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Background: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach. Methods: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet–induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation. Results: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet–induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart. Conclusions: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.

Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours. In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186. Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p

Objective Brown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status. Design Participants with newly diagnosed Graves’ disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity. Results Twenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean (r = 0.58, P = 0.01) and resting metabolic rate (RMR) (P < 0.01). Conclusion Hyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.

Background: Subclinical atherosclerosis can be present in individuals with an optimal cardiovascular risk factor profile. Traditional risk scores such as the Framingham risk score do not adequately capture risk stratification in low-risk individuals. The aim of this study was to determine if markers of metabolic syndrome and insulin resistance can better stratify low-risk individuals. Methods: A cross-sectional study of 101 healthy participants with a low Framingham risk score and no prior morbidities was performed to assess prevalence of subclinical atherosclerosis using computed tomography (CT) and ultrasound. Participants were compared between groups based on Metabolic Syndrome (MetS) and Insulin-Sensitivity Index (ISI-cal) scores. Results: Twenty three individuals (23%) had subclinical atherosclerosis with elevated CT Agatston score ≥1. Presence of both insulin resistance (ISI-cal

Brown adipose tissue (BAT) represents a pivotal scientific renaissance worthy as a strategy for obesity and diabetes since its re-discovery in adults over a decade ago. Equally compelling is the adoption of infrared thermography (IRT) in recent times as a precise and viable alternative methodology over the 'gold standard' PET-CT scan, given constraints of the latter's high ionizing radiation doses and costs. Unravelling BAT metabolic physiology in live humans has been challenging until recent rigorous validation of IRT against PET. Nevertheless, IRT remains a nascent technique with pitfalls unbeknownst to many researchers. Factors impacting its accuracy merit an in-depth scientific scrutiny. This article discusses the strengths and pitfalls of IRT as an emergent BAT detection technique and provides a mathematical proof of its limitations that BAT researchers should be cognizant of. Understanding these limitations of IRT can prompt extra efforts to control these uncertainties with greater rigour. In conclusion, this warrants further investigations of improving IRT quality via advanced auto-segmentation, powerful image processing of thermograms and protocol standardization along the lines of BARCIST 1.0 to minimize errors and enhance the confidence of the global BAT research community in IRT as a robust and reliable BAT research tool.

It is well established that thyroid dysfunction is linked to an increased risk of cardiovascular morbidity and mortality. The pleiotropic action of thyroid hormones strongly impacts the cardiovascular system and affects both the generation of the normal heart rhythm and arrhythmia. A meta-analysis of published evidence suggests a positive association of FT4 concentration with major adverse cardiovascular end points (MACE), but this association only partially extends to TSH. The risk for cardiovascular death is increased in both subclinical hypothyroidism and subclinical thyrotoxicosis. Several published studies found associations of TSH and FT4 concentrations, respectively, with major cardiovascular endpoints. Both reduced and elevated TSH concentrations predict the cardiovascular risk, and this association extends to TSH gradients within the reference range. Likewise, increased FT4 concentrations, but high-normal FT4 within its reference range as well, herald a poor outcome. These observations translate to a monotonic and sensitive effect of FT4 and a U-shaped relationship between TSH and cardiovascular risk. Up to now, the pathophysiological mechanism of this complex pattern of association is poorly understood. Integrating the available evidence suggests a dual etiology of elevated FT4 concentration, comprising both ensuing primary hypothyroidism and a raised set point of thyroid function, e. g. in the context of psychiatric disease, chronic stress and type 2 allostatic load. Addressing the association between thyroid homeostasis and cardiovascular diseases from a systems perspective could pave the way to new directions of research and a more personalized approach to the treatment of patients with cardiovascular risk.

Context An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. Objective We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. Design, Setting, and Participants A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100*BAT volume/ FDSA volume) was calculated. Main Outcome Measures Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. Results A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), −0.08 (−0.10, −0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, −0.008% (−0.013%, −0.003%); soleus muscle, −0.003% (−0.006%, −0.001%) of water content and lower fatty liver index at 6 years. Conclusions Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.

