Difficulties of Preoperative Diagnosis of Cribriform Morular Thyroid Carcinoma.

Background: Cribriform morular thyroid carcinoma has been recently renamed in the 2022 WHO classification as a thyroid tumor of uncertain histogenesis. The epidemiologic, pathological, and pathophysiological characteristics distinguish it from papillary thyroid carcinoma (PTC). Preoperative genetic testing plays a role in facilitating the differential diagnosis. Methods: This report presents a confirmed case of cribriform morular thyroid carcinoma. Initially, fine-needle aspiration cytology suggested a diagnosis of PTC. However, a genetic analysis did not reveal the typical mutations associated with follicular-cell-derived neoplasms. Results: A 31-year-old woman was found to have a thyroid nodule at the left lobe measuring 11.8 × 10.2 × 12.4 mm. Ultrasonography indicated a hypoechoic, solid nodule with regular margins. Cytology revealed a papillary structure of tall cells, leading to a PTC diagnosis. Nevertheless, the genetic analysis failed to detect mutations such as BRAF V600E, NRAS Q61R, NRAS Q61K, HRAS Q61R, or HRAS Q61K mutation or the fusion of CCDC6-RET, NCOA4-RET, PAX8-PPARG, ETV6-NTRK3, TPM3-NTRK1, IRF2BP2-NTRK1, or SQSTM1-NTRK1 in the aspirated follicular cells. The patient subsequently underwent total thyroidectomy with central lymph node dissection. Pathological examination revealed a cribriform pattern of spindle-shaped cells with morular areas. Immunohistochemical staining showed positive results for ß-catenin and TTF-1, except in the morular regions, and negative results for PAX8, thyroglobulin, and BRAF (clone VE1). The diagnosis was confirmed to be cribriform morular thyroid carcinoma. Conclusion: Significant cytological similarity exists between PTC and cribriform morular thyroid carcinoma. Preoperative genetic analysis is important to differentiate these two diseases. Cribriform morular thyroid carcinoma can be differentiated from common follicular-cell-derived tumors by the absence of typical mutations; the presence of nuclear and cytoplasmic expressions of ß-catenin; the presence of TTF-1, except in morular areas; and the absence of thyroglobulin.

Decomposing and simplifying the Fracture Risk Assessment Tool-a module from the Taiwan-specific calculator.

The Fracture Risk Assessment Tool (FRAX®) is a widely utilized country-specific calculator for identifying individuals with high fracture risk; its score is calculated from 12 variables, but its formulation is not publicly disclosed. We aimed to decompose and simplify the FRAX® by utilizing a nationwide community survey database as a reference module for creating a local assessment tool for osteoporotic fracture community screening in any country. Participants (n = 16384; predominantly women (75%); mean age = 64.8 years) were enrolled from the Taiwan OsteoPorosis Survey, a nationwide cross-sectional community survey collected from 2008 to 2011. We identified 11 clinical risk factors from the health questionnaires. BMD was assessed via dual-energy X-ray absorptiometry in a mobile DXA vehicle, and 10-year fracture risk scores, including major osteoporotic fracture (MOF) and hip fracture (HF) risk scores, were calculated using the FRAX®. The mean femoral neck BMD was 0.7 ± 0.1 g/cm2, the T-score was -1.9 ± 1.2, the MOF was 8.9 ± 7.1%, and the HF was 3.2 ± 4.7%. Following FRAX® decomposition with multiple linear regression, the adjusted R2 values were 0.9206 for MOF and 0.9376 for HF when BMD was included and 0.9538 for MOF and 0.9554 for HF when BMD was excluded. The FRAX® demonstrated better prediction for women and younger individuals than for men and elderly individuals after sex and age stratification analysis. Excluding femoral neck BMD, age, sex, and previous fractures emerged as 3 primary clinical risk factors for simplified FRAX® according to the decision tree analysis in this study population. The adjusted R2 values for the simplified country-specific FRAX® incorporating 3 premier clinical risk factors were 0.8210 for MOF and 0.8528 for HF. After decomposition, the newly simplified module provides a straightforward formulation for estimating 10-year fracture risk, even without femoral neck BMD, making it suitable for community or clinical osteoporotic fracture risk screening.

