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Abstract Aims Acute heart failure (AHF) is a clinical syndrome with a poor prognosis and a major public health concern worldwide. The aim of this study was to investigate whether carperitide administration improves the 1 year prognosis of patients with AHF and to check whether there is an optimal dose of the drug. Methods and results We analysed the data of COOPERATE‐HF‐J (the Consortium for Pooled Data Analysis regarding Hospitalized Patients with Heart Failure in Japan), combining two cohorts (NARA‐HF and REALITY‐AHF), which included 2435 patients with acute decompensated heart failure. The patients were divided into no carperitide (NO‐ANP, n = 1098); very low‐dose carperitide (VLD‐ANP,

Background Modification of arrhythmogenic substrates with extensive ablation comprising linear and/or complex fractional atrial electrogram ablation in addition to pulmonary vein isolation (PVI‐plus) can theoretically reduce the recurrence of atrial fibrillation. The DR‐FLASH score (score based on diabetes mellitus, renal dysfunction, persistent form of atrial fibrillation, left atrialdiameter >45 mm, age >65 years, female sex, and hypertension) is reportedly useful for identifying patients with arrhythmogenic substrates. We hypothesized that, in patients with persistent atrial fibrillation, the DR‐FLASH score can be used to classify patients into those who require PVI‐plus and those for whom a PVI‐only strategy is sufficient. Methods and Results This study is a post hoc subanalysis of the a multicenter, randomized controlled, noninferiority trial investigating efficacy and safety of pulmonary vein isolation alone for recurrence prevention compared with extensive ablation in patients with persistent atrial fibrillation (EARNEST‐PVI trial). This analysis focuses on the relationship between DR‐FLASH score and the efficacy of different ablation strategies. We divided the population into 2 groups based on a DR‐FLASH score of 3 points. A total of 469 patients were analyzed. Among those with a DR‐FLASH score >3 (N=279), the event rate of atrial arrhythmia recurrence was significantly lower in the PVI‐plus arm than in the PVI‐only arm (hazard ratio [HR], 0.45 [95% CI, 0.28–0.72]; P3 and DR‐FLASH score ≤3 (P value for interaction=0.020). Conclusions The DR‐FLASH score is a useful tool for deciding the catheter ablation strategy for patients with persistent atrial fibrillation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03514693.

Abstract Aims Exogenous atrial natriuretic peptide (ANP) may be a logical treatment for heart failure (HF) patients with ANP deficiency. Lower ANP concentrations may result from HF with preserved ejection fraction (HFpEF), which also results in lower brain natriuretic peptide levels in HFpEF relative to HF with reduced ejection fraction (HFrEF), although clinical features regarding circulating ANP in HFpEF and HFrEF have not been fully investigated during acute HF. Here, we characterized the differential regulation of circulating ANP and the efficacy of exogenous ANP (carperitide) in patients with acute HF, especially HFpEF. Methods and results Serum ANP levels before treatment and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 113 patients with acute HF who were divided into two groups: HFpEF vs. HFrEF. We mainly analysed the impact of baseline ANP levels and the presence of HFpEF on the diuretic effect of exogenous ANP. There was an inverse relationship between ANP levels and the diuretic effect of exogenous ANP (r2 = 0.19, P

