Association Between Early Initiation of Cardiac Rehabilitation and Short-Term Outcomes of Patients With Acute Heart Failure Admitted to the Intensive Care Unit.

Cardiac rehabilitation (CR) is a promising therapeutic option for chronic heart failure (HF). However, the extent to which early rehabilitation is beneficial for patients receiving critical care remains controversial. This study examined the association between the early initiation of CR and the short-term clinical outcomes of patients admitted to the intensive care unit (ICU) with acute HF. We used the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan, and included patients with acute HF admitted to the ICU within 2 days after hospital admission. We defined the early initiation of CR as its initiation within 2 days of hospital admission. We performed an overlap weighting based on the propensity scores and inverse probability of treatment weighting analysis to compare the clinical outcomes between patients with and without early initiation of CR. Among 25,362 eligible patients, 3,582 (14.1%) received an early initiation of CR. Overlap weighting created well-balanced cohorts, which showed that the early initiation of CR was related to lower in-hospital mortality (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.68 to 0.96) and shorter hospital stay. The inverse probability of treatment weighting analysis also showed that in-hospital mortality was lower in the patients with the early initiation of CR (OR 0.80, 95% CI 0.67 to 0.96). The instrumental variable analysis also demonstrated the association of the early initiation of CR with lower in-hospital mortality (OR 0.64, 95% CI 0.44 to 0.93). In conclusion, early initiation of CR after hospital admission was associated with better short-term outcomes in patients with acute HF admitted to the ICU, suggesting the potential of the early administration of CR for acute HF requiring intensive care.

HDL cholesterol and clinical outcomes in diabetes mellitus.

AIMS: HDL cholesterol (HDL-C) has been thought to protect against cardiovascular disease (CVD), whereas a U-shaped association of both low and extremely high HDL-C with a high mortality risk has been increasingly reported in recent years. However, whether this U-shaped association is universal regardless of the individual's clinical background, including lifestyle diseases, remains unclear. We examined whether fasting plasma glucose modifies the U-shaped association between the HDL-C level and clinical outcomes. METHODS AND RESULTS: This retrospective observational cohort study analysed data from the JMDC Claims Database between 2005 and 2021 for 3 282 389 participants without a history of CVD. The median age was 44 years (IQR, 36-51), and 1 878 164 participants (57.2%) were men. The median HDL-C level was 62 (IQR 52-74) mg/dL. The study participants were categorized according to fasting plasma glucose (FPG) levels (<100 mg/dL, 100-125 mg/dL, and ≥126 mg/dL). The primary endpoint was composite CVD outcome, consisting of myocardial infarction, stroke, and all-cause death. During a mean follow-up period of 1181 ± 932 days, 35 233 composite CVD events were recorded. The association between low HDL-C and CVD risk increased with the FPG level, and the relationship of high HDL-C with CV outcome was prominent only in people with diabetes mellitus. A similar relationship was observed in the individual subgroups and in each CV outcome. CONCLUSION: The U-shaped association between HDL-C and clinical outcomes was amplified with worsening glucose tolerance, suggesting a potential interaction between HDL-C levels and glycaemic status on clinical outcomes.

The aim of this study is to clarify whether fasting plasma glucose modifies the U-shaped association between HDL cholesterol and clinical outcomes. Key findings The U-shaped association between HDL cholesterol and clinical outcomes (including myocardial infarction, stroke, and death) was amplified with worsening glucose tolerance, suggesting a potential interaction between HDL cholesterol levels and glycaemic status on clinical outcomes.

The Semaphorin 3A-AKT axis-mediated cell proliferation in salivary gland morphogenesis and adenoid cystic carcinoma pathogenesis.

We recently demonstrated that Semaphorin 3 A (Sema3A), the expression of which is negatively regulated by Wnt/ß-catenin signaling, promotes odontogenic epithelial cell proliferation, suggesting the involvement of Sema3A in tooth germ development. Salivary glands have a similar developmental process to tooth germ development, in which reciprocal interactions between the oral epithelium and adjacent mesenchyme proceeds via stimulation with several growth factors; however, the role of Sema3A in the development of salivary glands is unknown. There may thus be a common mechanism between epithelial morphogenesis and pathogenesis; however, the role of Sema3A in salivary gland tumors is also unclear. The current study investigated the involvement of Sema3A in submandibular gland (SMG) development and its expression in adenoid cystic carcinoma (ACC) specimens. Quantitative RT-PCR and immunohistochemical analyses revealed that Sema3A was expressed both in epithelium and in mesenchyme in the initial developmental stages of SMG and their expressions were decreased during the developmental processes. Loss-of-function experiments using an inhibitor revealed that Sema3A was required for AKT activation-mediated cellular growth and formation of cleft and bud in SMG rudiment culture. In addition, Wnt/ß-catenin signaling decreased the Sema3A expression in the rudiment culture. ACC arising from salivary glands frequently exhibits malignant potential. Immunohistochemical analyses of tissue specimens obtained from 10 ACC patients showed that Sema3A was hardly observed in non-tumor regions but was strongly expressed in tumor lesions, especially in myoepithelial neoplastic cells, at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the Sema3A-AKT axis promotes cell growth, thereby contributing to morphogenesis and pathogenesis, at least in ACC, of salivary glands.

RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation.

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/ß-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/ß-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAFV600E-MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAFV600E-MEK/ERK pathway, promotes ameloblastoma development. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.