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We have investigated the structural, optical band gap, and electrical properties of (Fe 2 O 3 ) 0.5 x :(NiO) 1 − 0.5 x ( x  = 0.3, 0.4, 0.5, 0.6 and 0.7) epitaxial thin films grown on an atomically smooth substrate at room temperature. With increasing Fe 2 O 3 content, the rock-salt structure of the thin films transformed to a spinel structure above x  = 0.6. In terms of the local structure, the increased ratio of Fe 2+ ions to Fe 3+ ions indicates that the octahedral sites of FeO were continuously transformed into distorted octahedral and tetrahedral sites. On the other hand, the NiO matrix was not affected by the local structure change. Chemical composition of Fe 2 O 3 :NiO affected the crystal structure, the electrical conductivity and the optical band gap of direct transition (3.35 to 2.99 eV).

We have investigated the structural, optical band gap, and electrical properties of (Fe O ) :(NiO) (x = 0.3, 0.4, 0.5, 0.6 and 0.7) epitaxial thin films grown on an atomically smooth substrate at room temperature. With increasing Fe O content, the rock-salt structure of the thin films transformed to a spinel structure above x = 0.6. In terms of the local structure, the increased ratio of Fe ions to Fe ions indicates that the octahedral sites of FeO were continuously transformed into distorted octahedral and tetrahedral sites. On the other hand, the NiO matrix was not affected by the local structure change. Chemical composition of Fe O :NiO affected the crystal structure, the electrical conductivity and the optical band gap of direct transition (3.35 to 2.99 eV).

The exact relationship between solid papillary carcinoma (SPC) and invasive breast carcinoma of no special type (IBC-NST) with neuroendocrine differentiation and SPC and mucinous carcinoma (MC) of the breast remains unclear. To clarify the relationship, we conducted a comparative study of morphological and neuroendocrine features between ductal carcinoma in situ (DCIS, 72 cases) and SPC in situ (35 cases), and IBC-NST (103 cases) and invasive SPC (92 cases). We also conducted the study between MC associated with and without SPC. Synaptophysin, chromogranin A, and INSM1 were employed for the immunohistochemical study. IBC-NST had occasionally a morphological similarity with invasive SPC. While 123 of 127 cases with SPC demonstrated diffuse staining with one or more of the neuroendocrine markers, the only one case of DCIS and none of IBC-NST showed it. Type B was observed in 16 of 18 cases of MC associated with SPC and in 13 of 33 cases of MC without it. All the cases of MC with SPC and 6 of 33 cases without it showed diffuse staining for at least one of the neuroendocrine markers. In conclusion, a careful distinction between invasive SPC and IBC-NST with neuroendocrine differentiation is required. We assume that SPC in situ is a potential candidate for precursor of IBC-NST with neuroendocrine differentiation. MC of the breast is suggested to have two pathogenetic pathways through SPC in situ or non-SPC in situ. SPC in situ is thought to be less common as a precursor of MC than non-SPC in situ.

The recapitulation of bone formation via the in vitro generation of bone-like nodules is frequently used to understand bone development. However, current bone-induction techniques are slow and difficult to reproduce. Here, we report the formation of bone-like nodules within ten days, via the use of retinoic acid (RA) to induce the osteogenic differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblast-like and osteocyte-like cells that create human bone tissue when implanted in calvarial defects in mice. We also show that the induction of bone formation depends on cell signalling through the RA receptors RARα and RARβ, which simultaneously activate the BMP (bone morphogenetic protein) and Wnt signalling pathways. Moreover, by using patient-derived hiPSCs, the bone-like nodules recapitulated the osteogenesis-imperfecta phenotype, which was rescued via the correction of disease-causing mutations and partially by an mTOR (mechanistic target of rapamycin) inhibitor. The method of inducing bone nodules may serve as a fast and reproducible model for the study of the formation of both healthy and pathological bone. A fast in vitro model of the formation of bone-like nodules, enabled by the retinoic-acid-mediated induction of the osteogenic differentiation of patient-derived induced pluripotent stem cells, recapitulates the osteogenesis-imperfecta phenotype.