Abstract Aims Older adults at risk for malnutrition are known to have a high mortality rate. This study aimed to investigate whether the Mini Nutritional Assessment—Short Form (MNA‐SF) could predict midterm mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Methods and results We applied the MNA‐SF in 288 patients who had undergone TAVI from January 2016 to June 2019 at the St. Marianna University School of Medicine hospital. Using the MNA‐SF cut‐off value to indicate the risk of malnutrition, patients were divided into two groups, namely, those with an MNA‐SF score ≤11 (impaired MNA‐SF group) and those with an MNA‐SF score ≥12 (maintained MNA‐SF group). We used this value to investigate the association between the MNA‐SF and all‐cause mortality. Overall, 188 (65%) and 100 (35%) patients comprised the impaired MNA‐SF and maintained MNA‐SF groups, respectively, and 41 patients died after TAVI (mean follow‐up duration, 458 ± 315 days). Kaplan–Meier analyses showed that patients in the impaired MNA‐SF group had a significantly higher incidence of all‐cause mortality (hazard ratio 2.67; 95% confidence interval 1.29–6.21; P = 0.01). Multivariate Cox regression analyses showed that the MNA‐SF score was an independent predictor of all‐cause mortality after adjusting for the Society of Thoracic Surgeons risk score, Katz Index, and brain natriuretic peptide test results (hazard ratio 1.14; 95% confidence interval 1.01–1.28; P = 0.04). Conclusions The MNA‐SF was useful to screen for the risk of malnutrition in patients with TAVI and in predicting midterm prognoses in patients undergoing TAVI and could predict patient mortality after the procedure.

Background Stent thrombosis (ST) remains a significant medical issue. In particular, longer‐term mortality and clinical predictors after ST occurrence have yet to be elucidated. Methods and Results This was a multicenter, retrospective, observational study. A total of 187 definite ST cases from January 2008 to December 2017 were enrolled, and the long‐term clinical outcomes were investigated. The primary outcome measure was the cumulative mortality after ST occurrence. In addition, independent predictors of mortality were assessed. Among the stent types causing ST, bare‐metal stent, first‐generation drug‐eluting stent, second‐generation drug‐eluting stent, and third‐generation drug‐eluting stent comprised 31.0%, 19.3%, 36.9%, and 6.4% of cases, respectively. Median duration from stent implantation to ST was 680.5 (interquartile range, 33.8–2450.5) days. Cumulative mortality was 14.6%, 17.4%, 21.2%, 24.4%, and 33.8% at 1, 2, 3, 5 and 10 years, respectively. The cumulative mortality did not significantly differ by type of stent, and mortality of late ST was higher than that of early ST and very late ST; however, it did not reach statistical significance after the multivariate analysis. Independent predictors of mortality were hemodialysis (hazard ratio [HR], 7.80; 95% CI, 3.07–19.81; P

Cancer‐associated fibroblasts (CAFs) are key components of the dense, proliferating stroma observed in pancreatic ductal adenocarcinoma (PDAC), and CAF subpopulations drive tumor heterogeneity and play a major role in PDAC progression and drug resistance. CAFs consist of heterogenous subpopulations such as myoblastic CAF (myCAF) and inflammatory CAF (iCAF), and each has distinct essential roles. However, it is not clear how CAF subpopulations are formed in PDAC. Adipose‐derived MSCs (AD‐MSCs), which possess a high multilineage potential and self‐renewal capacity, are reported to be one of the in vivo CAF sources. Here, we aimed to investigate whether AD‐MSCs can act as precursors for CAFs in vitro. We recorded morphological features and collected omics data from two in vitro co‐culture models for recapitulating clinical PDAC. Additionally, we tested the advantages of the co‐culture model in terms of accurately modeling morphology and CAF heterogeneity. We showed that AD‐MSCs differentiate into two distinct CAF subpopulations: Direct contact co‐culture with PDAC cell line Capan‐1 induced differentiation into myCAFs and iCAFs, while indirect co‐culture induced differentiation into only iCAFs. Using these co‐culture systems, we also identified novel CAF markers that may be helpful for elucidating the mechanisms of CAFs in the tumor microenvironment (TME). In conclusion, AD‐MSCs can differentiate into distinct CAF subtypes depending on the different co‐culture conditions in vitro, and the identification of potential CAF markers may aid in future investigations of the mechanisms underlying the role of CAFs in the TME.

