Klotho Null Mutation Involvement in Adenosine A2B Receptor-Related Skeletal Muscle Degeneration.

Klotho is known for its age-suppressing function and has been implicated in sarcopenia pathology. It has recently been proposed that the adenosine A2B receptor plays a crucial role in skeletal muscle energy expenditure. However, the association between Klotho and A2B remains elusive. In this study, Klotho knockout mice, aged 10 weeks, and wild-type mice, aged 10 and 64 weeks, were used for comparison in indicators of sarcopenia (n = 6 for each group). PCR was performed to confirm the mice genotypes. Skeletal muscle sections were analyzed using hematoxylin and eosin staining as well as immunohistochemistry staining. The skeletal muscle cross-sectional area was significantly reduced in Klotho knockout mice and wild-type mice, aged 64 weeks, when compared with wild-type mice, aged 10 weeks, with a decreased percentage of type IIa and IIb myofibers. Likely impaired regenerative capacity, as reflected by the reduction of paired box 7 (Pax7)- and myogenic differentiation protein 1 (MyoD)-positive cells, was also observed in Klotho knockout mice and aged wild-type mice. 8-Hydroxy-2-deoxyguanosine expression was enhanced with Klotho knockout and aging, indicating higher oxidative stress. Adenosine A2B signaling was impaired, with a lower expression of the A2B receptor and the cAMP-response element binding protein in Klotho knockout and aged mice. The present study provides the novel finding that sarcopenia involves adenosine signaling under the influence of Klotho knockout.

Assessing herpes zoster vaccine efficacy in patients with diabetes: A community-based cohort study.

The effectiveness of herpes zoster (HZ) vaccines in patients with diabetes over the age of 50 remains an active area of research. Utilizing a real-world database from the US community, this study spanning from 2006 to 2023, aimed to evaluate the impact of HZ vaccination on newly diagnosed diabetes patients who received an HZ vaccination within 1 year of diagnosis. Exclusion criteria were established to omit patients with immune deficiencies. The cohort consisted of 53 885 patients, with an average age of 63.5 years, including 43% females and 58% whites. After implementing 1:1 propensity score matching for age, sex, race, comorbidities, diabetes medication, and hemoglobin A1c to ensure comparability, the study population was further stratified into four groups: N1 comparing any HZ vaccination to non-HZ vaccination (53 882 matched pairs), N2 for Shingrix versus non-HZ vaccination (16 665 matched pairs), N3 for Zostavax versus non-HZ vaccination (12 058 matched pairs), and N4 for Shingrix versus Zostavax (11 721 matched pairs). Cox proportional hazards regression analysis revealed a hazard ratio (HR) for HZ incidence post any HZ vaccination of 0.92 (95% confidence interval [CI]: 0.83-1.01). Additional analyses yielded HRs of 1.12 (95% CI: 0.93-1.34) for Shingrix versus non-HZ vaccine, 1.02 (95% CI: 0.86-1.20) for Zostavax versus non-HZ vaccine, and 1.06 (95% CI: 0.87-1.29) for Shingrix versus Zostavax. Subgroup analyses across age, sex, and follow-up duration also showed no significant differences. These findings underscore the lack of a significant benefit from HZ vaccination in newly diagnosed diabetes patients aged over 50, highlighting the necessity for further prospective research.

Relationship between Marriage and Prediabetes among Healthcare Workers: Mediating Effect of Triglycerides.

Background and Objectives: In the literature, relationships between being married and having prediabetes or diabetes are inconsistent. We aimed to investigate whether marriage is a protective or risk factor for prediabetes and to uncover new insights into its impact on prediabetes. Materials and Methods: In this cross-sectional observational study, questionnaires were distributed by email to 1039 staff members who participated in an employee health check from a hospital affiliated with a medical university in Taiwan. Fasting blood glucose and triglyceride (TG) levels were checked and the questionnaires elicited basic demographic characteristics and included the Copenhagen Burnout Inventory and Nordic Musculoskeletal Questionnaire. The chi-square test or Fisher's exact test, logistic regression, and mediation analysis were conducted for statistical analysis. Results: Among the group aged 20-37 years, married (OR = 1.89, 95%CI: 1.08, 3.33), obesity (OR = 2.95, 95%CI: 1.49, 5.83), neck and shoulder pain (OR = 1.31, 95%CI: 1.01, 1.69), and elevated TG levels (OR = 1.01, 95%CI: 1.00, 1.01) were independent risk factors for prediabetes (impaired fasting glucose). For those >38 years old, overweight (OR = 2.08, 95%CI: 1.27, 3.43), obesity (OR = 4.30, 95%CI: 2.38, 7.79), and elevated triglyceride (TG) (OR = 1.003, 95%CI: 1.00, 1.01) were the independent risk factors for impaired fasting glucose. Increased TG levels serve as a mediating factor (Zm = 2.64, p < 0.01) linking marriage to an increased risk of prediabetes for the group aged 20-37 years. Conclusions: TGs play a significant role in the association between marriage and prediabetes among the group aged 20-37 years. Therefore, dietary habits, especially those of young adult couples should be considered. Our findings connect marital status to prediabetes, facilitating advances in diabetes prevention.