Optimizing lipid control in Taiwanese diabetic patients: A collaborative consensus by the Diabetes Association of the Republic of China (Taiwan) and the Taiwanese Association of Diabetes Educators.

We present an in-depth analysis of dyslipidemia management strategies for patients with diabetes mellitus in Taiwan. It critically examines the disparity between established guideline recommendations and actual clinical practices, particularly in the context of evolving policies affecting statin prescriptions. The focus is on synthesizing the most recent findings concerning lipid management in patients with diabetes mellitus, with a special emphasis on establishing consensus regarding low-density lipoprotein cholesterol treatment targets. The article culminates in providing comprehensive, evidence-based recommendations tailored to the unique needs of those living with diabetes mellitus in Taiwan. It underscores the criticality of personalized care approaches, which incorporate multifaceted factors, and the integration of novel therapeutic options to enhance cardiovascular health outcomes.

The high-density lipoprotein cholesterol (HDL-C)-concentration-dependent association between anti-inflammatory capacity and sepsis: A single-center cross-sectional study.

INTRODUCTION: Known to have pleiotropic functions, high-density lipoprotein (HDL) helps to regulate systemic inflammation during sepsis. As preserving HDL-C level is a promising therapeutic strategy for sepsis, the interaction between HDL and sepsis worth further investigation. This study aimed to determine the impact of sepsis on HDL's anti-inflammatory capacity and explore its correlations with disease severity and laboratory parameters. METHODS AND MATERIALS: We enrolled 80 septic subjects admitted to the intensive care unit and 50 controls admitted for scheduled coronary angiography in this cross-sectional study. We used apolipoprotein-B depleted (apoB-depleted) plasma to measure the anti-inflammatory capacity of HDL-C. ApoB-depleted plasma's anti-inflammatory capacity is defined as its ability to suppress tumor necrosis factor-α-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical-vein endothelial cells. A subgroup analysis was conducted to investigate in septic subjects according to disease severity. RESULTS: ApoB-depleted plasma's anti-inflammatory capacity was reduced in septic subjects relative to controls (VCAM-1 mRNA fold change: 50.1% vs. 35.5%; p < 0.0001). The impairment was more pronounced in septic subjects with than in those without septic shock (55.8% vs. 45.3%, p = 0.0022). Both associations were rendered non-significant with the adjustment for the HDL-C level. In sepsis patients, VCAM-1 mRNA fold change correlated with the SOFA score (Spearman's r = 0.231, p = 0.039), lactate level (r = 0.297, p = 0.0074), HDL-C level (r = -0.370, p = 0.0007), and inflammatory markers (C-reactive protein level: r = 0.441, p <0.0001; white blood cell: r = 0.353, p = 0.0013). CONCLUSION: ApoB-depleted plasma's anti-inflammatory capacity is reduced in sepsis patients and this association depends of HDL-C concentration. In sepsis patients, this capacity correlates with disease severity and inflammatory markers. These findings explain the prognostic role of the HDL-C level in sepsis and indirectly support the rationale for targeting HDL-C as sepsis treatment.

Unravelling inulin molecules in food sources using a matrix-assisted laser desorption/ionization magnetic resonance mass spectrometry (MALDI-MRMS) pipeline.

