Increased fat mass is an established risk factor for the cardiometabolic diseases type 2 diabetes and cardiovascular disease (CVD) and is associated with increased risk of all-cause and CVD mortality. However, also very low fat mass associates with such an increased risk. Whether impaired metabolic health, characterized by hypertension, dyslipidemia, hyperglycemia, insulin resistance, and subclinical inflammation, may explain part of the elevated risk of cardiometabolic diseases that is found in many subjects with very low fat mass, as it does in many obese subjects, is unknown. An important pathomechanism of impaired metabolic health is disproportionate fat distribution. In this article the risk of cardiometabolic diseases and mortality in subjects with metabolically healthy and unhealthy normal weight and obesity is summarized. Furthermore, the change of metabolic health during a longer period of follow-up and its impact on cardiometabolic diseases is being discussed. Finally, the implementation of the concept of metabolic health in daily clinical practice is being highlighted.

WD40-repeat (WDR)-containing proteins constitute an evolutionarily conserved large protein family with a broad range of biological functions. In human proteome, WDR makes up one of the most abundant protein-protein interaction domains. Members of the WDR protein family play important roles in nearly all major cellular signalling pathways. Mutations of WDR proteins have been associated with various human pathologies including neurological disorders, cancer, obesity, ciliopathies and endocrine disorders. This review provides an updated overview of the biological functions of WDR proteins and their mutations found in congenital disorders. We also highlight the significant role of WDR proteins in ciliopathies and endocrine disorders. The new insights may help develop therapeutic approaches targeting WDR motifs.

The complex and dynamic nature of human physiology, as exemplified by metabolism, has often been overlooked due to the lack of quantitative and systems approaches. Recently, systems biology approaches have pushed the boundaries of our current understanding of complex biochemical, physiological, and environmental interactions, enabling proactive medicine in the near future. From this perspective, we review how state-of-the-art computational modelling of human metabolism, i.e., genome-scale metabolic modelling, could be used to identify the metabolic footprints of diseases, to guide the design of personalized treatments, and to estimate the microbiome contributions to host metabolism. These state-of-the-art models can serve as a scaffold for integrating multi-omics data, thereby enabling the identification of signatures of dysregulated metabolism by systems approaches. For example, increased plasma mannose levels due to decreased uptake in the liver have been identified as a potential biomarker of early insulin resistance by multi-omics approaches. In addition, we also review the emerging axis of human physiology and the human microbiome, discussing its contribution to host metabolism and quantitative approaches to study its variations in individuals.

The telomerase reverse transcriptase (TERT) gene, which is repressed in most differentiated human cells, can be reactivated by somatic TERT alterations and epigenetic modulations. Moreover, the recruitment, accessibility, and binding of transcription factors also affect the regulation of TERT expression. Reactivated TERT contributes to the development and progression of cancer through telomere lengthening-dependent and independent ways. In particular, because of recent advances in high-throughput sequencing technologies, studies on genomic alterations in various cancers that cause increased TERT transcriptional activity have been actively conducted. TERT reactivation has been reported to be associated with poor prognosis in several cancers, and TERT promoter mutations are among the most potent prognostic markers in thyroid cancer. In particular, when a TERT promoter mutation coexists with the BRAFV600E mutation, these mutations exert synergistic effects on a poor prognosis. Efforts have been made to uncover the mechanisms of these synergistic interactions. In this review, we discuss the role of TERT reactivation in tumorigenesis, the mechanisms of TERT reactivation across all human cancers and in thyroid cancer, and the mechanisms of interactions between BRAFV600E and TERT promoter mutations.

Male hypogonadism―rebadged by some as testosterone deficiency syndrome―is a clinical and biochemical diagnosis of increasing worldwide interest. Organic male hypogonadism―usually permanent―is well-established, but aging men may also exhibit lower serum testosterone levels; principally due to burden of extra-gonadal comorbidities such as obesity, diabetes and metabolic syndrome, but with an underlying intact hypothalamo-pituitary-testicular (HPT) axis capable of springing back into operation once comorbidities are addressed. Despite encouraging observational data and plausible theoretical underpinning, evidence for efficacy and safety of testosterone in this “aging” group of men is lacking; addressing comorbid illnesses remains the key priority instead. Nevertheless, in recent years, accumulation of misleading information online has triggered a global tsunami of testosterone prescriptions. Despite this, many men with organic hypogonadism remain undiagnosed or untreated; many more face a diagnostic odyssey before achieving care by the appropriate specialist. As testosterone therapy is not without risk several clinical practice guidelines have been published specialist societies to guide physicians on best practice. However, these are heterogeneous in key areas, reflecting divergent approaches to the same evidence basis. Herein, we navigate the major clinical practice guidelines on male hypogonadism and test their respective recommendations against current best evidence.

