiagnostic biopsy, 17 patients underwent diagnostic lobectomy and 3 (17.6%) patients were found to have malignant disease. CONCLUSIONS: Early (<3 months) repeat FNA does not affect diagnostic yield of the subsequent sample. Patients with suspicious thyroid nodules could therefore receive a repeat FNA as soon as needed, rather than waiting 3 months. The shortened biopsy interval would alleviate stress on patients with benign nodules and expedite surgical intervention in patients with malignancy.

The significance of enlarged cervical lymph nodes in diagnosing thyroid cancer.

INTRODUCTION: We aim to investigate the significance of enlarged cervical lymph nodes (ECLN) identified by initial surgeon-performed ultrasound (US) as a tool for determining the risk of malignancy in the patients presenting with suspicious thyroid nodules. METHODS: Radiological and surgical reports were retrospectively reviewed for the patients with suspicious thyroid nodules who underwent thyroidectomy and preoperative comprehensive neck US. Ultrasonographic features of the identified cervical lymph nodes were correlated with the final pathology report. Patients with malignancy other than papillary thyroid cancer (PTC) were excluded. RESULTS: The study consisted of 440 patients. On final pathology, PTC was found in 142 patients (32.3%), the remaining 298 (67.7%) exhibited benign findings. ECLN (>1 cm) were found in 66 (46.5%) patient with PTC compared to only 53 (17.8%) patients with benign nodules (P < 0.001). Of the 119 patients with ECLN, 54.6% had benign appearing ECLN with no suspicious features, 26.1% had one suspicious feature, and 19.3% had more than one suspicious features. Benign appearing ECLN had a positive predictive value (PPV) of 41.54%, negative predictive value (NPV) of 59.02%, sensitivity of 51.92%, and specificity of 48.65% in predicting malignancy as opposed to the absence of ECLN. While as opposed to benign looking ECLN, ECLN with only one suspicious feature had a PPV of 70.97%, NPV of 50.00%, sensitivity of 33.33%, and specificity of 83.02%, and ECLN with two or more suspicious feature had a PPV of 73.91%, NPV of 48.96%, sensitivity of 25.76%, and specificity of 88.68%. CONCLUSION: ECLN are associated with an increased likelihood of thyroid malignancy in the patients undergoing evaluation of a suspicious nodule. The risk of malignancy in thyroid nodules increases with the presence of suspicious ultrasonographic features on cervical lymph nodes.

Impact of thyroidectomy on cardiac manifestations of Graves' disease.

OBJECTIVES/HYPOTHESIS: Graves' disease (GD) has multiple adverse effects on the cardiovascular system. We aimed to examine the outcome of thyroidectomy in patients with cardiac manifestations of GD and evaluate their associated postoperative complications. STUDY DESIGN: Retrospective analysis using a prospectively collected database. METHODS: A retrospective analysis of our prospectively collected thyroid surgery database was performed. Forty patients with hyperthyroidism due to GD were identified, and each was appropriately age matched to a euthyroid patient with multinodular goiter (MNG). All patients underwent total thyroidectomy. Data relating to cardiac comorbidities were collected from preoperative and postoperative clinic notes, hospital admissions, electrocardiograms, echocardiograms, and blood work. Perioperative biochemical, cardiovascular, and postoperative outcomes were analyzed. RESULTS: Twenty-four (60%) GD patients and 14 (35.0%) MNG patients had cardiac manifestations (P = .001). Hypertension resolved in 41.7% of GD patients and 7.7% of MNG patients (P = .00002). Two of the three GD patients with congestive heart failure (CHF) had resolution of CHF with significant improvement in ejection fraction, whereas the one MNG patient with CHF saw no change. Additionally, the majority of GD patients saw a resolution of their tachycardia (68.8%) and atrial fibrillation (100%). Four postoperative complications occurred in both the GD and MNG groups (4/40, 10%). CONCLUSIONS: Surgical treatment of GD in patients with cardiac manifestations offers rapid clinical improvement of hypertension, impaired left ventricular systolic function, and arrhythmias. When performed by a high-volume surgeon, the complication rate is similar to thyroidectomy for other benign disease. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1256-1259, 2016.

Examining the Bethesda criteria risk stratification of thyroid nodules.

