Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations.

Objectives: To evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma® Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category. Methods: ITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated. Results: Five percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant. Conclusions: TSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.

Linoleic Acid-Rich Oil Supplementation Increases Total and High-Molecular-Weight Adiponectin and Alters Plasma Oxylipins in Postmenopausal Women with Metabolic Syndrome.

BACKGROUND: The onset of menopause increases the risk of metabolic syndrome (MetS). Adiponectin is an adipokine associated with insulin sensitivity that is lower in people with MetS. Supplementing diets with linoleic acid (LA)-rich oil increased adiponectin concentrations and improved glucose control in women with type 2 diabetes. The effect of LA on adipokines, especially total and the bioactive form of adiponectin, high-molecular-weight (HMW) adiponectin, in women with MetS is unknown. OBJECTIVES: The aim of this study was to explore the effect of supplementation of the diet with an oil rich in LA on adipokines in women with MetS. The effect of the LA-rich oil (LA-oil) on oxylipins, key metabolites that may influence inflammation and metabolism, was also explored. METHODS: In this open-label single-arm pilot study, 18 postmenopausal nondiabetic women with MetS enrolled in a 2-phase study were instructed to consume LA-rich vegetable oil (10 mL/d) as part of their habitual diets. Women consumed an oleic acid-rich oil (OA-oil) for 4 wk followed by an LA-oil for 16 wk. Fasting concentrations of adipokines, fatty acids, oxylipins, and markers of glycemia and inflammation were measured. RESULTS: After 4 wk of OA-oil consumption, fasting glucose and total adiponectin concentrations decreased whereas fasting C-reactive protein increased. After 16 wk of LA-oil supplementation total and HMW adiponectin and plasma oxylipins increased. Markers of inflammation and glycemia were unchanged after LA-oil consumption. CONCLUSIONS: Supplementation with LA-oil increased total and HMW adiponectin concentrations and altered plasma oxylipin profiles. Larger studies are needed to elucidate the links between these changes and MetS.This trial was registered at clinicaltrials.gov as NCT02063165.

The Impact of Bariatric Surgery on Short Term Risk of Clostridium Difficile Admissions.

BACKGROUND AND AIMS: Clostridium difficile infection (CDI) is major health care concern with reports linking it to obesity. Our aim was to investigate the little known impact of the two most common bariatric surgeries, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), on risk of CDI admissions. METHODS: This is a retrospective cohort study using the 2013 Nationwide Readmission Database. We examined inpatient CDI rates within 120 days after RYGB (n = 40,059) and VSG (n = 45,394). In a time to event analysis we also evaluated inpatient CDI rates up to 11 months post-surgery. We chose morbidly obese patients that underwent non-emergent ventral hernia repair (VHR) as additional surgical controls (n = 9673). RESULT: CDI rates were higher after RYGB than VSG in the first 30 days (odds ratio [OR] = 2.10; 95% confidence interval [CI], 1.05-4.20) with a similar but nonsignificant trend within 31-120 days. CDI rates were also higher after RYGB compared to VHR controls within 31-120 days after surgery (OR = 3.22, 95%CI: 1.31, 7.88, p = 0.01). In a time to event analysis with up to 11 months follow up, RYGB led to higher CDI compared to VSG (hazard ratio [HR] = 1.87; 95% CI, 1.12-3.13) with a trend towards higher CDI compared to VHR (HR = 1.95; 95% CI, 0.94-4.06). Similar CDI rates occurred after VSG vs VHR. CONCLUSIONS: RYGB may increase the risk of CDI hospitalization when compared to VSG and VHR controls. This data suggest VSG may be a better bariatric choice when post-surgical CDI risk is a concern.

A tale of two risks: smoking, diabetes and the subgingival microbiome.

Although smoking and diabetes have been established as the only two risk factors for periodontitis, their individual and synergistic impacts on the periodontal microbiome are not well studied. The present investigation analyzed 2.7 million 16S sequences from 175 non-smoking normoglycemic individuals (controls), smokers, diabetics and diabetic smokers with periodontitis as well as periodontally healthy controls, smokers and diabetics to assess subgingival bacterial biodiversity and co-occurrence patterns. The microbial signatures of periodontally healthy smokers, but not diabetics, were highly aligned with the disease-associated microbiomes of their respective cohorts. Diabetics were dominated by species belonging to Fusobacterium, Parvimonas, Peptostreptococcus, Gemella, Streptococcus, Leptotrichia, Filifactor, Veillonella, TM7 and Terrahemophilus. These microbiomes exhibited significant clustering based on HbA1c levels (pre-diabetic (<6.5%), diabetic (6.5-9.9%), diabetics >10%). Smokers with periodontitis evidenced a robust core microbiome (species identified in at least 80% of individuals) dominated by anaerobes, with inter-individual differences attributable largely to the 'rare biosphere'. Diabetics and diabetic smokers, on the other hand, were microbially heterogeneous and enriched for facultative species. In smokers, microbial co-occurrence networks were sparse and predominantly congeneric, while robust inter-generic networks were observed in diabetics and diabetic smokers. Smoking and hyperglycemia impact the subgingival microbiome in distinct ways, and when these perturbations intersect, their synergistic effect is greater than what would be expected from the sum of each effect separately. Thus, this study underscores the importance of early intervention strategies in maintaining health-compatible microbiomes in high-risk individuals, as well as the need to personalize these interventions based on the environmental perturbation.

Homoallyl-cyclopropylcarbinyl cation manifold. Trimethylsilyl versus aryl stabilization.

A series of E- and Z-1-aryl-5-trimethylsilyl-3-buten-1-yl trifluoroacetates were solvolyzed in CD3CO2D, and rates of reaction as well as products derived from these reactions were determined. Hammett plots showed a break, which was indicative of a mechanistic change from a kC process when the most electron-donating substituents were attached to the aryl group to a kDelta process involving formation of cyclized beta-silyl carbocation intermediates for electron-withdrawing groups. In the case of p-CH3O substitution (a kC extreme), the cationic intermediate captures solvent (95%) or loses a proton (5%). In the case of m-CF3 substitution (a kDelta extreme), the beta-silyl cation intermediate desilylates to give vinylcyclopropane products. Substituents with intermediate electronic properties give more complex product mixtures. Solvolysis of pure Z-trifluoroacetate (p-CH3) gives small amounts of E-trifluoroacetate (p-CH3) along with the E-substitution product. This isomerization suggests that the cyclized beta-silyl cation can isomerize and then reopen to a classical aryl-stabilized cation. By way of contrast, B3LYP/6-31G* computational studies show only cyclized beta-silyl cations as energy minima. Open kC cations are higher-energy nonminimum energy structures.