Longitudinal assessment of milestone development among internal medicine residents in Taiwan.

BACKGROUND/PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) milestones have been implemented in residency training worldwide. We investigated the development of individual competency in first-year residents (R1) and second-year postgraduate students (PGY2) who received internal medicine training in Taiwan. METHODS: A multicenter observational cohort study was conducted to evaluate the competency-based milestone evaluation designed by the Taiwan Society of Internal Medicine in 2019. The evaluation was based on the ACGME-accredited milestone ratings. Periodic evaluation of milestone achievements of R1 and PGY2, who entered the internal medicine residency training at six medical centers, was performed. Each resident was evaluated every 3 months. RESULTS: Among the 98 R1 enrolled in 2019, substantial improvement in sub-competencies, including skill in performing procedures (Patient Care 4), clinical knowledge (Medical Knowledge 1), knowledge of diagnostic testing and procedures (Medical Knowledge 2), and identify impact the cost of health care and practices cost-effective care (Systems Based Practice 3) during the two years of training. Among the 107 R1 and 46 PGY2 enrolled in 2020, no significant difference in baseline milestone ratings was observed. However, the milestone assessments of R1 in 2020 showed improvement in nearly all sub-competencies compared with the stationary status of PGY2 in 2020. CONCLUSION: We demonstrate the application of ACGME-based accredited milestone ratings to target the educational goals of internal medicine residency training in Taiwan. Differences in milestone ratings between different PGY training systems exist. The long-term impact of performance among different PGY training systems requires further investigation.

The Risk of Thyroid Cancer in Patients with Thyroid Nodule 3 Cm Or Larger.

OBJECTIVE: There are conflicting data on the risk of thyroid cancer in thyroid nodules 3 cm or larger, and few such studies on this issue have been conducted in Asia. This study aimed to examine the risk of thyroid cancer in patients with thyroid nodules 3 cm or larger. METHODS: This was a 7-year retrospective study conducted in a tertiary referral hospital in Taiwan. All patients with a thyroid nodule measuring ≥3 cm who underwent thyroid operation with or without fine-needle aspiration biopsy (FNAB) were included. The prevalence rate of thyroid cancer, as well as the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false-negative rate of FNAB for thyroid nodule ≥3 cm were also examined. RESULTS: A total of 132 patients were included in this study. Thyroid cancer was detected in 19 of 132 (14.4%) thyroid nodules measuring ≥3 cm. The performance of FNAB for detecting cancer in nodules 3 cm or larger without considering other ultrasonography parameters was relatively poor with a sensitivity of 50%, but the specificity (100%), PPV (100 %), and NPV (93.4 %) were excellent. CONCLUSION: The risk of thyroid cancer for thyroid nodules ≥3 cm in this study was low. The PPV and NPV of FNAB were high for the detection of cancer in large nodules. The decision to perform thyroidectomy should not be solely based on nodule size and should include other factors, such as ultrasound characteristics and surgical risk.

Dipeptidyl-Peptidase 4 Inhibitors did not Improve Renal Endpoints in Advanced Diabetic Kidney Disease.

OBJECTIVE: The efficacy of dipeptidyl-peptidase 4 inhibitors (DPP4is) in advanced diabetic kidney disease (DKD) is unknown. We investigated whether DPP4is confer renal protective benefits in DKD patients. METHODS: We conducted a retrospective cohort study between 2012 and 2018 in Taiwan. We only included type 2 diabetes patients with estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73 m2 and urine albumin to creatinine ratio between 300 and 5,000 mg/g. Patients with DPP4i prescriptions were selected as cases, while non-DPP4i users served as controls. We followed these patients until the presence of composite primary renal endpoints, which was defined by the earliest occur-rence of clinical renal outcomes. RESULTS: A total of 522 patients were included in the analysis, comprising 273 patients with a DPP4i prescription who were selected as cases and 249 patients without DPP4i prescription who were assigned as controls. Median follow-up duration for DPP4i users and nonusers was 2.2 years and 3.4 years, respectively. At baseline, the mean glycated hemoglobin levels for DPP4i users and nonusers were 8.1% and 8.3%, respectively. Among patients with DPP4i prescriptions, there was no reduction in composite primary renal outcome, with a crude hazard ratio (HR) of 1.50 (95% confidence interval [CI], 0.95 to 2.36). Similar results were observed for the risk of persistent eGFR <15 mL/min/1.73 m2, with a HR of 1.68 (95% CI, 0.90 to 3.13), doubling of serum creatinine level, with a HR of 1.05 (95% CI, 0.15 to 7.45), and end-stage renal disease, with a HR of 0.87 (95% CI, 0.14 to 5.19). CONCLUSION: DPP4i prescription did not reduce the risk of composite renal endpoints in DKD patients. ABBREVIATIONS: BMI = body mass index; CI = confidence interval; CVOT = cardiovascular outcomes trial; DPP4i = dipeptidyl-peptidase 4 inhibitor; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = glycated hemoglobin; HR = hazard ratio; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2D = type 2 diabetes; UACR = urine albumin to creatinine ratio.

