Search

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual’s change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope). We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m2to receive canagliflozin or guideline-recommended treatment except for SGLT2 inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, −30.8% (95% confidence interval −42.6 to −16.8). The between-group difference (canagliflozin group – control group) of change in eGFR slope (chronic – pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m2per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggests that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) patients often have exercise intolerance. Pulmonary rehabilitation (PR) to improve such patients' conditions is often not based on its exercise pathophysiology. We have reported that the oxygen consumption (ΔFO2) by expiratory gas analysis, i.e., the inspired-expired-expiratory mean oxygen concentration difference, is related to the minute ventilation-carbon dioxide output (V′E-V′CO2)-slope and oxygen uptake (V′O2) independent of the V′E. The aim of this study was to investigate how ΔFO2is related to dynamic ventilatory variables, chest computed tomography (CT), and echocardiography findings in NTM-PD patients to understand their pathophysiological conditions.

The hallmark of pathological cardiac hypertrophy is the decline in myocardial contractility caused by an energy deficit resulting from metabolic abnormalities, particularly those related to glucose metabolism. Here, we aim to explore whether D-Allose, a rare sugar that utilizes the same transporters as glucose, may restore metabolic equilibrium and reverse cardiac hypertrophy. Isolated neonatal rat cardiomyocytes were stimulated with phenylephrine and treated with D-Allose simultaneously for 48 h. D-Allose treatment resulted in a pronounced reduction in cardiomyocyte size and cardiac remodelling markers accompanied with a dramatic reduction in the level of intracellular glucose in phenylephrine-stimulated cells. The metabolic flux analysis provided further insights revealing that D-Allose exerted a remarkable inhibition of glycolysis as well as glycolytic capacity. Furthermore, in mice subjected to a 14-day continuous infusion of isoproterenol (ISO) to induce cardiac hypertrophy, D-Allose treatment via drinking water notably reduced ISO-induced cardiac hypertrophy and remodelling markers, with minimal effects on ventricular wall thickness observed in echocardiographic analyses. These findings indicate that D-Allose has the ability to attenuate the progression of cardiomyocyte hypertrophy by decreasing intracellular glucose flux and inhibiting glycolysis.

Bioluminescence (BL) generated by luciferase-coelenterazine (CTZ) reactions is broadly employed as an optical readout in bioassays and in vivo molecular imaging. In this study, we demonstrate a systematic approach to elucidate the luciferase-CTZ binding chemistry with a full set of regioisomeric CTZ analogs, where all the functional groups were regiochemically modified. When the chemical structures were categorized into Groups 1–6, the even-numbered Groups (2, 4, and 6) of the CTZ analogs are found to be exceptionally bright with NanoLuc enzyme. A CTZ analogue M2was the brightest with NanoLuc and the reason was deciphered by a computational analysis of the binding modes. We also report that (i) the regioisomeric CTZ analogs collectively create unique intensity patterns according to each marine luciferase, (ii) the quantitative structure–activity relationship analysis revealed the roles of respective functional groups of CTZ analogs, and (iii) the regioisomeric CTZ analogs also exert red shifts of the BL spectra and color variation: that is, the λmaxvalues are near 500 nm with NanoLuc, near 530 nm with ALuc16, and near 570 nm with RLuc86SG. The advantages of the regioisomeric CTZ analogs were finally demonstrated using (i) a dual-luciferase system with M2-specific NanoLuc and native CTZ-specific ALuc16, (ii) an estrogen activatable single-chain BL probe by imaging, and (iii) BL imaging of live mice bearing tumors expressing NanoLuc and RLuc8.6SG. This study is the first systematic approach to elucidate the regiochemistry in BL imaging studies. This study provides new insights into how CTZ analogs regiochemically work in BL reporter systems and guides the specific applications to molecular imaging.

Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients’ quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted.

2-Deoxy-d-glucose (2DG) induces anticancer effects through glycolytic inhibition but it may raise the risk of arrhythmia. The rare monosaccharide d-allose also has anticancer properties, but its cardiac effects are unknown. We examined the effects of d-allose on adenosine triphosphate (ATP) production in neonatal rat cardiomyocytes. We showed that 25 mM d-allose selectively reduced glycolytic ATP, but had minimal impact on mitochondrial ATP, while 1 mM 2DG strongly inhibited both. Furthermore, d-allose had less impact on cell viability and was less cytotoxic than 2DG; neither compound caused apoptosis. Thus, d-allose selectively diminished glycolytic ATP production with no apparent effects on cardiomyocytes.

Identifying the mechanisms of action of anticancer drugs is an important step in the development of new drugs. In this study, we established a comprehensive screening platform consisting of 68 oncogenes (MANO panel), encompassing 243 genetic variants, to identify predictive markers for drug efficacy. Validation was performed using drugs that targeted EGFR, BRAF, and MAP2K1, which confirmed the utility of this functional screening panel. Screening of a BRCA2-knockout DLD1 cell line (DLD1-KO) revealed that cells expressing SMOand GLI1were resistant to olaparib. Gene set enrichment analysis identified genes associated with DNA damage repair that were enriched in cells overexpressing SMOand GLI1. The expression of genes associated with homologous recombination repair (HR), such as the FANCfamily and BRCA1/2, was significantly upregulated by GLI1expression, which is indicative of PARP inhibitor resistance. Although not all representative genes of the nucleotide excision repair (NER) pathway were upregulated, NER activity was enhanced by GLI1. The GLI1 inhibitor was effective against DLD1-KO cells overexpressing GLI1both in vitro and in vivo. Furthermore, the combination therapy of olaparib and GLI1 inhibitor exhibited a synergistic effect on DLD1-KO, suggesting the possible clinical application of GLI1 inhibitor targeting cancer with defective DNA damage repair. This platform enables the identification of biomarkers associated with drug sensitivity, and is a useful tool for drug development.