Inulin, a polysaccharide characterized by a ß-2,1 fructosyl-fructose structure terminating in a glucosyl moiety, is naturally present in plant roots and tubers. Current methods provide average degrees of polymerization (DP) but lack information on the distribution and absolute concentration of each DP. To address this limitation, a reproducible (CV < 10 %) high throughput (<2 min/sample) MALDI-MRMS approach capable of characterizing and quantifying inulin molecules in plants using matched-matrix consisting of α-cyano-4-hydroxycinnamic acid butylamine salt (CHCA-BA), chicory inulin-12C and inulin-13C was developed. The method identified variation in chain lengths and concentration of inulin across various plant species. Globe artichoke hearts, yacón and elephant garlic yielded similar concentrations at 15.6 g/100 g dry weight (DW), 16.8 g/100 g DW and 17.7 g/100 g DW, respectively, for DP range between 9 and 22. In contrast, Jerusalem artichoke demonstrated the highest concentration (53.4 g/100 g DW) within the same DP ranges. Jerusalem artichoke (DPs 9-32) and globe artichoke (DPs 9-36) showed similar DP distributions, while yacón and elephant garlic displayed the narrowest and broadest DP ranges (DPs 9-19 and DPs 9-45, respectively). Additionally, qualitative measurement for all inulin across all plant samples was feasible using the peak intensities normalized to Inulin-13C, and showed that the ratio of yacón, elephant garlic and Jerusalem was approximately one, two and three times that of globe artichoke. This MALDI-MRMS approach provides comprehensive insights into the structure of inulin molecules, opening avenues for in-depth investigations into how DP and concentration of inulin influence gut health and the modulation of noncommunicable diseases, as well as shedding light on refining cultivation practices to elevate the beneficial health properties associated with specific DPs.

Cross-Validation of Metabolic Phenotypes in SARS-CoV-2 Infected Subpopulations Using Targeted Liquid Chromatography-Mass Spectrometry (LC-MS).

To ensure biological validity in metabolic phenotyping, findings must be replicated in independent sample sets. Targeted workflows have long been heralded as ideal platforms for such validation due to their robust quantitative capability. We evaluated the capability of liquid chromatography-mass spectrometry (LC-MS) assays targeting organic acids and bile acids to validate metabolic phenotypes of SARS-CoV-2 infection. Two independent sample sets were collected: (1) Australia: plasma, SARS-CoV-2 positive (n = 20), noninfected healthy controls (n = 22) and COVID-19 disease-like symptoms but negative for SARS-CoV-2 infection (n = 22). (2) Spain: serum, SARS-CoV-2 positive (n = 33) and noninfected healthy controls (n = 39). Multivariate modeling using orthogonal projections to latent structures discriminant analyses (OPLS-DA) classified healthy controls from SARS-CoV-2 positive (Australia; R2 = 0.17, ROC-AUC = 1; Spain R2 = 0.20, ROC-AUC = 1). Univariate analyses revealed 23 significantly different (p < 0.05) metabolites between healthy controls and SARS-CoV-2 positive individuals across both cohorts. Significant metabolites revealed consistent perturbations in cellular energy metabolism (pyruvic acid, and 2-oxoglutaric acid), oxidative stress (lactic acid, 2-hydroxybutyric acid), hypoxia (2-hydroxyglutaric acid, 5-aminolevulinic acid), liver activity (primary bile acids), and host-gut microbial cometabolism (hippuric acid, phenylpropionic acid, indole-3-propionic acid). These data support targeted LC-MS metabolic phenotyping workflows for biological validation in independent sample sets.

BRAF V600E Mutation Lacks Association with Poorer Clinical Prognosis in Papillary Thyroid Carcinoma.