BACKGROUND: The Bethesda criteria are proposed for appropriate stratification of malignancy risk in thyroid nodules, but controversy exists regarding their accuracy and reliability in decision making. Additionally, previous studies have suggested higher rates of both malignancy and false negative fine needle aspiration biopsy (FNA) associated with increasing nodule size. This study aims to determine the accuracy of ultrasound (US)-guided FNA using the current Bethesda criteria in surgical practice. We also aimed to investigate the relationship between nodule size and malignancy. METHODS: A retrospective analysis of US-guided FNAs by a single surgeon during a 4.5 year period. FNA results using Bethesda criteria were compared to final surgical pathology. RESULTS: 611 patients with thyroid nodules underwent US-guided FNA. FNA results in 375 subsequently excised thyroid nodules were recorded according to the Bethesda criteria: 192 (51%) benign, 65 (17%) atypia of unknown significance/follicular lesion of undetermined significance (AUS/FLUS), 42 (11%), suspicious for follicular neoplasm (SFN), 17 (5%) suspicious for malignancy (SM), 28 (8%) malignancy, and 31 (8%) non-diagnostic. Malignancy was confirmed by surgical pathology in 15%, 34%, 50%, 88%, 100%, and 39% of the above groups respectively. Sensitivity, specificity, and false-negative rate were 61%, 99%, and 15% respectively. No correlation existed between the size of nodules with indeterminate FNA results and malignancy rate (p=0.89), or size of nodules with non-diagnostic FNA and malignancy rate (p=0.50). CONCLUSION: The current Bethesda risk stratification system underestimated malignancy rates in benign, indeterminate and non-diagnostic cytopathologic categories in our experience. There was no positive linear correlation between nodule size and malignancy rate in these cytopathologic categories.

ROLE OF INSULIN SENSITIZERS ON CARDIOVASCULAR RISK FACTORS IN POLYCYSTIC OVARIAN SYNDROME: A META-ANALYSIS.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is associated with an increase in cardiovascular (CV) risk factors such as insulin resistance, with accompanying hyperinsulinemia and hyperlipidemia, which are predisposing factors for type 2 diabetes mellitus and CV disease. The aim of this meta-analysis is to examine the effect of insulin sensitizers on clinical and biochemical features of PCOS and risk factors for CV disease. METHODS: A systematic literature review was conducted, and randomized controlled clinical trials were identified by a search of bibliographic databases: Medline database (from 1966 forward), EMBASE (January 1985 forward), and Cochrane Central Register of Controlled Trials. Reviews of reference lists further identified candidate trials. Data was independently abstracted in duplicate by 2 investigators using a standardized data-collection form. Articles without a comparison group and randomization allocation were excluded. Reviewers worked independently and in duplicate to determine the methodological quality of trials, then collected data on patient characteristics, interventions, and outcomes. RESULTS: Of 455 studies, 44 trials were eligible. A random effects model was used. Significant unadjusted results favoring treatment with insulin sensitizers were obtained for body mass index (BMI) (effect size [ES] of 0.58), waist to hip ratio (WHR) (ES of 0.02), low-density-lipoprotein cholesterol (LDL-C) (ES of 0.11), fasting insulin (ES of 2.82), fasting glucose (ES of 0.10), free testosterone (ES of 1.88), and androstenedione level (ES of 0.76). CONCLUSION: Treatment with insulin sensitizers in women with PCOS results in improvement in CV factors such as BMI, WHR, LDL-C, fasting insulin, glucose, free testosterone, and androstenedione.

Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease.

AIMS: Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD. METHODS: A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months. RESULTS: 27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment. CONCLUSIONS: Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

Predictors of duloxetine versus other treatments among veterans with diabetic peripheral neuropathic pain: a retrospective study.

OBJECTIVE: This study used medical and pharmacy records from the Veterans Affairs (VA) health system to explore the predictors of duloxetine versus other treatments for patients with diabetic peripheral neuropathic pain (DPNP). METHODS: The electronic medical and pharmacy records from January 2004 to December 2008 were requested from the Veterans Integrated Service Network 16 data warehouse. All select patients received either duloxetine or other treatments [tricyclic antidepressants (TCAs), venlafaxine, gabapentin, and pregabalin] over the study period, with the first dispense date of the index agent as the index date. All patients must have 1(+) prior DPNP diagnosis (ICD-9-CM: 250.6x or 357.2), but no diagnoses of prior depression (ICD-9-CM: 296.2, 296.3, 300.4, 309.1, or 311.0), fibromyalgia (ICD-9-CM: 729.1), or neuralgia (ICD-9-CM: 729.2). Logistic regression was used to examine the predictors of receiving duloxetine versus other treatments, controlling for demographics, comorbidities, prior pain level, prior use of other medications, and opioid use. RESULTS: The analytical sample included 2,694 patients (duloxetine cohort, n = 216; other-treatment cohort, n = 2,478). Prior uses of gabapentin (odds ratio [OR] = 13.66, 95% confidence interval [CI]: 9.70-19.24), TCAs (OR = 5.40, 95% CI: 3.73-7.82), or venlafaxine (OR = 3.67, 95% CI: 1.67-8.06) were strong predictors of duloxetine. Other comorbidities associated with duloxetine were anxiety (OR= 2.08, 95% CI: 1.40-3.08), cerebrovascular disease (OR = 1.44, 95% CI: 1.01-2.07), and substance abuse (OR = 2.11, 95% CI: 1.10-4.03). Prior opioid users were 1.47 (95% CI: 1.02-2.12) times as likely to receive duloxetine as those without prior opioid use. Patients with self-reported severe pain were 1.66 (95% CI: 1.11-2.50) times as likely to receive duloxetine as those with no pain reported. CONCLUSION: DPNP patients in the VA healthcare system with prior other treatment use, select comorbid conditions, prior substance abuse, prior opioid use, and higher pain level were more likely to receive duloxetine.

