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OBJECTIVE Physical activity (PA), even at low intensity, promotes health and improves hyperglycemia. However, the effect of low-intensity PA captured with accelerometery on glucose variability in healthy individuals and patients with type 1 diabetes has not been examined. Quantifying the effects of PA on glycemic variability would improve artificial endocrine pancreas (AEP) algorithms. RESEARCH DESIGN AND METHODS We studied 12 healthy control subjects (five males, 37.7 ± 13.7 years of age) and 12 patients with type 1 diabetes (five males, 37.4 ± 14.2 years of age) for 88 h. Participants performed PA approximating a threefold increase over their basal metabolic rate. PA was captured using a PA-monitoring system, and interstitial fluid glucose concentrations were captured with continuous glucose monitors. In random order, one meal per day was followed by inactivity, and the other meals were followed by walking. Glucose and PA data for a total of 216 meals were analyzed from 30 min prior to meal ingestion to 270 min postmeal. RESULTS In healthy subjects, the incremental glucose area under the curve was 4.5 mmol/L/270 min for meals followed by walking, whereas it was 9.6 mmol/L/270 min (P = 0.022) for meals followed by inactivity. The corresponding glucose excursions for those with type 1 diabetes were 7.5 mmol/L/270 min and 18.4 mmol/L/270 min, respectively (P < 0.001). CONCLUSIONS Walking significantly impacts postprandial glucose excursions in healthy populations and in those with type 1 diabetes. AEP algorithms incorporating PA may enhance tight glycemic control end points.

OBJECTIVE We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age. RESEARCH DESIGN AND METHODS We examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects. RESULTS β-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age. CONCLUSIONS β-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

Background: Seventy-five percent of thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology are found to be benign postoperatively. A novel genomic test, the Afirma ® gene expression classifier (AGEC), has been available for clinical use in the United States, since late 2010. In 2010, two modest-sized validation studies showed that the AGEC could identify a benign gene expression signature in indeterminate cytology thyroid FNA samples with a negative predictive value >95%. The objective of this study was to evaluate how the AGEC impacted the joint decision of the endocrinologist and patient to operate when FNA cytology was indeterminate, but the AGEC reading of the nodule was benign. Methods: In this cross-sectional cohort study, data were contributed retrospectively by 51 endocrinologists at 21 practice sites that had previously obtained ≥3 benign AGEC readings in ≥1 cm nodules with indeterminate FNA cytology readings. Information regarding demographic data, nodule size and location, decision to operate, surgery type (hemithyroidectomy [HT] or total thyroidectomy [TT]), and reason for recommending surgery was retrospectively collected. Results: Compared to a 74% previous historical rate of surgery for cytologically indeterminate nodules, the operative rate fell to 7.6% during the period that AGEC were obtained in the clinical practices, a highly significant reduction in the decision to operate ( p <0.001). The rate of surgery on cytologically indeterminate nodules that were benign by the AGEC reading did not differ from the historically reported rate of operation on cytologically benign nodules ( p =0.41). The four primary reasons reported by the physicians for operating on nodules with a benign AGEC reading, in descending order: large nodule size (46.4%), symptomatic nodules (25.0%), rapidly growing nodules (10.7%), or a second suspicious or malignant nodule in the same patient (10.7%). These reasons are concordant with those typically given for operation on cytologically benign nodules. Conclusions: In a substantial group of medical practices, obtaining an AGEC test in patients with cytologically indeterminate nodules was associated with a striking reduction in the rate of diagnostic thyroidectomy. Approximately, one surgery was avoided for every two AGEC tests run on thyroid FNAs with indeterminate cytology.

Background Oral steroids are commonly used in the management of chronic rhinosinusitis (CRS) with and without nasal polyps (CRSwNP and CRSsNP, respectively). Past reports have included evaluation of the evidence for the use of oral steroids in CRS subtypes. However, a review with evidence‐based recommendations for all CRS subtypes has never been performed. The purpose of this article is to provide a comprehensive, evidence‐based approach for the utilization of oral steroids in the management of CRS. A systematic review of the literature was performed following recommendations of the Clinical Practice Guideline Manual, Conference on Guideline Standardization, and Appraisal of Guidelines and Research Evaluation. Inclusion criteria were: adult population ≥18 years old; CRS; oral steroids as the treatment group; and clearly defined primary clinical end‐point. This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Methods A systematic review of the literature was performed following recommendations of the Clinical Practice Guideline Manual, Conference on Guideline Standardization, and Appraisal of Guidelines and Research Evaluation. Inclusion criteria were: adult population ≥18 years old; CRS; oral steroids as the treatment group; and clearly defined primary clinical end‐point. This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Results This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Conclusion Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC.

BackgroundIschaemic stroke shares common traditional risk factors with coronary artery disease (CAD) and myocardial infarction (MI). This study evaluated whether genetic risk factors for CAD and MI also affect susceptibility to ischaemic stroke in Caucasians and African Americans.MethodsIncluded in the study were a Caucasian series (713 ischaemic stroke patients, 708 controls) and a small African American series (166 ischaemic stroke patients, 117 controls). Twenty single‐nucleotide polymorphisms (SNPs) previously shown to be associated with CAD or MI were genotyped and assessed for association with ischaemic stroke and ischaemic stroke subtypes using odds ratios (ORs) from multivariable logistic regression models.ResultsIn Caucasians, four SNPs on chromosome 9p21 were significantly associated with risk of cardioembolic stroke, the strongest of which was rs1333040 (OR 1.55, P = 0.0007); similar but weaker trends were observed for small vessel stroke, with no associations observed regarding large vessel stroke. Chromosome 9p21 SNPs were also associated with risk of ischaemic stroke in African Americans (rs1333040, OR 0.65, P = 0.023; rs1333042, OR 0.55, P = 0.070; rs2383207, OR 0.55, P = 0.070). The PSMA6 SNP rs1048990 on chromosome 14q13 was associated with overall ischaemic stroke in both Caucasians (OR 0.80, P = 0.036) and African Americans (OR 0.31, P = 0.020).ConclusionsOur results provide evidence that chromosome 9p21 variants are associated with cardioembolic ischaemic stroke in Caucasians and with overall ischaemic stroke in African Americans. The PSMA6 variant rs1048990 also appears to affect susceptibility to ischaemic stroke in both populations. These findings require validation, particularly the preliminary findings regarding African Americans given the small size of that series.

Background— Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. Methods and Results— A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P =0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02–1.25), P =0.04. Comparing the overall log likelihood χ 2 of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. Conclusions— In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.

Abstract Purpose: Previous studies have shown that the replication checkpoint, which involves the kinases ataxia telangiectasia mutated and Rad3 related (ATR) and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical acute myelogenous leukemia (AML) during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro. Experimental design: AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA, and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays. Results: Immunoblotting revealed increased Chk1 phosphorylation, a marker of checkpoint activation, in more than half of Chk1-containing AMLs after 48 hours of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S-phase arrest but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the antiproliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors. Conclusions: These results not only provide evidence for cytarabine-induced S-phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S-phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. Clin Cancer Res; 18(19); 5364–73. ©2012 AACR.