BACKGROUND: Previous literatures showed wide range of prevalence of BRAF V600E in papillary thyroid carcinoma (PTC). The correlation of BRAF V600E mutation with aggressive tumor characteristics and poor prognosis is controversial. The present study was designed to evaluate the association between BRAF V600E mutation with clinicopathological factors and tumor recurrence. PATIENTS AND METHODS: We performed a retrospective chart review of 672 patients who underwent thyroid surgery for PTC during 2013 and 2018. The prevalence of the BRAF V600E mutation was studied. Its correlation with clinicopathologic characteristics and aggressive features, including macroscopic extrathyroidal extension, lymph node metastasis, and distant metastasis, were analyzed with Fisher's exact test. RESULTS: A total of 672 patients who underwent surgical treatment for PTC were included in this study with a mean age of 49.7 (± 13.2) years; 76.8% of the patients were detected with BRAF V600E mutation. Mean tumor size was 1.30 (± 1.07) cm. A significant association was demonstrated between negative BRAF V600E and larger primary tumor size, distant metastasis, and advanced staging (p < 0.05), whereas there was no significant association with age, sex, lymph node metastasis, extrathyroidal extension, and multicentricity. Kaplan-Meier curve showed similar disease-free survival rate between the two groups. CONCLUSIONS: Negative BRAF V600E tumors show more aggressive behavior with a higher risk of developing distant metastasis in patients with PTC. The usefulness of BRAF in predicting the prognosis of PTC remains questionable. Further molecular analysis should be conducted for contribution to aggressive tumor phenotype.

Prediction of high visceral adipose tissue for sex-specific community residents in Taiwan.

Visceral adipose tissue accumulation is strongly linked with numerous chronic diseases; however, the accessibility for visceral adipose tissue measurement is limited. This study employed a cross-sectional design to determine the optimal strongest predictor of high visceral adipose tissue in each sex and identified the optimal cutoff value thereof. Purposive sampling was used to recruit 94 men and 326 women aged ≥40 years in southern Taiwan. Receiver operating characteristic curve analysis was used to explore the optimal predictor of high visceral adipose tissue (defined as ≥135 cm2 for men and ≥100 cm2 for women) in each sex. The waist-to-hip ratio was the strongest predictor for men, with a cutoff value of 0.96 yielding the maximum sensitivity (94.29%) and specificity (93.22%). By contrast, body mass index was the strongest predictor for women, with a cutoff value of 25.45 kg/m2 yielding the maximum sensitivity (87.18%) and specificity (87.55%). The results may serve as a reference for health policy-makers in screening for high visceral adipose tissue to identify individuals at high risk of developing chronic diseases for health promotion.

Residual risk of cardiovascular complications in statin-using patients with type 2 diabetes: the Taiwan Diabetes Registry Study.

BACKGROUND: The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. METHODS: Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged < 25 or > 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. RESULTS: The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log-alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. CONCLUSION: This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming.

Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (matOSpreg) is linked to offspring mental disorders. Environmental factors contribute to matOSpreg. However, the role of matOSpreg in childhood EBP is unclear. We investigated the associations between (i) matOSpreg and offspring EBP; (ii) social and prenatal environmental factors and matOSpreg; and (iii) social and prenatal factors and childhood EBP and evaluated whether matOSpreg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2'-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (mat8-OHGua36w) was associated with greater offspring total EBP at age four (ß = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (ß = 0.62, 95% CI (-0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both mat8-OHGua36w and childhood EBP (P-range < 0.001-0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher mat8-OHGua36w (P-range = 0.01-0.05). Higher matOSpreg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by matOSpreg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.

Investigating the role of utilitarian and hedonic goals in characterizing customer loyalty in E-marketplaces.