Background and aims: Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire 'gain-of-function' isoDGR motifs that might play a role in atherosclerotic pathology. Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo. Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor ‘outside in’ signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNFα to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin β1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68+ macrophages in vivo. Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of ‘outside-in’ signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix. Ministry of Education (MOE) National Medical Research Council (NMRC) This work was in part supported by grants from the National Medical Research Council of Singapore (NMRC–OF–IRG-0003-2016) and Ministry of Education of Singapore (MOE2018-T1-001-078).

Although long noncoding RNAs (lncRNAs) experience weaker evolutionary constraints and exhibit lower sequence conservation than coding genes, they can still conserve their features in various aspects. Here, we used multiple approaches to systemically evaluate the conservation between human and mouse lncRNAs from various dimensions including sequences, promoter, global synteny, and local synteny, which led to the identification of 1,731 conserved lncRNAs with 427 high-confidence ones meeting multiple criteria. Conserved lncRNAs, compared with non-conserved ones, generally have longer gene bodies, more exons and transcripts, stronger connections with human diseases, and are more abundant and widespread across different tissues. Transcription factor (TF) profile analysis revealed a significant enrichment of TF types and numbers in the promoters of conserved lncRNAs. We further identified a set of TFs that preferentially bind to conserved lncRNAs and exert stronger regulation on conserved than non-conserved lncRNAs. Our study has reconciled some discrepant interpretations of lncRNA conservation and revealed a new set of transcriptional factors ruling the expression of conserved lncRNAs.

The increasing prevalence of the chronic disease is of considerable concern to health-care organisations. Prevention programmes to patients with early chronic disease have the potential to improve individual health and quality of life through disease avoidance or delay and to save the medical cost of the health care system. Due to the limited budget in healthcare this study seeks to analyse the feasibility of a programme prior to implementation. A mathematical model is developed to determine incidence reduction rate at which the underlying cost break-even can be achieved; consequently, the programme would be feasible. We show the existence and uniqueness of the underlying incidence reduction and establish the feasibility frontier concerning the trade-offs between intervention effective period and incidence reduction rate. We use a diabetes prevention programme to demonstrate the efficiency and advantage of the model. The proposed model would inform decision-makers scientific principles in determining an intervention for implementation.

Brown adipose tissue (BAT) is a promising weapon to combat obesity and metabolic disease. BAT is thermogenic and consumes substantial amounts of glucose and fatty acids as fuel for thermogenesis and energy expenditure. To study BAT function in large human longitudinal cohorts, safe and precise detection methodologies are needed. Although regarded a gold standard, the foray of PET-CT into BAT research and clinical applications is limited by its high ionizing radiation doses. Here, we show that brown adipocytes release exosomes in blood plasma that can be utilized to assess BAT activity. In the present study, we investigated circulating protein biomarkers that can accurately and reliably reflect BAT activation triggered by cold exposure, capsinoids ingestion and thyroid hormone excess in humans. We discovered an exosomal protein, methylene tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L), to be overexpressed and detectable in plasma for all three modes of BAT activation in human subjects. This mitochondrial protein is packaged as a cargo within multivesicular bodies of the endosomal compartment and secreted as exosomes via exocytosis from activated brown adipocytes into the circulation. To support MTHFD1L as a conserved BAT activation response in other vertebrates, we examined a rodent model and also proved its presence in blood of rats following BAT activation by cold exposure. Plasma concentration of exosomal MTHFD1L correlated with human BAT activity as confirmed by PET-MR in humans and supported by data from rats. Thus, we deduce that MTHFD1L appears to be overexpressed in activated BAT compared to BAT in the basal nonstimulated state. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) Published version The study was funded by the Singapore Ministry of Health’s National Medical Research Council (NMRC) Clinician Scientist Award [grant number NMRC/CSA-INV/0003/2015] awarded to A/Prof. MKSL and also partly supported by the Agency for Science, Technology and Research (A*STAR).