AbstractAssuming that the discrepancy between the experimental value and the calculation value comes from the cross section, experimental error, and calculation error, Bayesian estimation of the cross section and these errors were studied. Uncertainty of the discrepancy between the experimental value and the design value is discussed by comparing the present estimation and the bias factor method. Comparison of the formulas shows that the design value obtained by the bias factor method is consistent with that obtained by estimation of the cross section and calculation error of the target system. In addition, the uncertainty of the discrepancy between the experimental value and the design value can be reduced by considering a correlation of the experimental error between the mock-up experiment and the target system. A case study was performed using mixed oxide critical assembly benchmarks. The result shows that the experimental value of the target system can be accurately predicted by considering the cross section, experimental error, and calculation error.

Supplemental Digital Content is Available in the Text.There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight- and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics.

Metal–organic cages (MOCs) composed of trinuclear zirconium clusters, Re-complex-based catalyst-incorporated linkers (Lcat), and catalyst-free linkers (L) are synthesized using varying ratios of Lcatand L([{Cp3Zr3(µ3-O)(µ2-OH)3}4LcatnL6-n]4+(n= 0.0–5.0, Cp = cyclopentadienyl)). Investigating the catalytic activity of the obtained MOCs revealed that the accumulation of the Re-complex-based catalytic centers affects the photochemical CO2reduction and CO2insertion into phenyl vinyl sulfone.Metal-organic cages (MOCs) composed of trinuclear zirconium clusters, Re-complex-based-catalyst-incorporated linkers (Lcat), and catalyst-free linkers (L) were synthesized with various ratios of Lcatand L. The MOCs can serve as catalysts for CO2reduction and CO2insertion reactions, and the effect of accumulation of active sites on the photocatalytic activity of MOCs was clarified for the first time.

Marine magnetic field surveys conducted near the sea bottom are useful in producing images of the oceanic crust in order to ascertain its volcanic eruption history, active hydrothermal systems, and hydrothermal deposit evolution. An autonomous underwater vehicle (AUV) can carry out self-controlled survey operations while maintaining a stable vehicle attitude at low altitudes above the seafloor. As a result of these benefits, AUVs have attracted attention for various missions. The total magnetic field intensity is generally used for subsurface magnetization images. Recently, vector magnetic anomaly analysis has been considered to be extremely effective for high-accuracy estimation of subsurface magnetization structures. However, correcting for the anomalous magnetic field produced by the vehicle body is one of the difficulties that hinders vector magnetic anomaly analysis. Therefore, we developed a magnetometer system designed for the AUV URASHIMA with a renewed navigation data distribution system. Experimental observation was carried out around a submarine mud volcano with a small magnetic anomaly off Tanegashima Island. The results show that correction for the magnetic field of the vehicle because of the attitude, especially for changes in pitch, is essential for near-bottom magnetic surveys using AUVs. Based on these results, we proposed a suitable data acquisition method to remove the pitching effects of the vehicle for figure-eight turns. Next, practical observation was carried out in the hydrothermal area, and the proposed correction method for magnetic data reduced the pitch variation effect. These results indicate that the correction for the magnetic field of the vehicle based using attitude data, especially for pitching variations, is required in order to obtain high-quality magnetic anomaly data using AUVs. However, a short-period variation of approximately 10 nT caused by abrupt pitch changes remains.

Aqueous battery electrolytes have attracted research attention owing to their safety and cost benefits. However, the narrow electrochemical window of water (1.23 V) has hindered steady operation at high voltages. The concept of highly concentrated aqueous electrolytes has recently led to the discovery of several Li- and K-salt hydrate melts with low hydration numbers (n) by mixing two or more salts, that is, eutectic hydrate melts. However, the lowest hydration number for Na-salt eutectic systems remained at n= 3.0, limiting the steady operation voltage. Herein, we report a room-temperature Na-salt eutectic dihydrate melt (n= 2.0) with a wide potential window of over 3 V, achieved by mixing two asymmetric imide salts, Na[N(SO2C2F5)(SO2CF3)] (NaPTFSI) and Na[N(SO2C3F7)(SO2CF3)] (NaHTFSI). The dihydrate melt enables reversible insertion/desertion of Na-ions into/from NaTiOPO4(1.6 V vs Na/Na+) and Na4Co3(PO4)2P2O7(4.4 V vs Na/Na+), both of which are located far beyond the stable potential windows of the conventional aqueous electrolytes.

In the bends of pipelines, a thrust force is generated depending on the internal water pressure and bending angles. Although heavy concrete blocks are generally installed at pipe bends to resist thrust force, the blocks can be considered as weak points during earthquakes. Thus, a lightweight thrust countermeasure of wrapping pipe bends with a geogrid was developed to resist thrust forces. However, when the effect of this reinforced method is insufficient or geogrids are difficult to install at pipe bends, the reinforcement of the passive area behind the pipe bends is required. In the present study, geocell reinforcements were proposed. To investigate the geocell reinforcements for pipe bends under lateral loading, lateral loading tests were conducted on a plate that simulates pipe bends, which was reinforced with a honeycomb-shaped geocell. As a result, the honeycomb-shaped geocell was effective against lateral loading, and the resistance increased when gravel with a high shear resistance was used as the filling material inside the geocell. Moreover, reinforcements using a geocell with multiple single cells can prevent plate floating.