Despite significant growth in sales in recent years, retaining customers remains a major challenge for the electronic marketplace (e-marketplace) industry worldwide, including Indonesia. The small basket size of Indonesian customers has created a highly price-sensitive market, making it difficult to nurture customer loyalty. This study investigates the factors affecting consumer behavior and loyalty in Indonesian e-marketplaces by employing a newly proposed E-Marketplace Customer Loyalty Model. Since customers' expectations have extended from mostly utilitarian-oriented goals to incorporate hedonic goals, the proposed model includes both utilitarian and hedonic-based constructs by integrating the Expectation-Confirmation Theory, e-service quality, and the Hedonic Information Systems Model. The proposed model was tested using a comparative approach of machine learning classification algorithms and partial least square, aiming to create a more robust model. The PLS analytical results of ECLM hiearchical component model from 678 customers show that the fulfillment of hedonic values via perceived enjoyment has a greater impact on customer satisfaction than utilitarian values of perceived service quality. Perceived enjoyment, personalization, and customer satisfaction positively affect customer loyalty. The classification results provide further evidence for all hypothesized relationships of the ECLM. The Sequential Minimal Optimization (SMO) algorithm has demonstrated superior performance compared with other classifiers in predicting the dependent variable in most cases. Based on findings, this study offers theoretical and practical implications, and recommendations for sustainable loyalty programs in e-marketplaces.

Effect of SGLT2 inhibitors versus DPP4 inhibitors on major and non-major osteoporotic fracture risks among general and high-risk type 2 diabetes patients: A nationwide retrospective cohort study.

AIMS: To retrospectively analyze the association of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) with a range of major and non-major fracture events, and explore heterogeneous treatment effect among high-risk patient subgroups. METHODS: Newly stable SGLT2i or DPP4i users in 2017 were identified in Taiwan's National Health Insurance Research Database and followed up until a fracture occurred, loss of follow-up, death, or December 31, 2018, whichever came first. Outcomes included composite major and non-major fractures and individual components in major fractures. Cox model and restricted mean survival time (RMST) analyses were utilized to assess the treatment effect on fractures. RESULTS: 21,155 propensity-score-matched SGLT2i and DPP4i users were obtained. Over 2 years, the hazard ratio and RMST difference for major fracture with SGLT2i versus DPP4i use were 0.89 (95% CI, 0.80, 1.00) and 1.51 (-0.17, 3.17) days, respectively, and those for non-major fracture with SGLT2i versus DPP4i use were 0.89 (0.81, 0.98) and 2.44 (0.47, 4.37) days, respectively. A 180-day lag time analysis for fracture outcomes showed consistent results with primary findings. A SGLT2is-associated harmful effect on major fractures (but not on non-major fractures) was observed among female patients and those with a diabetes duration of ≥ 8 years, prior fractures, and established osteoporosis. CONCLUSION: This study adds supporting real-world evidence for SGLT2is-associated bone safety for a wide range of fractures, which promotes the rational use of SGLT2is in routine care and highlights the importance of the close monitoring of patients with high fracture risks to maximize treatment benefits while reducing undesirable effects.

Melanoma clonal subline analysis uncovers heterogeneity-driven immunotherapy resistance mechanisms.

Intratumoral heterogeneity (ITH) can promote cancer progression and treatment failure, but the complexity of the regulatory programs and contextual factors involved complicates its study. To understand the specific contribution of ITH to immune checkpoint blockade (ICB) response, we generated single cell-derived clonal sublines from an ICB-sensitive and genetically and phenotypically heterogeneous mouse melanoma model, M4. Genomic and single cell transcriptomic analyses uncovered the diversity of the sublines and evidenced their plasticity. Moreover, a wide range of tumor growth kinetics were observed in vivo , in part associated with mutational profiles and dependent on T cell-response. Further inquiry into melanoma differentiation states and tumor microenvironment (TME) subtypes of untreated tumors from the clonal sublines demonstrated correlations between highly inflamed and differentiated phenotypes with the response to anti-CTLA-4 treatment. Our results demonstrate that M4 sublines generate intratumoral heterogeneity at both levels of intrinsic differentiation status and extrinsic TME profiles, thereby impacting tumor evolution during therapeutic treatment. These clonal sublines proved to be a valuable resource to study the complex determinants of response to ICB, and specifically the role of melanoma plasticity in immune evasion mechanisms.

Sex difference in the association of the triglyceride glucose index with obstructive coronary artery disease.