Despite emerging recognition of interactions between heart failure (HF) and liver dysfunction, the impact of cardiac hepatopathy on patients with HF undergoing cardiac resynchronization therapy (CRT) has not been fully elucidated. Albumin–bilirubin (ALBI) score is a new assessment of liver function. The relationship between liver dysfunction severity based on ALBI score and clinical outcomes of patients with HF receiving CRT is unclear. Clinical records of 274 patients who underwent CRT device implantation between March 2003 and October 2020 were retrospectively investigated. ALBI score was calculated based on serum albumin and total bilirubin levels obtained before CRT device implantation. Patients were divided into three groups based on ALBI score: first tertile (ALBI ≤  − 2.62, n  = 91)), second tertile (− 2.62 < ALBI <  − 2.13, n  = 92), and third tertile (ALBI ≥  − 2.13, n  = 91). The study endpoint was all-cause mortality. The third tertile group had more advanced NYHA functional class, lower hemoglobin levels, and higher total bilirubin, aspartate aminotransferase, γ-glutamyl transferase, and N-terminal Pro-B-type natriuretic peptide levels (all p  < 0.05). The third tertile group also had a higher prevalence of moderate or severe tricuspid regurgitation and higher tricuspid regurgitation pressure gradient (all p  < 0.05). CRT response rates were significantly lower in the third tertile group. During a median (interquartile range) follow-up of 30 (9–60) months, 104 (37.9%) patients died. The third tertile group had significantly higher rates of all-cause mortality (log-rank p  < 0.001). Higher ALBI score was significantly associated with all-cause mortality, even after adjusting for clinically relevant factors, a conventional validated risk score, and echocardiographic parameters related to right HF (all p  < 0.01). Higher ALBI score before CRT device implantation is associated with HF severity, hepatic congestion and impairment due to right HF, lower CRT response, and higher all-cause mortality in CRT recipients.

The renal arterial resistance index (RI) and the brachial–ankle pulse wave velocity (baPWV) are known as indicators of renal vascular resistance/systemic vascular damage and systemic arterial stiffness. The clinical significance of those parameters on clinical outcomes is poorly known in patients with and without heart failure with preserved ejection fraction (HFpEF). Baseline clinical data and the RI assessed by renal Doppler data, baPWV were obtained in patients with (HFpEF group, n  = 60) and without HFpEF (non-HFpEF group, n  = 51) who had a reduced estimated glomerular filtration rate (eGFR) of > 30 and < 60 mL/min/1.73 m 2 ). We investigated the association between the RI and baPWV and major clinical outcomes including hospitalization for heart failure, cardiovascular death, myocardial infarction or unstable angina or other cardiovascular events and death from another cause. The RI and baPWV were greater in the HFpEF group than in the non-HF group (0.75 ± 0.07 vs. 0.69 ± 0.08, p < 0.001; 2002 ± 430 vs. 1762 ± 300 cm/s, p  = 0.001). The RI correlated significantly with baPWV in the HFpEF ( r  = 0.382, p  = 0.003) and non-HFpEF groups ( r  = 0.414, p  = 0.002). During the median follow-up period of 54 months, major clinical outcomes occurred in 41 (36.9%) patients. The RI value, statin use and the presence of HFpEF were major factors for predicting clinical outcomes by multivariate analysis. Among the patients who had mild-to-moderate renal dysfunction, an increased RI and baPWV were observed in HFpEF patients as compared to non-HFpEF patients, but the baPWV similarly correlated with the RI value regardless of HFpFE patients or not. The strong association between the high RI value and presence of HFpEF and major clinical outcomes, suggests that not only the presence of HFpEF but also the high RI value may help to identify the high-risk patients leading to poor clinical outcomes.

Some patients with pacemakers present with first-degree atrioventricular (AV) block. To avoid right ventricular (RV) pacing, preserving intrinsic AV conduction as much as possible is recommended. However, there is no clear cutoff AV interval to determine whether intrinsic AV conduction should be preserved or RV pacing should be delivered. This study aimed to compare a pacing mode-preserving, intrinsic AV conduction with the DDD mode delivering RV pacing in terms of echocardiographic parameters in patients with first-degree AV block and to investigate whether RV pacing induces heart failure (HF). Stroke volume (SV) was measured to determine the optimal AV delay with the intrinsic AV conduction rhythm and the DDD pacing delivering RV pacing. Echocardiographic evaluation was performed for 6-month follow-up period. Seventeen patients were studied. At baseline, mean intrinsic PQ interval was 250 ± 40 ms. SV was greater with RV pacing with optimal AV delay of 160 ms than with intrinsic AV conduction rhythm in all patients. Therefore, pacemakers were set to the DDD to deliver RV pacing. During follow-up, seven patients developed HF. Mean baseline E/E′ ratio in patients who developed HF (HF group) during RV pacing was higher than in patients without HF (non = HF group; 17.9 ± 8 versus 11.5 ± 2, P  = 0.018) Even within HF group patients without a high baseline E/E′ ratio, it increased with RV pacing (22.2 ± 6 versus 11.6 ± 2; P  < 0.001). In patients with pacemaker and first-degree AV block, RV pacing with the optimal AV delay of 160 ms increased SV. However, the risk of HF may be increased with RV pacing if the E/Eʹ ratio is > 15 during intrinsic AV conduction or RV pacing. RV pacing should be avoided in patients with high E/Eʹ ratio under intrinsic AV conduction or RV pacing.

