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Objective To investigate and characterize the clinical and radiologic features of 10 patients with painful subacute thyroiditis with ultrasound findings considered suspicious for malignancy or for whom biopsy of a suspicious area was recommended by an attending radiologist. Patients and Methods Ten patients with painful subacute thyroiditis were seen from June 1, 2016, through January 1, 2019. All 10 patients presented to an endocrine or thyroid clinic with a neck ultrasound report stating findings suspicious for malignancy or nodular disease. Clinical, laboratory, radiographic, and pathologic data were (retrospectively collected and) reviewed. Results The mean ± SD patient age was 49.0±15.0 years at diagnosis; 8 patients were female. All the patients presented with a low or undetectable serum thyrotropin level. Six of 7 patients with available inflammatory markers had elevated levels. Thyrotropin receptor antibodies were absent in all 6 patients tested. On follow-up imaging, 8 patients had complete resolution or improvement of described findings, 1 was lost to follow-up, and 1 had an incidental nodule that was biopsied after the episode of thyroiditis and found to be papillary thyroid carcinoma. Conclusion Painful subacute thyroiditis demonstrates specific sonographic patterns that may be misdiagnosed as suspicious thyroid nodular disease. Recognition of the innocent and transient nature of these findings is important for the proper management and monitoring of these patients.

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and BMI. A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year hemoglobin A1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study (P = 0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.

Background: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However there exists significant variability in glycaemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. Methods: As an initiative of the Metformin Genetics Plus (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia, 5,485 white European adults with type 2 diabetes treated with sulfonylurea were recruited from 6 referral centres in Europe and North America. We first estimated heritability using generalized restricted maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy in each cohort using linear regression followed by meta-analysis. These results were supported by cis-eQTLs and functional validation in cellular models. Findings: After establishing that sulfonylurea response is heritable (37±11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction. The C-allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), p=2.4×10−8) lower HbA1c reduction. Similarly, the C-allele was associated with higher glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). The C-allele of rs10770791, near SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater HbA1c reduction (p=4.8×10 −8 ). In 1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced SLCO1B1 expression (p=1.61×10−7) which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use, sulfonylurea response and SCLO1B1 genotype was observed (p=0.001). In statin non-users (but not users), C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor. Interpretation: We have identified clinically important genetic effects at genomewide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important when prescribing glucose-lowering drugs. Funding Statement: Innovative Medicines Initiative, the National Institutes of Health, the Geisinger Health Plan Quality Pilot Fund. Declaration of Interests: ERP has received honoraria for speaking from Lilly and Sanofi. JCF has received honoraria for speaking at scientific conferences from Novo, and for consulting from Goldfinch Bio. All other authors declare no competing interest. Ethics Approval Statement: This study was approved by respective research ethics review boards and participants provided written informed consent.

A variety of inflammatory disorders, generically classified as "thyroiditis," can affect the thyroid gland diffusely, generating distinctive radiographic patterns. While a precise diagnosis can seldom be made based on sonographic appearance alone, interpreting these patterns in the correct clinical and biochemical context will help support the most appropriate diagnosis. We believe that the generic term "thyroiditis" is often not helpful and often may be incorrect. Therefore, it is important for radiologists to understand the sonographic and functional correlations to provide the most appropriate differential diagnosis in their reports. This brief review is designed to provide information and guidance for radiologists when dealing with various thyroid disorders which cause diffuse changes in the thyroid and underline the pitfalls most often encountered in clinical practice.

AIMS: To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications. METHODS: In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose

BACKGROUNDIn 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine.CONTENTIn this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with “normal” genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health.SUMMARYMany genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.