We live in a digital world where a variety of wearable medical devices are available. These technologies enable us to measure our health in our daily lives. It is increasingly possible to manage our own health directly through data gathered from these wearable devices. Likewise, healthcare professionals have also been able to indirectly monitor patients' health. Healthcare professionals have accepted that digital technologies will play an increasingly important role in healthcare. Wearable technologies allow better collection of personal medical data, which healthcare professionals can use to improve the quality of healthcare provided to the public. The use of continuous glucose monitoring systems (CGMS) is the most representative and desirable case in the adoption of digital technology in healthcare. Using the case of CGMS and examining its use from the perspective of healthcare professionals, this paper discusses the necessary adjustments required in clinical practices. There is a need for various stakeholders, such as medical staff, patients, industry partners, and policy-makers, to utilize and harness the potential of digital technology.

Background: People with disabilities are at risk of secondary conditions such as diabetes. The aim of this study was to evaluate the prevalence and risk of type 2 diabetes in South Korea, especially among people with all types of disabilities.
Methods: We conducted a cross-sectional study using data from the Korean National Health Insurance Service, with two disability-free controls matched for each participant with disabilities by age and sex. Information regarding the type, severity and grade of disabilities was obtained based on the National Disability Registry. Diagnosis of type 2 diabetes was defined according to the following criteria: presence of International Classification of Diseases, Tenth Revision, Clinical Modification codes E11, E12, E13, or E14 and claims for at least one oral anti-diabetic agent or insulin at baseline, or fasting glucose level ≥126 mg/dL.
Results: We included 1,297,806 participants with disabilities and 2,943,719 control. Out of 4,241,525 participants, 841,990 (19.9%) were diagnosed with diabetes. The prevalence of diabetes was higher in the disability group compared with individuals without disabilities (23.1% vs. 18.4%). The odds of having diabetes was higher in the disability group compared with the control group (adjusted odds ratio, 1.34; 95% confidence interval, 1.33 to 1.34). The results showed higher prevalence of diabetes in the mildly disabled group (23.2%) than in the severely disabled group (22.7%).
Conclusion: The prevalence and risk of diabetes were higher in people with disabilities compared with the general population. Physicians and public health authorities should focus on people with disabilities for proper diabetes management.

Background: Long-term glucocorticoid use increases fracture risk by reducing bone mass. This study evaluated the relationship between hip and vertebral fractures and the total amount of systematic glucocorticoid use.
Methods: We randomly selected 1,896,159 people aged 20 to 100 years who participated in the National Health Checkup program in 2006. The amount of glucocorticoids prescribed was calculated based on the defined daily dose (DDD). The total DDD was obtained by adding oral and parenteral glucocorticoids for 6 months from the index date. Subjects were categorized into four groups according to total glucocorticoid DDDs: non-users (DDDs=0), low users (0< DDDs ≤45), intermediate users (45< DDDs ≤90), and high users (90< DDDs). We followed them for 2 years. A multivariate Cox proportional hazard model was used to evaluate the effects of the total amount of glucocorticoid use on hip and vertebral fractures.
Results: Higher glucocorticoid use was associated with a higher risk of vertebral fracture. Relative to non-users, the vertebral fracture risk was 1.39 times higher in the low-user group, 1.94 times higher in the intermediate-user group, and 2.43 times higher in the high-user group. The risk of hip fracture was 1.72 times higher in intermediate users and 3.28 times higher in high users than in non-users.
Conclusion: As the amount of glucocorticoid use for 6 months increased, the risk of hip and vertebral fractures became higher. In order to prevent fractures, it is necessary for doctors to evaluate the total amount of glucocorticoid prescribed to the patient and to provide appropriate treatment.

Background: Radioactive iodine (RAI) remnant ablation is recommended in patients with papillary thyroid cancer (PTC) and extrathyroidal extension or central lymph node metastasis. However, there exists little evidence about the necessity of remnant ablation in PTC patients with low- to intermediate-risk, those have been increasing in recent decades.
Methods: This multicenter, prospective, non-randomized, parallel group clinical trial will enroll 310 eligible patients with low- to intermediate-risk of thyroid cancer. Inclusion criteria are patients who recently underwent total thyroidectomy for PTC with 3 or less tumors of size 1≤ to ≤2 cm with no microscopic extension and N0/x, or size ≤2 cm with microscopic extension and/or N1a (number of lymph node ≤3, size of tumor foci ≤0.2 cm, and lymph node ratio <0.4). Patients choose to undergo RAI ablation (131I, dose 1.1 GBq) or diagnostic whole-body scan (DxWBS) (131I or 123I, dose 0.074 to 0.222 GBq), followed by subsequent measurement of stimulated thyroglobulin (sTg) within 1 year. Survey for quality of life (QOL) will be performed at baseline and at 1 year after follow-up. The total enrollment period is 5 years, and patients will be followed up for 1 year. The primary endpoint is the non-inferiority of surgery alone to surgery with ablation in terms of biochemical remission (BCR) rate (sTg ≤2 ng/mL) without evidence of structural recurrence. The secondary endpoint was the difference of QOL.
Conclusion: This study will evaluate whether surgery alone achieves similar BCR and improved QOL compared to RAI ablation in patients with low- to intermediate-risk PTC within 1 year.