Tubular 3D liver tissue with enhanced capillary‐like structures branching from a large main channel is potentially useful for drug discovery because the perfusable main channel and capillary‐like structures enable mass transfer into and out from the tissue. Tubular liver tissue is comprised of the hepatocellular carcinoma cell line HepG2, human umbilical vein endothelial cells (HUVECs), and mesenchymal stem cells (MSCs), using a perfusion device functioning as the interface for an external pump. This study aimed to compare the expression of genes involved in drug metabolism between 2D‐cultured hepatocellular carcinoma cells and 3D‐cultured tubular liver tissue. Gene expression profiles of 2D‐cultured cells and tubular liver tissue were compared using RNA sequencing. Multidimensional scaling analysis revealed that culture dimensionality had a more prominent effect on gene expression profiles than perfusion conditions. More specifically, genes involved in drug metabolism such as CYP2D6, CYP2E1, NNMT, and SLC28A1 were slightly upregulated in the 3D cultures, while certain genes such as ALDH1B1, ALDH1A2, and SULT1E1 were downregulated. These results indicate that gene expression profiles are largely influenced by culture dimensionality and are potentially useful to researchers intending to switch from 2D culture to 3D culture of hepatocellular carcinoma or other tissue types.

Abstract Purpose To establish an automated pronuclei determination system by analysis using deep learning technology which is able to effectively learn with limited amount of supervised data. Methods An algorithm was developed by explicitly incorporating human observation where the outline around pronuclei is being observed in determining the number of pronuclei. Supervised data were selected from the time‐lapse images of 300 pronuclear stage embryos per class (total 900 embryos) clearly classified by embryologists as 0PN, 1PN, and 2PN. One‐hundred embryos per class (a total of 300 embryos) were used for verification data. The verification data were evaluated for the performance of detection in the number of pronuclei by regarding the results consistent with the judgment of the embryologists as correct answers. Results The sensitivity rates of 0PN, 1PN, and 2PN were 99%, 82%, and 99%, respectively, and the overlapping 2PN being difficult to determine by microscopic observation alone could also be appropriately assessed. Conclusions This study enabled the establishment of the automated pronuclei determination system with the precision almost equivalent to highly skilled embryologists.

Abstract Purpose Resveratrol is a well‐known potent activator of sirtuin‐1 (SIRT1). We investigated the direct effects of hypoxia and resveratrol on SIRT1/ peroxisome proliferator‐activated receptor‐gamma coactivator 1α (PGC‐1α) pathways, vascular endothelial growth factor (VEGF), hypoxia‐inducible factor (HIF)‐1α, and mitochondrial quantity in a steroidogenic human ovarian granulosa‐like tumor cell line (KGN) cells. Methods KGN cells were cultured with cobalt chloride (CoCl2; a hypoxia‐mimicking agent) and/or resveratrol. The mRNA and protein levels, protein secretion, and intracellular localization were assessed by real‐time PCR, Western blot analysis, ELISA, and immunofluorescence staining, respectively. Mitochondrial quantity was measured based on the mitochondrial DNA (mtDNA) copy number. Results CoCl2 simultaneously attenuated the levels of SIRT1 and mtDNA expression, and induced the levels of VEGF protein production. In contrast, resveratrol significantly increased the levels of SIRT1 and mtDNA copy number, but reduced VEGF production in normoxia. Resveratrol could recover CoCl2‐suppressed SIRT1 and mtDNA expression and antagonize CoCl2‐induced VEGF production. CoCl2 treatment resulted in a downregulation of PGC‐1α expression, and this effect was recovered by resveratrol. Resveratrol significantly suppressed the production of the CoCl2‐induced HIF‐1α and VEGF proteins. Conclusion These results suggest that resveratrol improves mitochondrial quantity by activating the SIRT1/PGC‐1α pathway and inhibits VEGF induction through HIF‐1α under hypoxic conditions.

Abstract A patient with late phase of COVID‐19 pneumonia presented peripheral cystic features on chest computed tomography, which were spontaneously resolved with no antibiotic therapy or surgery. Physicians should pay attention to follow up the late phase of COVID‐19 pneumonia for better understanding its progression and clinical course.