The COVID-19 pandemic has raised awareness about the global imperative to develop and stockpile vaccines against future outbreaks of emerging infectious diseases (EIDs). Prior to the pandemic, vaccine development for EIDs was stagnant, largely due to the lack of financial incentives for pharmaceutical firms to invest in vaccine research and development (R&D). This R&D requires significant capital investment, most notably in conducting clinical trials, but vaccines generate much less profit for pharmaceutical firms compared with other therapeutics in disease areas such as oncology. The portfolio approach of financing drug development has been proposed as a financial innovation to improve the risk/return trade-off of investment in drug development projects through the use of diversification and securitization. By investing in a sizable and well-diversified portfolio of novel drug candidates, and issuing equity and securitized debt based on this portfolio, the financial performance of such a biomedical “megafund” can attract a wider group of private-sector investors. To analyze the viability of the portfolio approach in expediting vaccine development against EIDs, we simulate the financial performance of a hypothetical vaccine megafund consisting of 120 messenger RNA (mRNA) vaccine candidates in the preclinical stage, which target 11 EIDs, including a hypothetical “disease X” that may be responsible for the next pandemic. We calibrate the simulation parameters with input from domain experts in mRNA technology and an extensive literature review and find that this vaccine portfolio will generate an average annualized return on investment of −6.0% per annum and a negative net present value of −$9.5 billion, despite the scientific advantages of mRNA technology and the financial benefits of diversification. We also show that clinical trial costs account for 94% of the total investment; vaccine manufacturing costs account for only 6%. The most important factor of the megafund’s financial performance is the price per vaccine dose. Other factors, such as the increased probability of success due to mRNA technology, the size of the megafund portfolio, and the possibility of conducting human challenge trials, do not significantly improve its financial performance. Our analysis indicates that continued collaboration between government agencies and the private sector will be necessary if the goal is to create a sustainable business model and robust vaccine ecosystem for addressing future pandemics.

The human error probabilities (HEP) can be estimated using multipliers that correspond to the level of performance shaping factors (PSFs) in the human reliability analysis (HRA). This paper focuses on the adjustment of multipliers through Bayesian inference based on Monte Carlo techniques using the experimental results from simulators. Markov Chain Monte Carlo (MCMC) and Bayesian Monte Carlo (BMC) are used as Bayesian inference methods based on Monte Carlo techniques. MCMC is utilized to obtain the posterior distribution of the multipliers. BMC is used for the estimation of the moments of the posterior distribution such as the mean and variance. The results obtained by MCMC and that by BMC well agree with the reference results. As a case study, the data assimilation was performed using the results of the simulator experiment of Halden reactor. The results show that the multiplier changes by the result of a particular scenario and HEP of another scenario that uses the same multiplier also changes by data assimilation. Also, in the case study, the correlation between multipliers is obtained by the data assimilation and the correlation contributes to the reduction of uncertainty of HEP.

Background: Remission is a key treatment target in systemic lupus erythematosus (SLE) management. Given the direct correlation between lupus flares and elevated risks of adverse pregnancy outcomes (APOs), securing remission before conception becomes crucial. However, the association between clinical remission with active serology, and the risk of APOs is not thoroughly understood. Additionally, determining the optimal glucocorticoid dosage during pregnancy to mitigate APO risks remains under-researched. This study investigated the risk of APOs in relation to remission/serological activity status in patients in clinical remission/glucocorticoid dosage. Methods: Pregnant patients with SLE, who were followed up at two Japanese tertiary referral centers, and had their remission status assessed at conception, were included in this study. We categorized the patients into two groups based on whether they achieved Zen/Doria remission at conception and analyzed the APO ratio. We also examined the influence of serological activity in pregnant patients with clinical remission and analyzed the optimal glucocorticoid dosage to minimize the APO ratio. Results: Of the 96 pregnancies included, 59 achieved remission at conception. Pregnant patients who achieved remission showed a significant decrease in the APO ratio compared with those who did not. (overall APO: odds ratio (OR) 0.27, 95% confidence interval (CI) 0.11–0.65, p< 0.01, maternal APO: OR 0.34, 95%CI 0.13–0.85, p= 0.021, neonatal APO: OR 0.39, 95%CI 0.17–0.90, p= 0.028). Conversely, no statistical difference was observed in the APO ratio based on serological activity in pregnant patients with clinical remission. (overall APO: OR 0.62, 95%CI 0.21–1.79, p= 0.37, maternal APO: OR 1.25, 95%CI 0.32–4.85, p= 0.75, neonatal APO: OR 0.83, 95%CI 0.29–2.39, p= 0.73). A glucocorticoid dose of prednisolone equivalent ≥ 7.5 mg/day at conception correlated with increased APO. (overall APO: OR 3.01, 95%CI 1.23–7.39, p= 0.016, neonatal APO: OR 2.98, 95% CI:1.23–7.22, p= 0.016). Conclusions: Even with active serology, achieving clinical remission can be a clinical target for reducing APOs in patients who wish to conceive. In addition, if clinically feasible, reducing the glucocorticoid dosage to < 7.5 mg/day before conception could be another predictive factor.

Background: Tacrolimus is one of the major treatment options for systemic lupus erythematosus (SLE) and is considered to be a pregnancy-compatible medication. Since little is known about tacrolimus safety during pregnancy complicated by SLE, this study was designed. Methods: We included SLE pregnant patients who were followed up at two Japanese tertiary referral centers. We performed multivariate logistic regression analysis to assess each adverse pregnancy outcome (APO) risk. Moreover, we assessed the influence of tacrolimus on the APO ratio in pregnant patients with lupus nephritis, and the impact of combined tacrolimus-aspirin therapy on the APO ratio relative to patients exclusively administered tacrolimus. Results: Of the 124 pregnancies, 29 were exposed to tacrolimus. Multivariate analysis showed no statistical difference in APO ratio. (overall APO: adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.23–2.03; p= 0.50; maternal APO: aOR, 1.17; 95% CI, 0.36–3.83; p= 0.80; neonatal APO: aOR, 1.10; 95% CI, 0.38–3.21; p= 0.86; PROMISSE APO: aOR, 0.50; 95% CI, 0.14–1.74; p= 0.27). Conclusions: Tacrolimus use during pregnancy with SLE and lupus nephritis showed no significant influence on APO, blood pressure, or renal function; therefore tacrolimus may be suitable for controlling lupus activity during pregnancy. In addition, when using tacrolimus during pregnancy, we should aim its trough concentration ≥ 2.6 ng/ml while paying careful attention to possible maternal side effects of tacrolimus. Trial registration: Retrospectively registered.

