BACKGROUND:The efficacy and safety of early direct oral anticoagulant (DOAC) (re)initiation in patients with non-valvular atrial fibrillation (NVAF) after acute onset of intracranial hemorrhage (ICH) are unknown. This study evaluated ischemic and hemorrhagic risks following early DOAC (re)initiation after ICH in patients with NVAF. METHODS AND RESULTS:SAFE-ICH is a multicenter prospective observational single-arm registry study at 32 Japanese hospitals. Eligible patients had NVAF, were aged ≥20 years, and (re)initiated DOAC ≤14 days following symptomatic ICH. Among 240 patients who (re)initiated DOAC (61.3% male; mean [±SD] age 79.4±9.3 years), intraparenchymal hemorrhage predominated (84.6%), followed by subdural (12.9%), intraventricular (1.7%), and epidural (0.8%) hemorrhage. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (3-16) and time to DOAC (re)initiation was 7 days (5-10 days). Edoxaban, apixaban, and rivaroxaban were used in 55.0%, 35.8%, and 9.2% of patients, respectively. The primary endpoint (composite of symptomatic ICH, any stroke, or death ≤30 days following DOAC [re]initiation) occurred in 12 (5.0%) patients. There were 4 recurrent ICH events (1.7%; all recurrent subdural hemorrhages). Five (2.1%) patients died of non-vascular causes. CONCLUSIONS:In Japanese patients with NVAF, early DOAC (re)initiation ≤14 days after ICH appears to have an acceptable risk for ischemic and hemorrhagic events, particularly in patients with intraparenchymal hemorrhage. In patients with subdural hematoma, early DOAC (re)initiation requires vigilant monitoring.
Objective:Progressive pulmonary fibrosis (PPF) is a chronic interstitial lung disease (ILD) characterised by fibrotic progression and poor prognosis, with effective treatment strategies for previously untreated patients remaining unclear. This study evaluated the efficacy and safety of upfront combination therapy with anti-inflammatory and antifibrotic agents in previously untreated PPF patients. Methods:This multicentre, single-arm phase 2 study enrolled 34 patients with ILD (including unclassifiable idiopathic interstitial pneumonia, idiopathic nonspecific interstitial pneumonia, fibrotic hypersensitivity pneumonitis and rheumatoid arthritis-associated ILD) all with evidence of PPF. Tacrolimus (0.0375 mg·kg-1 twice daily) and prednisolone (10 mg once daily) were initiated on day 1, with nintedanib (150 mg twice daily) added on day 8. The tacrolimus dosage was adjusted to maintain blood trough levels. The primary end-point was the change in the relative decline slope for forced vital capacity % predicted (%FVC) between before and after treatment. Results:The protocol treatment was associated with a substantial improvement in the relative %FVC decline slope, from -20.9% per year before to +11.2% per year after treatment. Subgroup analysis revealed greater improvement in patients with an increased lymphocyte percentage in bronchoalveolar lavage fluid or elevated blood biomarkers. Adverse events, such as diarrhoea (67.6%) and hepatic dysfunction (29.4%), were manageable, with no severe cases or treatment discontinuations. Conclusion:Early combination therapy with tacrolimus, prednisolone and nintedanib was associated with improved pulmonary function and was well tolerated in previously untreated PPF patients. Our findings suggest the potential of this regimen as an initial treatment strategy, but further validation in larger randomised controlled trials is warranted.
Dynamic epigenetic changes guide retinal progenitor cells (RPCs) toward diverse neuronal subtypes and Müller glia during retinal development. However, the epigenetic mechanisms that maintain RPC proliferative and neurogenic potential throughout the final stages of retinal cell genesis remain poorly understood. Here, we integrate RNA sequencing and assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate how mouse RPC progenitor competence is regulated. Our analysis reveals conserved chromatin accessibility and gene expression profiles in mouse RPCs throughout retinal cell genesis. Notably, the histone methyltransferase Setd8, which catalyzes H4K20 monomethylation, remains persistently expressed in RPCs but is barely detectable in adult Müller glia. Setd8 deletion in developing RPCs reduces proliferation, triggers apoptosis, and disrupts retinal laminar organization and ocular axis length. Additionally, Setd8 deficiency impairs the chromatin accessibility that is normally preserved in RPCs, leading to a partial acquisition of a transcriptomic profile associated with terminally differentiated cells. Our study indicates that Setd8 safeguards mouse RPC identity by maintaining RPC-specific chromatin accessibility, thereby ensuring proper retinal development.
Abstract Rationale Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease caused by inhalation of diverse antigens. In Japan, summer-type HP and bird-related HP are the most common forms of acute and chronic HP, respectively. Most studies have classified HP as acute or chronic rather than fibrotic or non-fibrotic. A refined understanding of these phenotypes is essential for prognosis and treatment. To our knowledge, this is the first nationwide report providing detailed characterization of HP subtypes. We aimed to clarify disease features using cases registered in a nationwide epidemiological survey, focusing on differences between fibrotic and non-fibrotic forms. Methods Cases with at least moderate diagnostic confidence according to HP guidelines were included. Data were collected via an electronic system and included demographics, symptoms, findings, laboratory results, pulmonary function, radiologic findings, and bronchoalveolar lavage fluid (BALF) analysis. Longitudinal data on pulmonary function, prognosis, and treatment were recorded annually. Environmental exposure history and causative antigens were also assessed. For analysis of pulmonary function decline, only cases with follow-up testing for over one year were included. Results From 90 institutions, 255 non-fibrotic and 506 fibrotic HP cases were collected. Fibrotic HP patients were older, more often had chronic onset, and more frequently had unknown antigens, resulting in lower diagnostic confidence. Biomarkers KL-6 and SP-D were higher in fibrotic HP (p = 0.011 and p < 0.0001), and forced vital capacity (FVC) was lower (p = 0.036). BALF lymphocyte fractions were elevated in both groups (63% vs. 36%). HRCT more frequently showed honeycombing and traction bronchiectasis in fibrotic HP, while non-fibrotic HP exhibited ground-glass opacities and centrilobular nodules. Glucocorticoids were prescribed in 40% of non-fibrotic and 49% of fibrotic cases; antifibrotics in 24% of fibrotic cases, mainly nintedanib. In non-fibrotic HP, fungi were the most frequent antigens, followed by birds; in fibrotic HP, birds predominated, followed by fungi. Humidifier-related and occupational exposures were also observed. In fibrotic HP, slower annual FVC decline was associated with acute onset, antigen identification, higher BMI, and lower baseline FVC (Table). Conversely, glucocorticoid or antifibrotic use correlated with greater decline. Cluster analysis divided fibrotic HP into two groups: The cluster with more smokers, lower KL-6, fewer ground-glass opacities, younger age, and more chronic onset, showed a greater annual FVC decline. Conclusions We analyzed the largest HP cohort to date. Antigen identification was a key factor associated with pulmonary function decline. Early recognition of causative antigens may help prevent disease progression. This abstract is funded by: Japan Agency for Medical Research and Development (AMED): Grant Number JP23ek0410101h0002