Background The previous large‐scale randomized controlled trial showed that routine thrombus aspiration (TA) during percutaneous coronary intervention (PCI) was associated with an increased risk of stroke. However, real‐world clinical evidence is still limited. Methods and Results We investigated the association between manual TA and stroke risk during primary PCI in the OACIS (Osaka Acute Coronary Insufficiency Study) database (N=12 093). The OACIS is a prospective, multicenter registry of myocardial infarction. The primary end point of the present study is stroke at 7 days. A total of 9147 patients who underwent primary PCI within 24 hours of hospitalization were finally analyzed (TA group, n=4448, versus non‐TA group, n=4699 patients). TA was independently associated with risk of stroke at 7 days (odds ratio [OR], 1.92 [95% CI, 1.19‒3.12]; P=0.008) in the simple logistic regression model, while the multilevel random effects logistic regression model with hospital treated as a random effect showed that manual TA was not associated with incremental risk of stroke at 7 days (OR, 0.91 [95% CI, 0.71‒1.16]; P=0.435). The 7‐day stroke risk of manual TA was significantly heterogeneous in different institutions (P for interaction=0.007). Conclusions Manual TA during primary PCI for patients with acute myocardial infarction was independently associated with the overall increased risk of periprocedural stroke. However, this result was substantially skewed because of institution specific risk variation, suggesting that the periprocedural stroke may be preventable by prudent PCI procedure or appropriate periprocedural management. Registration URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000005464. Unique identifier: UMIN000004575.

Recent clinical trials have demonstrated that anti‐PD‐1 blocking antibodies showed remarkable clinical efficacy in a subset of non‐small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non‐small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti‐PD‐1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD.

Abstract Purpose To study the association between stromal cell‐derived factor‐1 (SDF‐1/CXCL12) and vascular endothelial growth factor (VEGF) concentrations in individual human ovarian follicles and IVF outcomes. Methods Concentrations of SDF‐1 and VEGF in 261 follicular fluid samples were measured with enzyme‐linked immunosorbent assay. IVF outcome parameters were included in fertilization rate, cleavage rate, embryo morphology on day 3, and blastocyst morphology on day 5. Results The follicular concentration of SDF‐1 and VEGF was not significantly associated with fertilization and cleavage outcome, and embryo morphology. The rates of full blastocysts and good‐quality blastocysts were significantly higher in follicles with an SDF‐1 concentration of 275‐350 pg/mL than in the follicles with SDF‐1 concentrations of

Abstract Background Toe flexor muscles play an important role in posture and locomotion, and poor toe flexor strength is a risk factor for falls. In this cross-sectional study, we estimated the age-related change in toe flexor strength and compared it with that of handgrip strength. Independent factors predicting toe flexor and handgrip strength were also determined. Methods A total of 1401 male (aged 35–59 years) study participants were divided into five groups according to their chronological age; 35–39, 40–44, 45–49, 50–54, and 55–59 years. Toe flexor and handgrip strength, anthropometry, and resting blood pressure were measured. Fasting blood samples were collected to measure blood glucose, triglycerides, high- and low-density lipoprotein-cholesterols, and albumin. A self-administered lifestyle questionnaire was conducted. Results Decline in absolute toe flexor and handgrip strength began in the age groups 50–55 and 55–59 years, respectively. In comparison to the mean values of the youngest group, relative toe flexor strength (87.0 ± 26.6%) was significantly lower than handgrip strength (94.4 ± 13.1%) for the oldest group. Multiple regression analyses showed that independent factors predicting both toe flexor and handgrip strength were lean body mass, age, serum albumin, drinking habit, and fat mass. Additionally, fasting blood glucose, diastolic blood pressure, sleeping time and exercise habit were predicting factors of toe flexor strength but not of handgrip strength. Conclusions Age-related reduction in toe flexor strength was earlier and greater than handgrip strength, and toe flexor strength reflects body composition and metabolic status.