•TP53signature can predict the pathological complete response in breast cancer.•TP53signature is a predictor for survival benefit from neoadjuvant chemotherapy.•Benefit from chemotherapy is grater in mutant than in wild-type signature group.

To characterize glucagon-like peptide (GLP)-I signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and [...]

OBJECTIVE--Despite the beneficial effects of resveratrol (RSV) on cardiovascular disease and life span, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of RSV in db/db mice, a model of type 2 diabetes. RESEARCH DESIGN AND METHODS--db/db mice were treated with RSV (0.3% mixed in chow) for 8 weeks. We measured urinary albumin excretion (UAE), histological changes (including mesangial expansion, fibronectin accumulation, and macrophage infiltration), oxidative stress markers (urinary excretion and mitochondrial content of 8-hydroxy-2'-deoxyguanosine [8-OHdG], nitrotyrosine expression), and manganese-superoxide dismutase (Mn-SOD) activity together with its tyrosine-nitrated modification and mitochondrial biogenesis in the kidney. Blood glucose, glycated hemoglobin, and plasma lipid profiles were also measured. The phosphorylation of 5'-AMP-activated kinase (AMPK) and expression of silent information regulator 1 (SIRT1) in the kidney were assessed by immunoblotting. RESULTS--RSV significantly reduced UAE and attenuated renal pathological changes in db/db mice. Mitochondrial oxidative stress and biogenesis were enhanced in db/db mice; however, Mn-SOD activity was reduced through increased tyrosine-nitrated modification. RSV ameliorated such alterations and partially improved blood glucose, glycated hemoglobin, and abnormal lipid profile in db/db mice. Activation of AMPK was decreased in the kidney of db/db mice compared with db/m mice. RSV neither modified AMPK activation nor SIRT1 expression in the kidney. CONCLUSIONS--RSV ameliorates renal injury and enhanced mitochondrial biogenesis with Mn-SOD dysfunction in the kidney of db/db mice, through improvement of oxidative stress via normalization of Mn-SOD function and glucose-lipid metabolism. RSV has antioxidative activities Via AMPK/SIRT1-independent pathway., Resveratrol (RSV; 3,5,4'-trihydroxystilbene) is reported to be beneficial in cardiovascular diseases (1) and renal diseases (2-4), including ischemic/reperfusion injury (5). The beneficial effects are thought to be due to its [...]

The nasal mucosa functions as a frontline biological defense against various foreign substances and pathogens. Maintaining homeostasis of the nasal epithelium is necessary to promote good health. Nasal epithelia are constantly replaced under normal conditions. However, hereditary diseases, including primary ciliary dyskinesia and cystic fibrosis, can result in intractable dysfunction of the nasal mucosa. Since there is no treatment for this underlying condition, extrinsic manipulation is necessary to recover and maintain nasal epithelia in cases of hereditary diseases. In this study, we explored the use of airway epithelial cells (AECs), including multiciliated airway cells, derived from human induced pluripotent stem cells (iPSCs) on porcine atelocollagen vitrigel membranes, as a candidate of a therapeutic method for irreversible nasal epithelial disorders. To confirm the regenerative capacity of iPSC-derived AECs, we transplanted them into nasal cavities of nude rats. Although the transplanted cells were found within cysts isolated from the recipient nasal respiratory epithelia, they survived in some rats. Furthermore, the surviving cells were composed of multiple cell types similar to the human airway epithelia. The results could contribute to the development of novel transplantation-related technologies for the treatment of severe irreversible nasal epithelial disorders.Impact StatementNasal respiratory epithelia are important for the functions of nasal cavity, including humidifying the air and filtering various toxic substances. However, hereditary diseases, including primary ciliary dyskinesia and cystic fibrosis, can result in intractable dysfunction of the nasal mucosa. Our novel method to transplant airway epithelial cells derived from human induced pluripotent stem cells will be a candidate method to replace malfunctioned nasal respiratory epithelia in such a situation. To secure our method's safety, we used porcine atelocollagen vitrigel membranes, which prevent the immune response and bovine spongiform encephalopathy, as a scaffold.

We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.

We report lateral photoconductive properties of multilayer-stacked undoped InAs/GaAs quantum dots (QDs) for the application of photoconductive terahertz (THz) antenna devices that operate in a 1.5 μm-telecom-wavelength band. The excitation power-dependent photocurrent showed a high value without saturation under high excitation power for the excitation wavelength of 1460 nm. From the reflection pump-probe signal, a fast photocarrier lifetime was derived. These results, together with the low dark current characteristic, support the applicability of the multilayer-stacked undoped InAs/GaAs QDs to photoconductive THz antennas operating in a 1.5 μm-wavelength band.

Oxidative stress is implicated to play an important role in the development of diabetic vascular complications, including diabetic nephropathy. It is unclear whether oxidative stress is primarily enhanced in the diabetic glomeruli or whether it is merely a consequence of diabetes-induced glomerular injury. To address this issue, we examined diabetic glomeruli to determine whether oxidative stress is enhanced, as well as examined the role of protein kinase C (PKC)-β activation in modulating NADPH oxidase activity. Urinary 8-hydroxydeoxyguanosine excretion and its intense immune-reactive staining in the glomeruli were markedly higher in diabetic than in control rats, and these alterations were ameliorated by a treatment with a selective PKC-β inhibitor, ruboxistaurin (RBX; LY333531) mesylate, without affecting glycemia. NADPH oxidase activity, which was significantly enhanced in diabetic glomeruli and the source of reactive oxygen species (ROS) generation, was also improved by RBX treatment by preventing the membranous translocation of p47phox and p67phox from cytoplasmic fraction without affecting their protein levels. Adenoviral-mediated PKC-[β.sub.2] overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells. We now demonstrate that oxidative stress is primarily enhanced in the diabetic glomeruli due to a PKC-β-dependent activation of NADPH oxidase resulting in ROS generation., Increased oxidative stress has been shown in patients with diabetes (1,2) and has been implicated in the development and progression of diabetic microvascular complications, including diabetic nephropathy (3). Indeed, enhanced [...]