Insulin resistance (IR) is associated with cardiovascular disease in non-diabetic patients. The triglyceride-glucose (TyG) index, incorporating serum glucose and insulin concentrations, is a surrogate insulin resistance marker. We investigated its association with obstructive coronary artery disease (CAD) and sex differences therein. Patients with stable angina pectoris requiring invasive coronary angiography between January 2010 and December 2018 were enrolled. They were divided into two groups according to TyG index. Two interventional cardiologists diagnosed obstructive CAD by angiography review. Demographic characteristics and clinical outcomes were compared between groups. Relative to lower index, patients with higher (≥ 8.60) TyG index had higher BMIs and more prevalent hypertension, diabetes, and elevated lipid profiles [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), fasting plasma glucose (FPG)]. Higher TyG index increased women's obstructive CAD risk after multivariate adjustment (adjusted odds ratio (aOR) 2.15, 95% confidence interval (95% CI) 1.08-4.26, p = 0.02) in non-diabetic populations compared with men. No sex difference was found for diabetic patients. Higher TyG index significantly increased the obstructive CAD risk, overall and for non-diabetic women. Larger-scale studies are needed to confirm our findings.

A Shift in Molecular Drivers of Papillary Thyroid Carcinoma Following the 2017 World Health Organization Classification: Characterization of 554 Consecutive Tumors With Emphasis on BRAF-Negative Cases.

Most studies for comprehensive molecular profiling of papillary thyroid carcinoma (PTC) have been performed before the 2017 World Health Organization (WHO) classification, in which the diagnostic criteria of follicular variants of PTC have been modified and noninvasive follicular thyroid neoplasm with papillary-like nuclear features has been introduced. This study aims to investigate the shift in the incidence of BRAF V600E mutations in PTCs following the 2017 WHO classification and to further characterize the histologic subtypes and molecular drivers in BRAF-negative cases. The study cohort consisted of 554 consecutive PTCs larger than 0.5 cm between January 2019 and May 2022. Immunohistochemistry for BRAF VE1 was performed for all cases. Compared with a historical cohort of 509 PTCs from November 2013 to April 2018, the incidence of BRAF V600E mutations was significantly higher in the study cohort (86.8% vs 78.8%, P = .0006). Targeted RNA-based next-generation sequencing using a FusionPlex Pan Solid Tumor v2 panel (ArcherDX) was performed for BRAF-negative PTCs from the study cohort. Eight cribriform-morular thyroid carcinomas and 3 cases with suboptimal RNA quality were excluded from next-generation sequencing. A total of 62 BRAF-negative PTCs were successfully sequenced, including 19 classic follicular predominant PTCs, 16 classic PTCs, 14 infiltrative follicular PTCs, 7 encapsulated follicular PTCs, 3 diffuse sclerosing PTCs, 1 tall cell PTC, 1 solid PTC, and 1 diffuse follicular PTC. Among them, RET fusions were identified in 25 cases, NTRK3 fusions in 13 cases, BRAF fusions in 5 cases including a novel TNS1::BRAF fusion, NRAS Q61R mutations in 3 cases, KRAS Q61K mutations in 2 cases, NTRK1 fusions in 2 cases, an ALK fusion in 1 case, an FGFR1 fusion in 1 case, and an HRAS Q61R mutation in 1 case. No genetic variants, from our commercially employed assay, were detected in the remaining 9 cases. In summary, the incidence of BRAF V600E mutations in PTCs significantly increased from 78.8% to 86.8% in our post-2017 WHO classification cohort. RAS mutations accounted for only 1.1% of the cases. Driver gene fusions were identified in 8.5% of PTCs and were clinically relevant given the emerging targeted kinase inhibitor therapy. Of the 1.6% of cases for which no driver alteration was detected, the specificity of drivers tested and tumor classification require further investigation.

Natural history and survival rate of familial amyloidosis with polyneuropathy: A nationwide databank.