Therapeutic plasma exchange (TPE) for thyroid storm has recently been upgraded to a category II indication after decades though its recommendation level still remains at Grade 2C according to the American Society for Apheresis (ASFA). In the absence of prospective randomized controlled trials due to the rarity of thyroid storm, retrospective data from case series continue to elevate the clinical evidence supporting TPE as a life-saving modality for complicated thyroid storm patients. We report three cases of life-threatening thyroid storm from Graves' disease rescued by TPE via rapid reduction in circulating thyroid hormones. Each patient underwent TPE when it was judged that other thyroid storm treatment options were futile or unsafe. The first patient received 4 cycles of TPE while the second patient received 9 cycles of TPE, and the third patient received 2 cycles of TPE with satisfactory clinical improvement. Plasma FT4 and TSH receptor antibody levels of the first case declined by 41.3% and >50% respectively right after the first round of TPE; plasma FT4 of the second patient dropped by up to 31.6% during the course of TPE; plasma FT4 and TSH receptor antibody of the third patient declined by 66% and 56.2% respectively after the first cycle of TPE. This demonstrates the safety, efficacy, and feasibility of TPE in thyroid storm especially when other therapeutic interventions are contraindicated. TPE operates via the elimination of serum proteins-bound thyroid hormones, thyroid autoantibodies, cytokines, and catecholamines in addition to increasing unsaturated binding sites for thyroid hormones.

Objectives. The COVID-19 pandemic has made a major impact on hospital services globally, including the care of persons with diabetes and endocrine disorders. The aim of this study is to describe the epidemiology of COVID-19 in the ASEAN Federation of Endocrine Societies (AFES) member countries; to describe challenges, changes and opportunities in caring for patients with endocrine diseases, as well as in fellowship training programs, and endocrine-relatedresearch in the AFES countries. Methodology. The AFES ASEAN Survey Of Needs in Endocrinology (AFES A.S.-O.N.E.) was an open-ended questionnaire that was sent to the presidents and representatives of the AFES member countries by email. Responses from Societies were collated and synthesized to obtain perspectives on the emergent issues in endocrinology in the Southeast Asian region during this pandemic. Results. The burden of COVID-19 cases varied widely across the AFES member countries, with the least number of cases in Vietnam and Myanmar, and the greatest number of cases in either the most populous countries (Indonesia and the Philippines), or a country with the highest capability for testing (Singapore). The case fatality rate was also the highest for Indonesia and the Philippines at around 6%, and lowest for Vietnam at no fatalities. The percentage with diabetes among patients with COVID-19 ranged from 5% in Indonesia to 20% in Singapore, approximating the reported percentages in China and the United States. The major challenges in managing patients with endocrine diseases involved inaccessibility of health care providers, clinics and hospitals due to the implementation of lockdowns, community quarantines or movement control among the member countries. This led to disruptions in the continuity of care, testing and monitoring, and for some, provision of both preventive care and active management including surgery for thyroid cancer or pituitary and adrenal tumors, and radioactive iodine therapy. Major disruptions in the endocrine fellowship training programs were also noted across the region, so that some countries have had to freeze hiring of new trainees or to revise both program requirements and approaches to training due to the closure of outpatient endocrine clinics. The same observations are seen for endocrine-related researches, as most research papers have focused on the pandemic. Finally, the report ends by describing innovative approaches to fill in the gap in training and in improving patient access to endocrine services by Telemedicine. Conclusion. The burden of COVID-19 cases and its case fatality rate varies across the AFES member countries but its impact is almost uniform: it has disrupted the provision of care for patients with endocrine diseases, and has also disrupted endocrine fellowship training and endocrine-related research across the region. Telemedicine and innovations in training have been operationalized across the AFES countries in an attempt to cope with the disruptions fromCOVID-19, but its over-all impact on the practice of endocrinology across the region will only become apparent once we conquer this pandemic.

Our aim was to explore optimal treatment decisions for HbA1c control for type 2 diabetes mellitus patients and assess the impact on potential improvements in quality of life compared with current guidelines. We analyzed a large dataset of HbA1c levels, diabetes-related key risk factors and medication dispensed to 70,069 patients with type 2 diabetes from polyclinics and a large public hospital in Singapore during January 1, 2008, to December 31, 2015. A Markov decision process (MDP) model was developed to determine the optimal treatment policy concerning medication management for glycemic control over a long-term treatment period. We assessed the model performance by comparing quality-adjusted life years (QALYs) gained by the model with those derived by a conventional Markov model informed by current clinical guidelines. Numerical results showed that optimal treatment strategies derived by the MDP model could increase the total expected QALYs by as much as 0.27 years for patients at higher risk such as old age, high HbA1c levels and smokers. In particular, the improvements in QALYs gained for patients with HbA1c levels of 9% (75 mmol/mol) and above were higher than those with lower HbA1c levels. However, the potential improvements appeared to be marginal for patients at lower risk compared with current guidelines. Use of data-driven prescriptive analytics would help clinicians make evidence-based treatment decisions for HbA1c control for patients with type 2 diabetes, in particular for those at high risk.