Purpose: We describe a pull-through pull-back technique to revascularize the left common carotid artery (LCCA) that was unintentionally covered during thoracic endovascular aortic repair (TEVAR).Case Report: A 69-year-old man presented with back pain secondary to acute type B aortic dissection with an intimal tear in the proximal descending aorta. Serial computed tomography (CT) revealed an enlarged descending aorta and proximal progression of the aortic dissection. He underwent left carotid-subclavian artery bypass and TEVAR, 10 days after admission. The Valiant Navion stent graft without a bare stent was deployed proximally; however, the LCCA was unintentionally covered by the stent graft during this procedure. A pull-through form was created between the left axillary and femoral arteries using a 0.035-inch guide wire. The pull-through guide wire was gently pulled, and the greater curvature of the proximal end of the stent graft was displaced distally. Angiography confirmed restoration of antegrade blood flow into the LCCA. The patient’s postoperative course was uneventful. Follow-up CT performed 6 months postoperatively confirmed preserved blood flow into the LCCA without endoleak nor stent migration.Conclusion: The pull-through pull-back technique is a feasible troubleshooting strategy for accidental coverage of supra-aortic vessels during TEVAR.

症例は22歳の女性。インターネットで購入したオオミフクラギの種子を自殺目的に摂取した。摂取から約12時間30分後，嘔吐・ふらつきを主訴に救急搬送された。来院時，興奮状態で嘔吐を繰り返しており，心拍数は54/分と徐脈で，心電図はMobitz II型房室ブロックであった。血清カリウム値は5.8mEq/Lと高カリウム血症を認めた。鎮静下に経口気管挿管・人工呼吸管理とし，高カリウム血症に対してグルコン酸カルシウムの静脈内投与とグルコース・インスリン療法を開始した。初療室で心室細動となったため，電気ショックを含めた心肺蘇生術を開始し，ECPR目的にVA–ECMOを導入した。ECPR施行後に心静止となったため，経静脈ペーシングも導入した。ICUに入室後は血液浄化療法でカリウムの補正に努めた。しかしながら，安定した自己心拍の再開は得られず，多臓器不全のため来院18時間後に死亡確認となった。オオミフクラギの種子は南アジアや東南アジアでは他殺や自殺目的に使用される自然毒として一般的である。その主たる毒性成分であるケルベリンは致死的な不整脈や高カリウム血症を惹起する高い心毒性を有することが知られている。そのうえ特異的な拮抗薬はなく，治療法も確立していない。我が国では報告例も少なく，非常に重篤な経過をたどる可能性が高いため，ケルベリン中毒を認知しておくべきと考える。 We report a case of fatality from ingestion of the seeds of Cerbera odollam（C. odollam）. The patient was a 22–year–old woman who ingested seeds of C. odollamto commit suicide and was transported to hospital in about 12 hours and 30 minutes. On admission, she was agitated and vomiting repeatedly, with a heart rate of 54 beats/minute and an electrocardiogram showing Mobitz type 2 atrioventricular block. A blood test revealed hyperkalemia. Endotracheal intubation and artificial respiration were performed, and intravenous administration of calcium gluconate and glucose/insulin therapy were started. Since ventricular fibrillation occurred during observation in the primary care unit, CPR was started, and VA–ECMO was introduced for ECPR. Since she became asystolic, intravenous pacing was commenced. After admission to the ICU, continuous hemodiafiltration was introduced to correct the raised potassium. However, the heartbeat did not recover, resulting in multiple organ failure, and she died 18 hours after her visit. The seeds of C. odollamhave been used for poisoning and suicide in South and Southeast Asia, and the main toxic component, cerberine induces fatal arrhythmias and hyperkalemia. There is no specific antidote for cerberine poisoning, and no treatment has been established. Although there are few reports in Japan, emergency physicians need to take initial measures in anticipation of a sudden change because it is readily available and can have a very serious outcome.

Improvement in metal mold characteristics such as wear resistance, corrosion resistance and mold releasability is essential for plastic molding. In this study, factors of the mold releasability were investigated by quantitative evaluations of adhesion forces between the processed metal mold surfaces and the molded resins in compression molding of thermosetting phenol resin. Die sinking EDM was employed as the processed surfaces of the metal molds. As the mold releasability tests, the molded thermosetting phenol resin onto the EDMed surface was pulled up in the perpendicular direction from the surface. Consequently, the mold releasability could be quantitatively evaluated by measuring a maximum tensile load which means a mold release force when the molded resin is separated from the EDMed surface.

Magnesium (Mg) alloys for metal electroplating require a surface pretreatment, i.e., the removal of the spontaneously oxidized surface layer (MgO, Mg(OH)2, and MgCO3). However, the use of highly toxic and/or corrosive acids in conventional pretreatment processes has become an issue. In this study, a facile and less toxic pretreatment is demonstrated and applied in aluminum (Al) electroplating. The immersion of the AZ31 Mg alloy into acetic anhydride (Ac2O) removed the spontaneously oxidized surface layer and formed a thin but stable magnesium acetate (Mg(OAc)2) layer that protects the metal substrate from further oxidation. The Al electroplating bath is a concentrated diglyme (G2)-AlCl3organic solution that can readily dissolve Mg(OAc)2to enable direct plating onto a metal substrate. The as-deposited Al layer has a compact and crack-free morphology that improves the corrosion resistance and hardness (2.7 GPa). Owing to the lack of an interfacial oxidized layer, heat treatment led to the successful diffusion of Mg and Al atoms, which increased the hardness to 4.4 GPa. The Ac2O pretreatment of Mg alloys enables the successful Al electroplating and subsequent heat treatment.

Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target.

Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation is a more promising treatment for out-of-hospital cardiac arrest (OHCA) than conventional cardiopulmonary resuscitation (CCPR). However, previous studies that compared ECPR and CCPR included mixed groups of patients with or without target temperature management (TTM). In this study, we compared the neurological outcomes of OHCA between ECPR and CCPR with TTM in all patients. We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed adult cases of cardiogenic OHCA treated with TTM were eligible for this study. We used univariate and multivariable analyses in all eligible patients to compare the neurological outcomes after ECPR or CCPR. We also conducted propensity score analyses of all patients and according to the interval from witnessed OHCA to reaching the target temperature (IWT) of ≤600, ≤480, ≤360, ≤240, and ≤120 minutes. We analyzed 1146 cases. The propensity score analysis did not show a significant difference in favorable neurological outcomes (defined as a Glasgow–Pittsburgh Cerebral Performance Category of 1–2 at 1 month after collapse) between EPCR and CCPR (odds ratio: OR 4.683 [95% confidence interval: CI 0.859–25.535], p= 0.747). However, ECPR was associated with more favorable neurological outcomes in patients with IWT of ≤600 minutes (OR 7.089 [95% CI 1.091–46.061], p= 0.406), ≤480 minutes (OR 10.492 [95% CI 1.534–71.773], p= 0.0168), ≤360 minutes (OR 17.573 [95% CI 2.486–124.233], p= 0.0042), ≤240 minutes (OR 38.908 [95% CI 5.045–300.089], p= 0.0005), and ≤120 minutes (OR 200.390 [95% CI 23.730–1692.211], p< 0.001). This study revealed significant differences in the neurological outcomes between ECPR and CCPR in patients with TTM whose IWT was ≤600 minutes.

ABSTRACTA cross-section adjustment method based on Bayesian theory was derived for adjusting the specific cross-section set. The present method gives the ‘a posteriori’ distribution of the specific cross-section and does not require the adjustment of the other cross-sections. In the derivation, the experimental error, calculation error, and cross-section error are assumed to distribute normally and to be independent of each other. The adjusted specific cross-sections and the covariance between them are the same as those obtained by the conventional cross-section adjustment method. In addition, the adjustment of covariance between the adjusted cross-section and the other cross-section is not necessarily required in the derivation. For introducing these features of the present method, the specific cross-sections were adjusted by using the criticality of the light-water moderated uranium benchmark. The result shows that the uncertainty of the multiplication factor is reduced by the present method, and the reduction is drastically smaller than that by the conventional method.

Over the past few decades, surgical outcomes of acute type A aortic dissection (ATAAD) have improved [1].

In recent times, disturbances, such as pandemics, natural disasters, and social unrest have put universities in unstable situations, affecting educational processes. The duration of unstable situations is unpredictable and can be weeks or years. Despite these disruptions, universities have to continue to fulfil their mission to educate young people. This paper discusses the notion of the resilient university with a particular focus on academic continuity. In order to investigate the migration to online learning under the COVID-19 pandemic and examine student and faculty perceptions and lessons learned, a literature study on resilient organizations and academic continuity and a case study of the World Maritime University (WMU) were undertaken. The case study employed two methods: a focus group (qualitative) and online questionnaire (quantitative and qualitative). The results show that in order to ensure academic continuity and build resilience, the university has to develop anticipation, coping, and adaptation capabilities and act on lessons learned. The research findings revealed the capability of a university in coping with the unexpected challenges and a potential to become a resilient university.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors were developed for treatment of renal anemia. Patients applicable for HIF-PHD inhibitor treatment experience complications such as chronic kidney disease, whereby water and electrolyte homeostasis is disrupted. The effects of hypoxia-inducible factor stabilization on salt accumulation in the setting of reduced renal function remain unclear. In the present study, we investigated the effect of a HIF-PHD inhibitor, molidustat, on salt distribution and excretion in rats with subtotal nephrectomy-induced chronic kidney disease. Male Wistar rats were subjected to 5/6 nephrectomy. After confirming blood pressure elevation (>150 mmHg, at 4 weeks after surgery), rats were treated with molidustat. After 1 week of treatment, molidustat did not significantly improve blood cell volume or blood pressure. Distribution of sodium, potassium, and water in skin, carcass, and bone samples was not affected by molidustat. Furthermore, molidustat had no significant effect on urinary sodium excretion or concentration in response to acute oral salt loading (1 g/kg). In conclusion, molidustat did not affect distribution or excretion of salt in rats subjected to a model of nephron loss.

Introduction Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities.Methods The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients’ body mass index (BMI) and visceral fat area (VFA).Results Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups (P= .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR (P= .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR (P= .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR (P= .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups (P= .017, < .001, and < .001, respectively).Conclusion LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.

AbstractWe developed a cross-section adjustment method based on Bayesian theory for adjusting the independent cross-section set that is given by dividing the cross-section set. While all cross sections have to be adjusted in the conventional cross-section adjustment method, the independent cross-section set can be individually adjusted in the developed method. In addition, the covariance of cross sections that are assumed to be independent of each other is not adjusted in the developed method. The adjusted cross sections and the covariance are the same in both methods. The cross-section adjustment was performed using the criticality of the light water–moderated uranium benchmark. The result shows that the uncertainty of the multiplication factor is reduced from 0.005 to 0.007 Δk/k to 0.003 to 0.005 Δk/k by the developed method. The reduction is smaller than that by the conventional method since the developed method does not adjust the covariance of cross sections that are assumed to be independent of each other.

•Single injection of α-syn PFF in the mice striatum induced the spreading of α-syn.•Low dose of MPTP (10 mg/kg.b.wt) further enhanced this spreading and neuronal death.•Low dose of MPTP in α-syn PFF injected mice causes significant motor deficit.•High dose of MPTP (25 mg/kg.b.wt.) reduced the spreading of α-syn.•High dose of MPTP caused nuclear translocation of α-syn.

