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No prospective studies have investigated the relationship between nutritional status, tolerability to antifibrotic therapy, and mortality in patients with fibrotic interstitial lung diseases (ILDs). This prospective longitudinal study enrolled 290 consecutive patients with fibrotic ILDs who initiated antifibrotic therapy, including 164 with idiopathic pulmonary fibrosis (IPF) and 126 with non-IPF. Nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI). Overall, 106 patients (36.6%) were classified as having malnutrition-related risk (GNRI < 98) at baseline. The prevalence of malnutrition-related risk was comparable between patients with IPF and non-IPF, although it tended to be higher in the non-IPF group than in the IPF group. Patients with malnutrition-related risk showed higher cumulative incidence of antifibrotic therapy discontinuation. Importantly, in both IPF and non-IPF groups, the mortality risk was significantly higher in patients with malnutrition-related risk than in those without. Longitudinally, a lower GNRI at 1 year was associated with shorter survival. In multivariable analyses, baseline malnutrition-related risk was independently associated with increased risk of therapy discontinuation and mortality, even after adjusting for the ILD–gender–age–physiology index. These findings indicate that assessment of nutritional status helps predict antifibrotic therapy tolerability and mortality risk in patients with fibrotic ILD.

BackgroundSome patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP.MethodsThis nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis.ResultsIn 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters.InterpretationThese observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

•Sarcopenia predicts poor outcomes in elderly patients with cardiovascular disease.•Prestroke sarcopenia is an independent predictor of functional outcome after a stroke.•Prestroke sarcopenia should be assessed in elderly patients who have had a stroke. The association between prestroke sarcopenia and functional outcomes in patients who have had a stroke has not, to our knowledge, been evaluated to date. We aimed to investigate the prevalence of prestroke sarcopenia, and determine whether prestroke sarcopenia is associated with functional outcomes in elderly patients who have suffered an acute stroke. We assessed prestroke sarcopenia in elderly patients with acute stroke using the SARC-F questionnaire. Patients were divided into two groups according to their SARC-F score: non-sarcopenia (SARC-F score <4) and prestroke sarcopenia (SARC-F score ≥4). The study endpoint was the modified Rankin Scale score at 3 mo after the stroke (0–3, good outcome; 4–6, poor outcome). The Mann-Whitney U-test, Pearson χ2 test, Fisher exact test, and logistic regression were used in the statistical analyses. Of the 152 patients (81 men; median age [interquartile range]: 76 [11] y) enrolled, the prevalence rate of prestroke sarcopenia was 18% (27 patients). These 27 patients showed poor functional outcome at 3 mo after the stroke (50% versus 12%, prestroke sarcopenia versus nonsarcopenia; P < 0.001). After adjusting for variables, prestroke sarcopenia was an independent predictor of poor functional outcome at 3 mo after stroke (odds ratios: 7.39, 95% confidence interval: 1.47–37.21, P = 0.02). Prestroke sarcopenia is an independent predictor of functional outcome at 3 mo after a stroke. Our findings highlight the importance of detecting prestroke sarcopenia in elderly patients with acute stroke.

SARC-F is a screening tool for sarcopenia; however, it has not yet been established whether SARC-F scores predict functional outcomes. Therefore, we herein investigated the relationship between SARC-F scores and functional outcomes in stroke patients. The primary outcome in the present study was the modified Rankin Scale (mRS) 3 months after stroke. The relationship between SARC-F scores and poor functional outcomes was examined using a logistic regression analysis. Furthermore, the applicability of SARC-F scores to the assessment of poor functional outcomes was analyzed based on the area under the receiver operating curve (ROC). Eighty-one out of the 324 patients enrolled in the present study (25%) had poor functional outcomes (mRS ≥ 4). The results of the multivariate analysis revealed a correlation between SARC-F scores (OR = 1.29, 95% CI = 1.05–1.59, p = 0.02) and poor functional outcomes. A cut-off SARC-F score ≥ 4 had low-to-moderate sensitivity (47.4%) and high specificity (87.3%). The present results suggest that the measurement of pre-stroke SARC-F scores is useful for predicting the outcomes of stroke patients.

The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints. Current sequencing technologies can shed light on the stepwise progression of lung adenocarcinoma. Here, the authors characterize tumor progression in lung adenocarcinomas from an early stage using short and long read whole-genome sequencing, bulk and spatial transcriptomics, and epigenomics.

Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed \"hepatic crown-like structures (hCLS)\" in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.

