Citations

As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (± SEM) age of 33.0 ± 1.6 yr, had had diabetes for a mean (±SEM) duration of 17.4 ± 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of <0.1 pmol/ml, consistent with clinically insignificant endogenous insulin secretion. There was no change in C-peptide response at 4 or 8 mo compared with baseline values, whether or not the patient's glucose control remained unchanged (CIT group) or significantly improved to near-normoglycemia (CSII group). In a subgroup of 34 patients at three centers, the 24-h mean glucose concentration was significantly lower in the CSII group compared with the CIT group at 4 mo (126 ± 10 versus 176 ± 14 mg/dl) and at 8 mo (121 ± 5 versus 183 ± 15 mg/dl) (P < 0.005). Although the 24-h mean serum free immunoreactive insulin levels were shown to be no different at baseline (27.4 ± 3.8 versus 26.2 ± 3.1 μU/ml) or after 4 mo (22.5 ± 3.2 versus 25.6 ± 3.2) or 8 mo (26.5 ± 3.4 versus 28.8 ± 3.4) of CIT or CSII therapy, respectively, the mean increase of free insulin concentrations in relation to the main meals was greater in the CSII group (P < 0.05). The mean serum free insulin levels achieved with both CIT and CSII were significantly greater than the 24-h mean free insulin level obtained in 12 normal subjects (12.2 ± 1.4 μU/ml) (P < 0.001).

The accuracy of continuous interstitial fluid (ISF) glucose sensing is an essential component of current and emerging open- and closed-loop systems for type 1 diabetes. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. We performed the first direct measurement of this phenomenon to our knowledge in eight healthy subjects under an overnight fasted condition. Microdialysis catheters were inserted into the abdominal subcutaneous space. After intravenous bolus administrations of glucose tracers, timed samples of plasma and ISF were collected sequentially and analyzed for tracer enrichments. After accounting for catheter dead space and assay noise, the mean time lag of tracer appearance in the interstitial space was 5.3–6.2 min. We conclude that in the overnight fasted state in healthy adults, the physiological delay of glucose transport from the vascular to the interstitial space is 5–6 min. Physiological delay between blood glucose and ISF glucose, therefore, should not be an obstacle to sensor accuracy in overnight or fasting-state closed-loop systems of insulin delivery or open-loop therapy assessment for type 1 diabetes.

BackgroundMost patients with left ventricular assist devices (LVADs) have concomitant cardiovascular implantable electronic devices (CIEDs). However, clinical presentation and outcome of CIED infection in the setting of LVAD has not been previously described.MethodsWe retrospectively reviewed 247 patients who underwent LVAD implantation at Mayo Clinic campuses in Minnesota, Arizona, and Florida, from January 2005 to December 2011. Demographic and clinical data of patients who met criteria for CIED infection were extracted.ResultsOf 247 patients with LVADs, 215 (87%) had CIED at the time of LVAD implantation and six (2.8%) subsequently developed CIED infections. Three patients developed CIED lead‐related endocarditis and the other three had pocket infection. All three instances of CIED pocket infection were preceded by device generator exchange, whereas all three patients with CIED lead‐related endocarditis had prior LVAD‐related infections. Causative pathogens included Pseudomonas aeruginos (1), coagulase‐negative staphylococci (2), methicillin‐resistant Staphylococcus aureus (1), a gram‐positive bacillus (1), and culture negative (2). All patients underwent complete CIED removal along with antimicrobial therapy. The three patients with CIED lead‐related endocarditis and prior LVAD infections received chronic suppressive antibiotic therapy, and one patient had LVAD exchange. All but one remained alive at the last follow‐up with a median duration of 15 months (7–46 months) from the time of CIED infection.ConclusionPatients who are receiving LVAD therapy and develop CIED infection should be managed with complete CIED removal. Chronic suppressive antibiotic therapy is warranted in cases that have concomitant LVAD infection.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society

Abstract Background: Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Methods: Tissue microarrays (TMA) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was conducted for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histologic type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. Results: The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of endometrioid carcinoma compared with HGSC became significant [RR 0.60; 95% confidence interval (CI), 0.37–0.93; P = 0.021], consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Conclusions: Research cohorts, particularly those across different centers within consortia, show significant variability in original histologic type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Impact: Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology. Cancer Epidemiol Biomarkers Prev; 22(10); 1677–86. ©2013 AACR.

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m 2 , thus, limiting pediatric application of this device. This unique case report shares this pediatric institution’s first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m 2 ) below the recommendation of 1.7m 2 . A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.

Objective: To determine the temporal trends in diagnosis and management of pediatric overweight/obesity by primary care providers at a single medical center. Patients: Children 2 to 18 years old undergoing a general medical examination during 3 calendar years (2003, 2006, and 2009). The number of visits for general medical examination were 6390 in 2003, 6646 in 2006, and 7408 in 2009. Methods: We performed a retrospective review of the electronic medical records for weight related diagnostic and/or management terms and laboratory screening in children with body mass index at or greater than the 85th percentile (n = 1630 in 2003, 1495 in 2006, and 1730 in 2009). Results: There was a significant increase in the diagnosis of obesity among obese children seen in 2009 (53.3%) compared with 2006 (36%, P < .001) and 2003 (24.3%, P < .001). Weight-related counseling was documented in a higher proportion of obese children in 2009 (49.4%) compared with 2006 (34.8%) and 2003 (26.6%). There was a significant increase in counseling regarding screen time in 2009 compared with 2006. A significant increase in screening for nonalcoholic fatty liver disease was also noted (30.5% in 2009 vs 21.9% in 2006, P = .018). Conclusions: There has been steady improvement in the rates of obesity diagnosis and obesity-related counseling by primary care providers. However, continued efforts to increase awareness of these issues are needed as nearly half of obese children remained undiagnosed and recommended laboratory screening for obesity-related comorbidities was performed in only a third of obese children.