Radioactive iodine (RAI) ablation is a beneficial, adjuvant therapy for the management of differentiated thyroid cancer (DTC) after thyroidectomy. The goal of RAI is to destroy remnant thyroid and microscopic cancerous tissue. Radioactive iodine uptake is enhanced by elevating TSH levels and initiating a low iodine diet (LID) prior to ablation. An ideal LID should preferably not exceed 50 mcg/day of dietary iodine for 1-2 weeks, although the duration may be shortened to a week with a structured patient education programme. A pre-ablation spot urinary iodine concentration (UIC) of

Aim: SLCO1B1 variants are associated with intermediate outcomes that may increase risk of death/myocardial infarction (MI) in statin-treated patients. Patients & methods: In high-risk Caucasians undergoing cardiac catheterization, we tested the association between rs4149056/625T>C and rs2306283/492A>G with low-density lipoprotein cholesterol (LDL-c) over 3 years (n = 1402) and death/MI over 6 years (n = 2994), accounting for statin use or type during follow-up. Results: Carriers of the rs4149056 C allele had 6.2 ± 1.7 mg/dl higher LDL-c per C allele (p < 0.001) but were not at higher risk for death/MI (p = 0.9). We found no associations between rs2306283 and LDL-c or death/MI (p > 0.6). Conclusion: Functional SLCO1B1 variants are not associated with death/MI in patients commonly treated with statins, despite higher LDL-c in carriers of the rs4149056 C allele. Original submitted 3 November 2014; Revision submitted 5 January 2015

Background & Aims Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-λ genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients. Methods A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended. Results The rs12979860 CC genotype (found in ∼40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67–12.57; P = 9.0 × 10−6), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1). Conclusions rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.

Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients’ perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59) were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c). GGST patients had trends (p = 0.2) towards improved statin necessity and concerns. The largest changes were the “need for statin to prevent sickness” (p < 0.001) and “concern for statin to disrupt life” (p = 0.006). GGST patients had more statin prescriptions (p < 0.001), higher statin use (p < 0.001), and greater decrease in LDL-c (p = 0.059) during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients’ perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.

Objective: To report an unusual case of concurrent pancreatic adenocarcinoma and metastatic insulinoma causing severehypoglycemia in a patient with diabetes.Methods: The clinical presentation, biochemical studies, and relevant imaging of this patient are presented and the pertinentliterature is reviewed.Results: A 59-year-old man with a history of unresectable pancreatic adenocarcinoma and diabetes was admitted for persistenthypoglycemia, meeting all criteria for Whipple’s triad and requiring high-dose dextrose infusion. Prior outpatient abdominalimaging had revealed hepatic lesions that were biopsied and found to be a high-grade neuroendocrine carcinoma. On admission, laboratory evaluation revealed inappropriately suppressed beta-hydroxybutyrate levels, and inappropriately elevated insulin, C-peptide, and proinsulin levels. An octreotide scan revealed uptake in the hepatic lesions but not in the pancreatic head mass. Immunohistochemistry staining of prior liver biopsy samples was negative for insulin. Diazoxide therapy was initiated, butdiscontinued after the onset of hypotension. The hypoglycemia resolved only after trans-arterial chemoembolization of lesionsboth in the left and the right liver lobes, in combination with continued octreotide. Unfortunately, he subsequently developedrecurrent hypoglycemia three weeks later and ultimately passed away after transitioning to hospice care.Conclusions: Insulinomas are rare neoplasms of the pancreas that are characterized by insulin hypersecretion, which can bedebilitating and potentially life-threatening. The diagnosis of metastatic insulinoma is difficult to make in the setting of multiplecomorbidities and requires precise biochemical studies. Multiple medical treatments are available but the overall prognosis ispoor.

Background & Aims IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naive patients with CHC. Methods Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. Results CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs . 22.5% (9/40; p =0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p =0.001) of CC patients in the Duke cohort. Conclusions IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

20 G2) were included. SVR was defined as undetectable HCVRNA at 24 weeks of follow up. The SNP analysis of rs12979860 variant was determined in 50ng of DNA by RT-PCR using specific oligonucleotide primers and probes to amplify the sequence target in DNA (Tib MoLBIOL GmbH, Berlin Germany). All HCV patients were genotyped as CC, CT or TT. Results: CT and TT variants were present in 45 and 18 subjects (56% and 23%, respectively) of the studied population. CC polymorphism had the lowest frequency in our cohort (21%, CI 95%: 12.89–31.83%) and it was strongly associated with response to standard treatment (OR 2.95); 76% of CC carriers achieved SVR compared with 55.5% and 44.4% of SVR in patients with CT and TT variants.