AimsMalnutrition is common and associated with worse clinical outcomes in patients with heart failure (HF). The Controlling Nutritional Status (CONUT) score is an integrated index for evaluating diverse aspects of the complex mechanism of malnutrition. However, the relationship between the severity of malnutrition assessed by the CONUT score and clinical outcomes of HF patients receiving cardiac resynchronisation therapy (CRT) has not been fully clarified.MethodsClinical records of 263 patients who underwent pacemaker or defibrillator implantation for CRT between March 2003 and October 2020 were retrospectively evaluated. The CONUT score was calculated from laboratory data obtained before CRT device implantation. Patients were divided into three groups: normal nutrition (CONUT scores 0–1, n=58), mild malnutrition (CONUT scores 2–4, n=132) and moderate or severe malnutrition (CONUT scores 5–12, n=73). The primary endpoint was all-cause mortality.ResultsThe moderate or severe malnutrition group had a lower body mass index, more advanced New York Heart Association functional class, higher Clinical Frailty Scale score, lower levels of haemoglobin and higher levels of N-terminal probrain natriuretic peptide (all p<0.05). In the moderate or severe malnutrition group, the CRT response rate was significantly lower than for the other two groups (p=0.001). During a median follow-up period of 31 (10–67) months, 103 (39.1%) patients died. Kaplan-Meier analysis revealed that the moderate or severe malnutrition group had a significantly higher mortality rate (log-rank p<0.001). A higher CONUT score and CONUT score ≥5 remained significantly associated with all-cause mortality after adjusting for previously reported clinically relevant factors and the conventional risk score (VALID-CRT risk score) (all p<0.05).ConclusionsA higher CONUT score before CRT device implantation was strongly associated with HF severity, frailty, lower CRT response rate and subsequent long-term all-cause mortality.

Aims Multi‐organ dysfunction was recently reported to be a common condition in patients with heart failure (HF). The Model for End‐stage Liver Disease eXcluding International normalized ratio (MELD‐XI) score reflects liver and kidney function. The prognostic relevance of this score has been reported in patients with a variety of cardiovascular diseases who are undergoing interventional therapies. However, the relationship between the severity of hepatorenal dysfunction assessed by the MELD‐XI score and the long‐term clinical outcomes of HF patients receiving cardiac resynchronization therapy (CRT) has not been evaluated. Methods and results Clinical records of 283 patients who underwent CRT implantation between March 2003 and October 2020 were retrospectively evaluated (mean age 67 ± 12, 22.6% female). Blood samples were collected before CRT implantation. Patients were divided into three groups based on tertiles of the MELD‐XI score: first tertile (MELD‐XI = 9.44, n = 95), second tertile (9.44 < MELD‐XI < 13.4, n = 94), and third tertile (MELD‐XI ≥ 13.4, n = 94). The primary endpoint was all‐cause mortality. Compared with the other groups, the third tertile group exhibited significantly older age, higher prevalence of diabetes mellitus and hypertension, lower haemoglobin level, and higher N‐terminal pro‐brain natriuretic peptide level (all P < 0.05). The functional CRT response rate was also significantly lower in the third tertile group (P = 0.011). During a median follow‐up of 30 months (inter‐quartile range, 9–67), 105 patients (37.1%) died. Kaplan–Meier analysis revealed that patients with a higher MELD‐XI score had a greater risk of all‐cause mortality (log‐rank test: P < 0.001). Even after adjustment for clinically relevant factors and a conventional risk score, the MELD‐XI score was still associated with mortality (adjusted hazard ratio: 1.04, 95% confidence interval: 1.00–1.07, P = 0.014, and adjusted hazard ratio: 1.04, 95% confidence interval: 1.01–1.09, P = 0.005, respectively). A higher MELD‐XI score was associated with a greater risk of all‐cause mortality than a lower MELD‐XI score regardless of whether a pacemaker or defibrillator was implanted (log‐rank test: P = 0.010 and P < 0.001, respectively). Conclusions Impaired hepatorenal function assessed by the MELD‐XI score was associated with older age, higher prevalence of multiple co‐morbidities, severity of HF, lower CRT response rates, and subsequent all‐cause mortality in HF patients undergoing CRT implantation. These results suggest that the MELD‐XI score can provide additional prognostic information and may be useful for improving risk stratification in this population.

We previously reported that maternal fructose consumption increases blood corticosterone levels in rat offspring. However, the underlying mechanism of action remains unclear. In the present study, we aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring (GC; corticosterone in rodents and cortisol in humans). Female Sprague Dawley rats received HFCS solution during gestation and lactation. The male offspring were fed distilled water from weaning to 60 days of age. We investigated the activities of GC-metabolizing enzymes (11β-Hsd1 and 11β-Hsd2) in various tissues (i.e., liver, kidney, adrenal glands, muscle, and white adipose tissue) and epigenetic modification. 11β-Hsd2 activity decreased in the kidney of the HFCS-fed dams. Moreover, the epigenetic analysis suggested that miR-27a reduced Hsd11b2 mRNA expression in the kidney of offspring. Maternal HFCS-induced elevation of circulating GC levels in offspring may be explained by a decrease in 11β-Hsd2 activity via renal miR-27a expression. The present study may allow us to determine one of the mechanisms of GC elevation in rat offspring that is often observed in the developmental origins of the health and disease (DOHaD) phenomenon.