OBJECTIVE: Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, a rare autosomal-dominant disease, has gained attention in recent years owing to treatment improvements. However, epidemiological real-world mega database of nationwide natural history and survival rates, especially with the specific mutation of Ala97Ser, are limited. METHODS: Taiwan National Health Insurance Research Database contains data from over 23 million individuals; Among them, 175 ATTRv amyloidosis patients validated by rare disease registry were enrolled. Multivariable Cox proportional hazard analyses were applied to investigate the association between baseline characteristics and all-cause mortality. FINDINGS: From 2008 to 2020, the annual incidence and prevalence rates of specific mutations (Ala97Ser) leading to ATTRv amyloidosis with polyneuropathy were 0.04-1.14 and 0.04-4.79 per million in Taiwan, respectively. In Taiwan, these patients exhibited male predominance with a mean age at validation of 62.75 years. At the 5th year after validation, patients exhibited a survival rate of approximately 50%, with higher mortality in male patients (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.15-4.31) and patients older at validation (HR: 1.10, 95% CI: 1.06-1.15). The two most common departments in outpatient were neurology and family medicine, and neurology and cardiology in inpatient. The three most common causes of death registered were unspecified amyloidosis (30.6%), organ-limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%). INTERPRETATION: The annual prevalence rate of specific mutation (Ala97Ser)-dominant ATTRv amyloidosis with polyneuropathy in Taiwan is comparable to the mid- to high-prevalence country level of the research by Schmidt et al. The extraordinarily high mortality, especially among patients older at validation, may reflect the inadequate awareness and the necessity of early intervention with novel disease-modifying regimens.

Targeted lipidomics coupled with machine learning for authenticating the provenance of chicken eggs.

Free-range eggs are ethically desirable but as with all high-value commercial products, the establishment of provenance can be problematic. Here, we compared a simple one-step isopropanol method to a two-step methyl-tert-butyl ether method for extracting lipid species in chicken egg yolks before liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The isopropanol method extracted 937 lipid species from 20 major lipid subclasses with high reproducibility (CV < 30 %). Machine learning techniques could differentiate conventional cage, barn, and free-range eggs using an external test dataset with an accuracy of 0.94, 0.82, and 0.82, respectively. Lipid species that differentiated cage eggs were predominantly phosphocholines and phosphoethanolamines whilst the free-range egg lipidomes were dominated by acylglycerides with up to three fatty acids. The lipid profiles were found to be characteristic of the cage, barns, and free-range eggs. The lipidomic analysis together with the statistical modeling approach thus provides an efficient tool for verifying the provenance of conventional chicken eggs.

A Complete Pipeline for Untargeted Urinary Volatolomic Profiling with Sorptive Extraction and Dual Polar and Nonpolar Column Methodologies Coupled with Gas Chromatography Time-of-Flight Mass Spectrometry.

Volatolomics offers an opportunity for noninvasive detection and monitoring of human disease. While gas chromatography-mass spectrometry (GC-MS) remains the technique of choice for analyzing volatile organic compounds (VOCs), barriers to wider adoption in clinical practice still exist, including: sample preparation and introduction techniques, VOC extraction, throughput, volatolome coverage, biological interpretation, and quality control (QC). Therefore, we developed a complete pipeline for untargeted urinary volatolomic profiling. We optimized a novel extraction technique using HiSorb sorptive extraction, which exhibited high analytical performance and throughput. We achieved a broader VOC coverage by using HiSorb coupled with a set of complementary chromatographic methods and time-of-flight mass spectrometry. Furthermore, we developed a data preprocessing strategy by evaluating internal standard normalization, batch correction, and we adopted strict QC measures including removal of nonlinearly responding, irreproducible, or contaminated metabolic features, ensuring the acquisition of high-quality data. The applicability of this pipeline was evaluated in a clinical cohort consisting of pancreatic ductal adenocarcinoma (PDAC) patients (n = 28) and controls (n = 33), identifying four urinary candidate biomarkers (2-pentanone, hexanal, 3-hexanone, and p-cymene), which can successfully discriminate the cancer and noncancer subjects. This study presents an optimized, high-throughput, and quality-controlled pipeline for untargeted urinary volatolomic profiling. Use of the pipeline to discriminate PDAC from control subjects provides proof of principal of its clinical utility and potential for application in future biomarker discovery studies.