Synthetic mRNA therapeutics have the potential to revolutionize healthcare, as they enable patients to produce therapeutic proteins inside their own bodies. However, convenient methods that allow external control over the timing and magnitude of protein production after in vivodelivery of synthetic mRNA are lacking. In this study, we validate the in vivoutility of a synthetic self-amplifying mRNA (RNA replicon) whose expression can be turned off using a genetic switch that responds to oral administration of trimethoprim (TMP), a US Food and Drug Administration (FDA)-approved small-molecule drug. After intramuscular electroporation, the engineered RNA replicon exhibited dose-dependent and reversible expression of its encoded protein upon TMP administration. The TMP serum level needed for maximal downregulation of protein translation was approximately 45-fold below that used in humans for therapeutic purposes. To demonstrate the therapeutic potential of the technology, we injected mice with a TMP-responsive RNA replicon encoding erythropoietin (EPO) and successfully controlled the timing and magnitude of EPO production as well as changes in hematocrit. This work demonstrates the feasibility of controlling mRNA kinetics in vivo, thereby broadly expanding the clinical versatility of mRNA therapeutics.

Background Hepatectomy has a high risk of perioperative bleeding due to the underlying disease. Here, we investigated the postoperative impact of allogeneic blood transfusion during hepatectomy.Methods The surgical outcomes in 385 patients who underwent hepatic resection for hepatocellular carcinoma were retrospectively reviewed. The association of allogeneic blood transfusion with surgical outcomes and remnant liver regeneration data was analyzed.Results Eighty-six patients (24.0%) received an allogeneic blood transfusion and 272 patients (76.0%) did not. After propensity score matching, the incidence rates of postoperative complication (Clavien-Dindo grade >IIIA), posthepatectomy liver failure, and massive ascites were significantly higher for the group that received a blood transfusion than for the group that did not receive blood transfusion (P< .001, P= .001, and <.001, respectively). Postoperative measures of total bilirubin, albumin, platelet count, prothrombin time, aspartate aminotransferase, and alanine aminotransferase were significantly more favorable in patients without blood transfusion until day 7 after surgery. There were no correlations in the remnant liver regeneration at 7 days, and 1, 2, 5, and 12 months postoperatively between the 2 groups (P= .585, .383, .507, .261, and .430, respectively). Regarding prognosis, there was no significant difference in overall and recurrence-free survival between the 2 groups (P= .065 and .166, respectively).Conclusion Allogeneic transfusion during hepatectomy strongly affected remnant liver function in the early postoperative period; however, this was not related to the remnant liver regeneration volume. Despite that the allogeneic transfusion resulted in poorer postoperative laboratory test results and increased postoperative complication and mortality rates, it had no effect on the long-term prognosis.

Due to the increasing pressure from stricter environmental regulations to reduce emissions in shipping, the maritime industry has been striving for finding more effective measures. Existing measures are often not enough to comply with new regulations. Among various alternative measures, it is not easy for decision-makers (shipowners and operators) to choose the most suitable alternative measure as it involves with multi-criteria decision-making where the prioritization of a number of alternatives vis-à-vis multiple criteria evaluation is undertaken. Further challenges on such analysis are the lack of information as well as its subjectivity and/or the inconsistency. This study proposes an integrative fuzzy multi-criteria decision-making method that combines fuzzy analytic hierarchy process (AHP) and fuzzy technique for order performance by similarity to ideal solution (TOPSIS) for the selection of technological alternatives for regulatory compliance under vague environment. Nine criteria within three sustainability aspects (social, economic and environmental aspects) were analysed and evaluated as regards four possible alternatives. The weights of these aspects and criteria were determined by the fuzzy AHP; meanwhile, alternatives were prioritized by the fuzzy TOPSIS. According to the outputs of the proposed decision-making framework, the study revealed that low-sulphur fuels are the best suitable alternative for regulatory compliance. The following alternatives are methanol, scrubbers and liquefied natural gas in order. Sensitivity analysis was conducted to tell us that the proposed framework is robust. This proposed method will be potentially applicable to other fields where decisions are required to make under vague information conditions.

AbstractThe void reactivity of a fuel assembly with a streaming channel was measured in a simulated light water reactor critical lattice. The void reactivity was defined as the difference of reactivity ρ between different void conditions. Stainless steel and Zircaloy are candidates for the streaming channel material. Aluminum was used in this measurement because it is inexpensive and its absorption cross section is similar to that of Zircaloy. Two types of streaming channels were used: one made of aluminum and the other made of stainless steel. The two streaming channels were compared in terms of the difference in void reactivity. Measured values were calculated using a continuous-energy Monte Carlo code, MCNP6.1, with the JENDL-4.0 and ENDF/B-VIII.0 nuclear data libraries. The measured values and the calculated values agree within an error range of approximately 10% for the aluminum streaming channel and approximately 20% for the stainless steel streaming channel. The streaming effect of reactivity was deduced from the changes of migration area and buckling, which were measured using the water-height coefficient of reactivity and the axial fission-rate distribution.

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.

