Differences in iron kinetics during cardiac load between patients with atrial fibrillation and those with sinus rhythm.

INTRODUCTION: The prevalence of atrial fibrillation (AF) increases with age. Although most AF cases are caused by irregular electrical impulses near the pulmonary vein, not all elderly individuals develop AF. Moreover, risk factors such as hypertension and diabetes do not always lead to AF, even in severe conditions such as pneumonia. We aimed to examine iron kinetics, including ferritin, in patients with AF and individuals in normal sinus rhythm (NSR) using peripheral blood samples. METHODS: This case-control study included 178atients who visited the outpatient clinic of a cardiovascular and arrhythmia specialist at the National Center for Geriatrics and Gerontology between August and October 2023. Patients with missing iron-related blood tests and those with pacemaker implantation were excluded. Iron parameters (ferritin, free iron, transferrin saturation) were compared between AF (n = 53) and NSR (n = 125) groups. RESULTS: The AF group had higher Log brain natriuretic peptide (BNP) levels, indicating increased cardiac load (AF 2.18 vs NSR 1.53). However, there were no significant differences in iron parameters between the AF and NSR groups. After matching for age, sex, and coronary artery disease, the AF group showed an increasing trend in ferritin and a decreasing trend in free iron with BNP elevation, suggesting chronic inflammation. In contrast, the NSR group showed no significant changes in iron parameters with BNP elevation. CONCLUSION: Patients with AF are more likely to have elevated ferritin levels and decreased free iron levels during cardiac overload. Thus, they are more likely to present with chronic inflammation associated with cardiac overload in AF. Future studies should investigate the mechanisms underlying this phenomenon and its implications for AF treatment.

Evolution of a Large Language Model for Preoperative Assessment Based on the Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery.

Background: The Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery standardizes preoperative cardiovascular assessments. The present study investigated the efficacy of a large language model (LLM) in providing accurate responses meeting the JCS 2022 Guideline. Methods and Results: Data on consultation requests, physicians' cardiovascular records, and patients' response content were analyzed. Virtual scenarios were created using real-world clinical data, and a LLM was then consulted for such scenarios. Conclusions: Google BARD could accurately provide responses in accordance with the JCS 2022 Guideline in low-risk cases. Google Gemini has significantly improved its accuracy in intermediate- and high-risk cases.

Effects of Radio-Taiso on Health-Related Quality of Life in Older Adults with Frailty: A Randomized Controlled Trial.

BACKGROUND: Radio-Taiso could be a sustainable public health strategy for maintaining quality of life (QoL) in older adults with frailty. This study aimed to investigate whether Radio-Taiso provided greater benefits for health-related quality of life (HR-QoL) and to identify the mechanisms underlying the effectiveness in this population. METHODS: A 12-week randomized controlled trial enrolled 226 older Japanese adults with pre-frailty or frailty, assessed using the modified frailty phenotype. Participants were randomly allocated to the intervention (Radio-Taiso + nutrition program) or control (nutrition program) groups. The Radio-Taiso program comprised five 60-min group sessions and daily practice at the participants' homes. The primary outcome was the change in the mental domain of HR-QoL, assessed using the SF-36®. The secondary outcomes included six physical fitness items and exercise self-efficacy. RESULTS: Overall, 104 and 105 participants in the intervention and control groups, respectively, were analyzed based on the intention-to-treat principle. The median (interquartile range) daily practice rate of Radio-Taiso was 94.1% (73.2-98.8%). Although general linear models adjusted for baseline values and allocation stratification factors showed that the intervention group obtained greater benefits (adjusted mean differences [95% confidence intervals]) in the up-and-go (0.3 [0.1, 0.6] s), 2-min step-in-place (-3.2 [-6.2, -0.2] steps) tests, and exercise self-efficacy scale (-1.4 [-2.6, -0.1] points) than the control group, there were no group differences in changes in the mental domain score of HR-QoL. CONCLUSIONS: Radio-Taiso provided greater benefits for agility/dynamic balance, aerobic endurance, and exercise self-efficacy in older adults with frailty; however, these changes do not improve HR-QoL.