Inhibition of Trimethylamine N-Oxide Attenuates Neointimal Formation Through Reduction of Inflammasome and Oxidative Stress in a Mouse Model of Carotid Artery Ligation.

Aims: Trimethylamine-N-oxide (TMAO) is a metabolite generated from dietary choline, betaine, and l-carnitine, after their oxidization in the liver. TMAO has been identified as a novel independent risk factor for atherosclerosis through the induction of vascular inflammation. However, the effect of TMAO on neointimal formation in response to vascular injury remains unclear. Results: This study was conducted using a murine model of acutely disturbed flow-induced atherosclerosis induced by partial carotid artery ligation. 3,3-Dimethyl-1-butanol (DMB) was used to reduce TMAO concentrations. Wild-type mice were divided into four groups [regular diet, high-TMAO diet, high-choline diet, and high-choline diet+DMB] to investigate the effects of TMAO elevation and its inhibition by DMB. Mice fed high-TMAO and high-choline diets had significantly enhanced neointimal hyperplasia and advanced plaques, elevated arterial elastin fragmentation, increased macrophage infiltration and inflammatory cytokine secretion, and enhanced activation of nuclear factor (NF)-κB, the NLRP3 inflammasome, and endoplasmic reticulum (ER) stress relative to the control group. Mice fed high-choline diets with DMB treatment exhibited attenuated flow-induced atherosclerosis, inflammasome expression, ER stress, and reactive oxygen species expression. Human aortic smooth muscle cells (HASMCs) were used to investigate the mechanism of TMAO-induced injury. The HASMCs were treated with TMAO with or without an ER stress inhibitor to determine whether inhibition of ER stress modulates the TMAO-induced inflammatory response. Innovation: This study demonstrates that TMAO regulates vascular remodeling via ER stress. Conclusion: Our findings demonstrate that TMAO elevation promotes disturbed flow-induced atherosclerosis and that DMB administration mitigates vascular remodeling, suggesting a rationale for a TMAO-targeted strategy for the treatment of atherosclerosis. Antioxid. Redox Signal. 38, 215-233.

Optimal body composition indices cutoff values based on all-cause mortality in the elderly.

The cutoffs of body composition indices are inconclusive in older populations. This study is designed toward determining the optimal cutoffs of the body composition indices based on the association with all-cause mortality. During 2009 and 2010, a cohort population of 1200 was enrolled in central western Taiwan. Of the 1200 subjects, 428 older subjects (mean age: 72.5 ± 5.4 yrs.; 47.7 % were women) were censored in this study. The waist circumference (WC) and body mass index (BMI) were measured using standard anthropometric methods. A multi-frequency bioelectrical impedance analysis device was utilized to estimate each participant's body composition indices, including percent body fat (PBF) and skeletal muscle mass index (SMMI). All claims records of death from 2009 to 2018 in the National Health Insurance Research Databank were identified. A receiver operating characteristic curve method and the highest Youden index were used to identify the optimal cutoffs. A Cox proportional hazards regression analysis was used to model associations between each of the recommended cutoff values with all-cause mortality. The all-cause mortality rate was 20.09 % after a follow-up period of 5.86 ± 2.39 person-years. The significant indices cutoff value was identified to be WC (86.7 cm) for older women and BMI (23.8 kg/m2) and as WC (77.6 cm), and SMMI (8.7 kg/m2) for older men. The recommended optimal cutoffs of the body composition indices were gender-specific and can be utilized to predict the risk of all-cause mortality.