To assess BAT activity in humans at a population level, infrared thermography (IRT) represents a safe, readily repeatable and affordable alternative to 18F-FDG-PET. Building upon a previously proposed method by our laboratory, we further refined the image computational algorithm to quantify BAT activation in the cervical-supraclavicular (C-SCV) region of healthy young men under thermo-neutral and cold exposure conditions. Additionally, we validated the whole-body calorimeter (WBC) in reliably measuring cold-induced thermogenesis. The temperature gradient between C-SCV-deltoid regions, and the corresponding difference in heat power output, increased upon cold air exposure relative to thermo-neutral conditions (by 74.88 %, p

The prediction utility of Framingham Risk Score in populations with low conventional cardiovascular risk burden is limited, particularly among women. Gender-specific markers to predict cardiovascular risk in overtly healthy people are lacking. In this study we hypothesize that postprandial responses triggered by a high-calorie meal test differ by gender in their ability to triage asymptomatic subjects into those with and without subclinical atherosclerosis. A total of 101 healthy Chinese subjects (46 females, 55 males) at low risk of coronary heart disease completed the study. Subjects underwent cardiovascular imaging and postprandial blood phenotyping after consuming a standardized macronutrient meal. Prediction models were developed using logistic regression and subsequently subjected to cross-validation to obtain a de-optimized receiver operating characteristic (ROC) curve. Distinctive gender differences in postprandial trajectories of glucose, lipids and inflammatory markers were observed. We used gender-specific association with different combinations of postprandial predictors to develop 2 models for predicting risk of subclinical atherosclerosis in males (ROC AUC = 0.7867, 95% CI 0.6567, 0.9166) and females (ROC AUC = 0.9161, 95% CI 0.8340, 0.9982) respectively. We report novel postprandial models for predicting subclinical atherosclerosis in apparently healthy Asian subjects using a gender-specific approach, complementing the conventional Framingham Risk Score.Clinical Trial Registration: The trial was registered at clinicaltrials.gov as NCT03531879.

Both hyperthyroidism and elevated plasma branched chain amino acids (BCAA) are associated with insulin resistance. BCAA utilization and clearance relative to thyroid status changes remains unclear. We investigate amino acids changes, specifically BCAA, during the transition from hyperthyroidism to euthyroidism, and the impact of active brown adipose tissue (BAT) on the metabolic effects of BCAA. Newly diagnosed Graves' disease participants were recruited. Hyperthyroidism was treated via a titration dosing regimen of thionamide anti-thyroid drug to establish euthyroidism over 12-24 weeks. All underwent energy expenditure (EE) measurement within a chamber calorimeter, 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging and plasma amino acids measurement during hyperthyroidism and euthyroidism. PET BAT maximum standardized uptake value (SUVmax), SUVmean and MR supraclavicular fat fraction (FF) quantified BAT activity. Twenty-two patients completed the study. Plasma BCAA level was significantly reduced in BAT-positive but not in BAT-negative patients during the transition from hyperthyroidism to euthyroidism. Plasma valine but not leucine and isoleucine correlated positively with insulin and HOMA-IR in hyperthyroidism. Plasma valine, leucine and isoleucine correlated with insulin and HOMA-IR in euthyroidism. Plasma valine correlated with insulin and HOMA-IR in BAT-negative but not in BAT-positive participants in both hyperthyroid and euthyroid state. However, the change (i.e. decrease) in plasma valine concentration from hyperthyroid to euthyroid state was affected by BAT-status. BAT utilizes and promotes BCAA plasma clearance from hyperthyroid to euthyroid state. Active BAT can potentially reduce circulating BCAA and may help to ameliorate insulin resistance and improve metabolic health.Clinical trial registration: The trial was registered at clinicaltrials.gov as NCT03064542. National Medical Research Council (NMRC) Published version The study was supported by the National Medical Research Council Award grant. Grant number: NMRC/ CSA-INV/0003/2015.