Prolonged COVID-19 Infection in a Patient with Complete Remission from Follicular Lymphoma with Hyperosmolar Hyperglycemic Syndrome.

An 81-year-old woman undergoing B-cell depletion therapy developed COVID-19 and a hyperglycemic hyperosmotic state. She had a history of multiple vaccinations against coronaviruses but had persistent antigen positivity. Strategies to prevent the development of COVID-19 in immunosuppressed patients have not been established. Moreover, there is no standard treatment for prolonged antigen positivity. In this case, we were able to follow IgG antibodies during the course of treatment. The absence of N-IgG antibody titer elevation despite an effective immune response triggered by the vaccine is of great interest. The impaired humoral response observed in patients with lymphoma after anti-CD20 treatment implies the need for a justified different vaccination strategy for these patients. Furthermore, negative N-IgG titers in the immunosuppressed state may serve as an indicator of resistance to therapy.

Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.

Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.

Effects of a home-based Radio-Taiso exercise programme on health-related quality of life in older adults with frailty: protocol for an assessor-blind randomised controlled trial.

INTRODUCTION: Few clinical trials have examined the effects of home-based exercise programmes on health-related quality of life (HR-QoL) in older adults with frailty. Radio-Taiso is the most famous exercise programme in Japan. A home-based Radio-Taiso exercise programme may serve as an accessible, scalable and sustainable care intervention for older adults with frailty. The primary aim of this trial is to test whether older adults with frailty who are prescribed our home-based Radio-Taiso exercise programme will receive greater benefits for HR-QoL compared with those who are not prescribed the exercise programme. Potential mechanisms underlying the effectiveness of the programme and the effects of the programme on daily lifestyle will also be investigated. METHODS AND ANALYSIS: This assessor-blind randomised controlled trial will be conducted at the Tokyo Metropolitan Institute of Gerontology (TMIG) in Itabashi-ku, Tokyo, Japan. From April to May 2022, 226 older adults with prefrailty or frailty according to the revised Japanese version of the Cardiovascular Health Study criteria will be included from a large database. After a baseline assessment in June 2022, participants will be randomly assigned to the intervention (home-based Radio-Taiso exercise and nutrition programme) or control (nutrition programme) groups at a 1:1 ratio. After intervention completion, a follow-up assessment will be conducted in September 2022. The primary outcome is the change in the mental domain of HR-QoL assessed using SF-36. Secondary outcomes include physical and role/social domains and subscales of HR-QoL, frailty phenotype, physical fitness, posture, cognition, exercise self-efficacy, depressive symptoms, brain-derived neurotrophic factor, social network, habitual energy intake, physical activity and sleep conditions. ETHICS AND DISSEMINATION: The Research Ethics Committee of TMIG has approved the research protocol. This trial will be conducted in accordance with the principles of the Declaration of Helsinki. The findings will be presented at international academic conferences and published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: UMIN000047229.

Mechanistic insights into ectodomain shedding: susceptibility of CADM1 adhesion molecule is determined by alternative splicing and O-glycosylation.

Ectodomain shedding (shedding) is a post-translational modification, which liberates the extracellular domain of membrane proteins through juxtamembrane processing executed mainly by the ADAM (a disintegrin and metalloprotease) family of metalloproteases. Because shedding alters characteristics of cells in a rapid and irreversible manner, it should be strictly regulated. However, the molecular mechanisms determining membrane protein susceptibility to shedding (shedding susceptibility) are largely unknown. Here we report that alternative splicing can give rise to both shedding-susceptible and shedding-resistant CADM1 (cell adhesion molecule 1) variant proteins. We further show that O-glycans adjacent to the shedding cleavage site interfere with CADM1 shedding, and the only 33-bp alternative exon confers shedding susceptibility to CADM1 by inserting five non-glycosylatable amino acids between interfering O-glycans and the shedding cleavage site. These results demonstrate that shedding susceptibility of membrane protein can be determined at two different levels of its biosynthesis pathway, alternative splicing and O-glycosylation.