偶発性低体温症による心肺停止の蘇生と体温管理に，veno–arterial extracorporeal membrane oxygenation （V–A ECMO）が有用だった症例を経験したので報告する。症例は73歳の女性。3月某日の昼前，側溝にはまっているところを発見され，救急要請となった。初期波形は心静止で，搬送中に心室細動となった。電気的除細動に抵抗性で，病院到着後も一貫して心室細動が持続した。膀胱温は23.3℃で，偶発性低体温症による難治性心室細動と考え，V–A ECMOを用いて心肺蘇生と復温を行う方針とした。救急隊接触から69分後にV–A ECMOを駆動開始し，救急隊接触から206分後に膀胱温が32℃に達したため，電気的除細動を行ったところ，心拍再開した。引き続き体温管理療法を行い，膀胱温34℃を24時間維持した。入院2日目にV–A ECMOは離脱できた。頭部CTでは散在性の脳梗塞を合併したものの，入院8日目には簡単な意思疎通が可能になり，入院9日目には意識レベルは清明まで改善した。心停止時間は最低206分間と長時間であったが，高度の低体温では神経学的予後が期待できる可能性があるので，心停止時間が長くとも，V–A ECMOを用いた管理を検討するべきである。 In March, an ambulance was called for a 73–year–old woman discovered in the gutter. The woman’s initial electrocardiogram showed asystole, which, during transportation, became ventricular fibrillation. Her condition was sustained even after arriving at the hospital; her bladder temperature was 23.3℃, and her condition was considered to be intractable ventricular fibrillation due to accidental hypothermia. We performed cardiopulmonary resuscitation and reheating using veno–arterial extracorporeal membrane oxygenation (V–A ECMO). Driving V–A ECMO was started after 69 minutes from the initial emergency service contact, given that the bladder temperature had reached 32℃. Defibrillation was performed 206 minutes after initial contact, and the normal heart rate was resumed. Targeted temperature management was continued, and on the second day of hospitalization, V–A ECMO was discontinued. Even though her head CT showed a scattered cerebral infarction, she was able to communicate easily on the eighth day, and her level of consciousness fully improved by the ninth day. Her cardiac arrest time was prolonged, with a minimum of 206 minutes, a neurological prognosis can be expected in severe hypothermia cases, and management using V–A ECMO should be considered.

Background Decision-making regarding the operability of thoracic aortic disease in nonagenarian patients remains controversial because outcomes of open surgical repair of the thoracic aorta are unclear. We investigated the surgical and nonsurgical outcomes of acute thoracic aortic syndrome treatment in nonagenarians.Methods After evaluating data in our institute from April 2016 to March 2020, we included 10 nonagenarians who needed surgical intervention on the thoracic aorta via a median sternotomy for acute thoracic aortic syndrome. The mean age of the cohort was 91.9 ± 2.1 years. Five patients underwent open surgical repair of the thoracic aorta (surgical group), and 5 refused surgery (nonsurgical group). All patients in the surgical group performed activities of daily living independently, with a mean clinical frailty scale of 3.2 ± 0.4. The surgical group included 4 patients with type A aortic dissection and one with a ruptured thoracic aortic aneurysm. Hemiarch replacement was performed in 3 patients and total arch replacement in 2. The mean follow-up period was 17.8 ± 5.1 months.Results Hospital mortality rates were 0% in the surgical and 80% in the nonsurgical group. The mean length of hospitalization was 28.4 ± 6.7 days in the surgical group. The 1-year survival rates were 100% in the surgical group and 20% in the nonsurgical group.Conclusion Open surgical repair for acute thoracic aortic syndrome via median sternotomy is a reasonable treatment option even in nonagenarians. Involvement of family members is important for decision-making to devise the optimal treatment strategy (surgical vs. medical).

ABSTRACTMacroautophagy/autophagy plays a vital role in the homeostasis of diverse cell types. Vascular endothelial cells contribute to vascular health and play a unique role in vascular biology. Here, we demonstrated that autophagy defects in endothelial cells induced IL6 (interleukin 6)-dependent endothelial-to-mesenchymal transition (EndMT) and organ fibrosis with metabolic defects in mice. Inhibition of autophagy, either by a specific inhibitor or small interfering RNA (siRNA) for ATG5(autophagy related 5), in human microvascular endothelial cells (HMVECs) induced EndMT. The IL6 level was significantly higher in ATG5siRNA-transfected HMVECs culture medium compared with the control HMVECs culture medium, and neutralization of IL6 by a specific antibody completely inhibited EndMT in ATG5siRNA-transfected HMVECs. Similar to the in vitrodata, endothelial-specific atg5knockout mice (Atg5 Endo; Cdh5-Cre Atg5 flox/flox mice) displayed both EndMT-associated kidney and heart fibrosis when compared to littermate controls. The plasma level of IL6 was higher in Atg5 Endo compared to that of control mice, and fibrosis was accelerated in Atg5 Endo treated with a HFD; neutralization of IL6 by a specific antibody inhibited EndMT and fibrosis in HFD-fed Atg5 Endo associated with the amelioration of metabolic defects. These results revealed the essential role of autophagy in endothelial cell integrity and revealed that the disruption of endothelial autophagy could lead to significant pathological IL6-dependent EndMT and organ fibrosis.Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; EndMT: endothelial-to-mesenchymal transition; HES: hematoxylin and eosin stain; HFD: high-fat diet; HMVECs: human microvascular endothelial cells; IFNG: interferon gamma; IL6: interleukin 6; MTS: Masson’s trichrome staining; NFD: normal-fat diet; siRNA: small interfering RNA; SMAD3: SMAD family member 3; TGFB: transforming growth factor β; TNF: tumor necrosis factor; VEGFA: vascular endothelial growth factor A

A concentrated aluminum chloride (AlCl3)–diglyme (G2) electrolyte is used to prepare hard and corrosion-resistant aluminum (Al) electrodeposited films. The Al electrodeposits obtained from the electrolyte with an AlCl3/G2 molar ratio x= 0.4 showed a void-free microstructure composed of spherical particles, in stark contrast to flake-like morphologies with micro-voids for lower x. Neutral complexes rarely exist in the x= 0.4 electrolyte, resulting in a relatively high conductivity despite the high concentration and high viscosity. Nanoindentation measurements for the Al deposits with >99% purity revealed that the nanohardness was 2.86 GPa, three times higher than that for Al materials produced through electrodeposition from a well-known ionic liquid bath or through severe plastic deformation. Additionally, the void-free Al deposits had a <100> preferential crystal orientation, which accounted for better resistance to free corrosion and pitting corrosion. Discussions about the compact microstructure and <100> crystal orientation of deposits obtained only from the x= 0.4 concentrated electrolyte are also presented.