Liraglutide protects against glucolipotoxicity-induced RIN-m5F ß-cell apoptosis through restoration of PDX1 expression.

Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic ß-cells. Glucolipotoxicity-mediated ß-cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse ß-cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining ß-cell function and survival, and glucolipotoxicity can activate mammalian sterile 20-like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of ß-cells. Interestingly, previous research has demonstrated that increased glucagon-like peptide-1 (GLP-1) signalling effectively protects ß cells from glucolipotoxicity-induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F ß-cells and demonstrate that the GLP-1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating ß-cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect ß-cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity.

Early cardiovascular risk and all-cause mortality following an incident of severe hypoglycaemia: A population-based cohort study.

AIMS: Severe hypoglycaemia is associated with a high risk of cardiovascular events in patient with diabetes. The aim of this study was to clarify the temporal relationship between hypoglycaemia and cardiovascular events. MATERIALS AND METHODS: This observational cohort study was conducted using Taiwan's Longitudinal Cohort of Diabetes Patients Database, which included 360 000 patients with newly diagnosed diabetes during the period 1999 to 2001. Patients with the first severe hypoglycaemia after 2002 served as the study cohort. Each patient in the study cohort was matched with two control patients without severe hypoglycaemia, based on a propensity score. A joinpoint regression model was used to determine trends in all-cause mortality and incidence of cardiovascular disease (CVD) events in both cohorts. RESULTS: A total of 10 157 patients with severe hypoglycaemia and 20 314 matched controls were recruited. Patients with severe hypoglycaemia had a significantly higher risk of CVD (HR, 7.28; 95% CI, 5.19-10.20) and all-cause mortality (HR, 19.92; 95% CI, 13.42-29.56) during the first month compared with those without. In patients with severe hypoglycaemia, the incidence of CVDs dropped by 17.29% monthly during the first 4 months and slowly decreased (-0.67%) during subsequent months. All-cause mortality decreased by 16.55% and 3.24% monthly during months 0-6 and months 6-17, respectively. CONCLUSIONS: Severe hypoglycaemia is associated with a greater risk of cardiovascular events and death, especially during the first month following a hypoglycaemic episode. Patients prone to severe hypoglycaemia should be made aware of the elevated risk of subsequent cardiovascular events.

CHA2 DS2 -VASc scores for outcome prediction in acute ischaemic stroke.

BACKGROUND: The CHADS2 and CHA2 DS2 -VASc scores are clinical risk stratification instruments that are used clinically to assess the risk of stroke in patients with atrial fibrillation (AF). The aim of this study was to evaluate whether the prestroke CHADS2 and CHA2 DS2 -VASc scores could be useful for predicting infarction severity and long-term outcomes in patients with acute ischaemic stroke. MATERIALS AND METHODS: This prospective study included all 1494 patients who had acute ischaemic stroke without haemorrhagic transformation which was evidenced with magnetic resonance (MR) imaging during hospitalization. Total infarction volume and arterial stenosis score were calculated based on MR imaging. National Institutes of Health Stroke Scale scores (NIHSSs) were obtained at admission and discharge by board-certified neurologists. The clinical outcomes were defined as composite endpoints of restroke and mortality and were recorded with the mean follow-up period of 37.5 months. RESULTS: There were 195 (13.1%) patients with AF. The patients with AF had significantly higher median CHADS2 and CHA2 DS2 -VASc scores than the patients without AF (P < .001). Patients with higher CHADS2 and CHA2 DS2 -VASc scores had significantly higher total infarction volume, arterial stenosis score and NIHSS scores at discharge and poorer clinical outcomes. After adjusting for age, gender and AF, only CHA2 DS2 -VASc scores could predict both restroke and composite endpoints. CONCLUSIONS: Prestroke CHA2 DS2 -VASc scores appear to have better clinical value for predicting the severity of infarction and long-term clinical outcomes in acute ischaemic stroke patients with and without AF.