Chromosomal backgrounds of cancerous mutations still remain elusive. Here, we conduct the phasing analysis of non-small cell lung cancer specimens of 20 Japanese patients. By the combinatory use of short and long read sequencing data, we obtain long phased blocks of 834 kb in N50 length with >99% concordance rate. By analyzing the obtained phasing information, we reveal that several cancer genomes harbor regions in which mutations are unevenly distributed to either of two haplotypes. Large-scale chromosomal rearrangement events, which resemble chromothripsis events but have smaller scales, occur on only one chromosome, and these events account for the observed biased distributions. Interestingly, the events are characteristic of EGFR mutation-positive lung adenocarcinomas. Further integration of long read epigenomic and transcriptomic data reveal that haploid chromosomes are not always at equivalent transcriptomic/epigenomic conditions. Distinct chromosomal backgrounds are responsible for later cancerous aberrations in a haplotype-specific manner. Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.

M-COPA (1), which contains diene and 3-picolylamine moieties in its side chain and seven stereogenic centers in a multisubstituted octalin skeleton, strongly inhibits the growth of several cancer cell lines. Expecting the improvement of conformational flexibility of basic and coordinating 3-pyridylmethylamino group on M-COPA and its physical properties, we efficiently synthesized its amine analogs by replacing its amide group with an amino group through the Weinreb amide-type Horner–Wadsworth–Emmons reaction. The cytotoxic properties of 1 and its analogs were evaluated against NCI-H226, a lung cancer cell line, HeLa, a cervical cancer cell line, and GIST-T1, a gastrointestinal stromal tumor cell line. The evaluation results indicated that the structural alteration from amide moiety to amine moiety lowered the pharmacological activity but remained strong cytotoxicity.

•TMT measurement using brain CT is a reliable method for elderly acute stroke.•Sarcopenia risk was independently associated with TMT in elderly patients with acute stroke.•TMT was not associated with functional outcome in elderly patients with acute stroke. Pre-stroke sarcopenia associated with poor functional outcomes. However, diagnosis of pre-stroke sarcopenia is often difficult in patients with acute stroke. Thus, we investigated the reliability and validity of measuring temporal muscle thickness (TMT) as an indicator of sarcopenia risk and its relationship with functional outcome in older patients with acute stroke. We conducted a cross-sectional and longitudinal study of the patients with acute elderly stroke in a single neurosurgical hospital. We measured TMT manually using brain computed tomography (CT) by two examiners. Sarcopenia risk, malnutrition risk, inflammation, comorbidities, and modified Rankin Scale (mRS) scores at 3 months after stroke were additionally assessed. Inter-rater reliability of TMT was determined by calculating the intra-class correlation coefficient ([ICC] 2,1). Multiple linear regression analyses was used to determine whether sarcopenia risk was independently associated with TMT, and logistic regression was used to evaluate the relationship between TMT and poor functional outcome (mRS > 3). A total 289 acute elderly stroke patients (163 men and 126 women; mean age: 76 years) were enrolled in this study. Regarding the reproducibility of TMT, good reliability was found; ICC2,1 = 0.759 (95 % confidence interval = 0.705–0.804). Multiple linear regression analyses for TMT after adjusting for potential confounders showed that sarcopenia risk was independently associated with TMT in older patients with acute stroke (β = -0.138, p = 0.02). After adjusting for variables, disease severity and comorbidities were the only independent predictors for poor functional outcome, but not TMT. TMT measurement using brain CT is a reliable and variable method to evaluate sarcopenia risk, but is not related to functional outcome in older patients with acute stroke.

Age-related decline in the ability of bone marrow (BM) to recruit transplanted hematopoietic stem and progenitor cells (HSPCs) limits the potential of HSPC-based medicine. Using in vivo imaging and manipulation combined with integrative metabolomic analyses, we show that, with aging, degradation of non-neurogenic acetylcholine disrupts the local Chrm5-eNOS-nitric oxide signaling, reducing arterial dilation and decreasing both BM blood flow and sinusoidal wall shear stress. Consequently, aging BM microenvironment impairs transendothelial migration of transplanted HSPCs, and their BM homing efficiency is reduced, mediated by decreased activation of Piezo1. Notably, pharmacological activation of Piezo1 improves HSPC homing efficiency and post-transplant survival of aged recipients. These findings suggest that age-related dysregulation of local arteries leads to impaired HSPC homing to BM by decreasing shear stress. Modulation of these mechanisms may improve the efficacy and safety of clinical transplantation in elderly patients. The ability of bone marrow to recruit transplanted hematopoietic stem cells decreases with age. Here, the authors demonstrate that this decline is caused by reduced sinusoidal shear stress due to increased non-neuronal acetylcholine degradation.