Urinary catalytic iron in obesity.

INTRODUCTION: Obesity precedes the development of many cardiovascular disease risk factors, including type 2 diabetes mellitus (DM), hypertension, and chronic kidney disease. Catalytic iron, which has been associated with these chronic diseases, may be one of the links between obesity and these multifactorial diverse disorders. OBJECTIVE: We investigated whether urinary catalytic iron is increased in obese individuals without DM and overt kidney disease. STUDY DESIGN: We measured urinary catalytic iron using established methods in 200 randomly selected individuals without DM [100 who were obese (body mass index ≥30 kg/m(2)) and 100 who were nonobese (body mass index ≤27)]. Participants were selected from an outpatient clinic and community setting and were part of an ongoing cross-sectional study of obesity in individuals between the ages of 18 and 70 years. RESULTS: There was a significant difference in mean (95% CI) urinary catalytic iron excretion between the obese participants and the nonobese participants, 463 (343-582) nmol/mg [52.3 (38.8-65.8) nmol/µmol] vs 197 (141-253) nmol/mg [22.3 (15.9-28.6) nmol/µmol]; P < 0.001. The significant predictors of increased urinary catalytic iron were obesity (P = 0.001) and waist-to-hip ratio (P = 0.03). CONCLUSIONS: Our study results demonstrate that obesity and waist-to-hip ratio are associated with increased urinary catalytic iron, which may be a useful marker of oxidative stress. Additional studies are needed to determine the role of catalytic iron in increased cardiovascular disease and chronic kidney disease associated with obesity.

Thyroid storm in a patient with fulminant hepatic failure.

This manuscript describes a 28-year-old patient with a history of Graves' disease who was transferred to Tulane University Hospital with fulminant hepatic failure. He reported associated nausea, vomiting, anorexia, as well as jaundice and abdominal discomfort for a period of 3 weeks prior to his admission. His thyroid function tests on admission were TSH, 0.013 µU/mL; T3, 94.9 µU/mL; T4, 9.37 µU/mL; Free T4, >6 µU/mL. His liver function tests were characteristic of hepatic failure. The patient underwent an emergent liver transplant. His surgery was complicated by heart failure and acute respiratory distress syndrome. Given the patients clinical presentation and laboratory results, a diagnosis of thyroid storm was made and a decision was made to proceed with an emergent thyroidectomy. The posttransplant multiorgan dysfunction was rapidly reversed by prompt thyroidectomy and decisive management. The patient was discharged from the hospital with normal thyroid and liver function tests.

Black thyroid associated with thyroid carcinoma.

Objective. Black thyroid is a rare pigmented change seen almost exclusively in patients upon minocycline ingestion, and the process has previously been thought to be generally benign. There have been 61 reported cases of black thyroid. We are aware of 13 cases previously reported in association with thyroid carcinoma. This paper reports six patients with black thyroid pigmentation in association with thyroid carcinoma. Design. The medical records of six patients who were diagnosed with black thyroid syndrome, all of whom underwent thyroid surgery, were reviewed. Data on age, gender, race, preoperative fine needle aspiration biopsy (FNA), thyroid function levels, and pathology reports were collected. Main Outcome. The mean age was 60 years. There were 5 females, 4 of whom were African American. All patients were clinically and biochemically euthyroid. Black pigmentation was not diagnosed in preoperative FNA, and only one patient had a preoperative diagnosis of papillary thyroid carcinoma. The other patients underwent surgery and were found to have black pigmentation of the thyroid associated with carcinoma. Conclusions. FNA does not diagnose black thyroid, which is associated with thyroid carcinoma. Thyroid glands with black pigmentation deserve thorough pathologic examination, including several sections of each specimen.

Plasmacytoma in the thyroid.

OBJECTIVE: The paper presents a case of plasmacytoma unexpectedly found in a goiter. PATIENT MATERIAL AND METHODS: The patient presented with compressive symptoms, including dyspnea and dysphagia and had no documented prior history of multiple myeloma. Physical examination revealed thyromegaly with no specific nodule. Computerized tomographic (CT) scan of the neck and chest showed diffuse homogenous enlargement of both the thyroid lobes extending into the mediastinum. Total thyroidectomy was done because of the compressive symptoms. RESULTS: Pathology revealed evidence of fibrosis surrounding small nodules of residual follicles with massive infiltration by plasma cells. The pathologic diagnosis was plasmacytoma. CONCLUSION: Plasmacytoma should be added to the list of causes of diffuse thyromegaly.