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Objective: This study aims to assess the utility of newly developed objective methods for the evaluation of intracranial abnormal amyloid deposition using PET/CT histogram without use of cortical ROI analyses., Methods: Twenty-five healthy volunteers (HV) and 38 patients with diagnosed or suspected dementia who had undergone 18 F-FPYBF-2 PET/CT were retrospectively included in this study. Out of them, 11 C-PiB PET/CT had been also performed in 13 subjects. In addition to the conventional methods, namely visual judgment and quantitative analyses using composed standardized uptake value ratio (comSUVR), the PET images were also evaluated by the following new parameters: the skewness and the mode-to-mean ratio (MMR) obtained from the histogram of the brain parenchyma; Top20%-map highlights the areas with high tracer accumulation occupying 20% volume of the total brain parenchymal on the individual's CT images. We evaluated the utility of the new methods using histogram compared with the visual assessment and comSUVR. The results of these new methods between 18 F-FPYBF-2 and 11 C-PiB were also compared in 13 subjects., Results: In visual analysis, 32, 9, and 22 subjects showed negative, border, and positive results, and composed SUVR in each group were 1.11 ± 0.06, 1.20 ± 0.13, and 1.48 ± 0.18 (p < 0.0001), respectively. Visually positive subjects showed significantly low skewness and high MMR (p < 0.0001), and the Top20%-Map showed the presence or absence of abnormal deposits clearly. In comparison between the two tracers, visual evaluation was all consistent, and the ComSUVR, the skewness, the MMR showed significant good correlation. The Top20%-Maps showed similar pattern., Conclusions: Our new methods using the histogram of the brain parenchymal accumulation are simple and suitable for clinical practice of amyloid PET, and Top20%-Map on the individual's brain CT can be of great help for the visual assessment., (© 2024. The Author(s).)

Aims: Kidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors., Methods and Key Findings: Gene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis., Significance: Renal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

To maintain the oxygen supply, the production of red blood cells (erythrocytes) is promoted under low-oxygen conditions (hypoxia). Oxygen is carried by hemoglobin in erythrocytes, in which the majority of the essential element iron in the body is contained. Because iron metabolism is strictly controlled in a semi-closed recycling system to protect cells from oxidative stress caused by iron, hypoxia-inducible erythropoiesis is closely coordinated by regulatory systems that mobilize stored iron for hemoglobin synthesis. The erythroid growth factor erythropoietin (EPO) is mainly secreted by interstitial fibroblasts in the renal cortex, which are known as renal EPO-producing (REP) cells, and promotes erythropoiesis and iron mobilization. Intriguingly, EPO production is strongly induced by hypoxia through iron-dependent pathways in REP cells. Here, we summarize recent studies on the network mechanisms linking hypoxia-inducible EPO production, erythropoiesis and iron metabolism. Additionally, we introduce disease mechanisms related to disorders in the network mediated by REP cell functions. Furthermore, we propose future studies regarding the application of renal cells derived from the urine of kidney disease patients to investigate the molecular pathology of chronic kidney disease and develop precise and personalized medicine for kidney disease., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Background: The MitraClip G4 system is a new iteration of the transcatheter edge-to-edge repair system. We assessed the impact of the G4 system on routine practice and outcomes in secondary mitral regurgitation (2°MR)., Methods and results: Consecutive patients with 2°MR treated with either the MitraClip G2 (n=89) or G4 (n=63) system between 2018 and 2021 were included. Baseline characteristics, procedures, and outcomes were compared. Inverse probability of treatment weighting and Cox regression were used to adjust for baseline differences. Baseline characteristics were similar, except for a lower surgical risk in the G4 group (Society of Thoracic Surgeons Predicted Risk of Mortality ≥8: 38.1% vs. 56.2%; P=0.03). In the G4 group, more patients had short (≤2 mm) coaptation length (83.7% vs. 54.0%; P<0.001) and fewer clips were used (17.5% vs. 36.0%; P=0.02). Acceptable MR reduction was observed in nearly all patients, with no difference between the G4 and G2 groups (100% vs. 97.8%, respectively; P=0.51). The G4 group had fewer patients with high transmitral gradients (>5mmHg; 3.3% vs. 13.6%; P=0.03). At 1 year, there was no significant difference between groups in the composite endpoint (death or heart failure rehospitalization) after baseline adjustment (10.5% vs. 20.2%; hazard ratio 0.39; 95% confidence interval 0.11-1.32; P=0.13)., Conclusions: The G4 system achieved comparable device outcomes to the early-generation G2, despite treating more challenging 2°MR with fewer clips.

Background: A high score for controlling nutritional status (CONUT) due to poor nutritional status has been associated with adverse outcomes in patients with chronic heart failure. However, because little is known about the effect of CONUT score on mortality rates after transcatheter mitral valve repair, we evaluated nutrition screening tools for prognosis prediction in patients undergoing transcatheter mitral valve repair using the MitraClip TM system. Methods and Results: We retrospectively analyzed 148 patients with severe mitral regurgitation (MR) who underwent MitraClip TM implantation between April 2018 and April 2021. The preprocedural CONUT scores were assessed at the time of hospitalization, the primary outcome was all-cause death, and the analysis was of the mortality and incidence rates of cardiac events 1 year post-operation. Functional MR was of ischemic origin in the majority of patients (69.6%), with a mean left ventricular ejection fraction of 48.9±15.8%. Kaplan-Meier curves indicated that all-cause death was significantly worse in the high-CONUT score group than in the low-CONUT score group. Cox hazard analysis showed a significant association between all-cause death and CONUT score, as well as MitraScore. Conclusions: Preprocedural CONUT score, as well as MitraScore, in patients undergoing transcatheter edge-to-edge mitral valve repair may predict an increased risk of all-cause death. This knowledge should allow the heart team to accurately assess the clinical implications and prognostic benefits of the procedure in individual patients., Competing Interests: S.K. and M.I. are consultants at Abbott Medical in Japan. Y.J.A. is a member of Circulation Reports’ Editorial Team. The other authors have no conflicts of interest to declare., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

This study aimed to define basicervical and transcervical shear fractures using area classification and to determine the optimal osteosynthesis implants for them. The clinical outcomes of 1042 proximal femur fractures were investigated. A model of the proximal femur of a healthy adult was created from computed tomography images, and basicervical and transcervical shear fractures were established in the model. Osteosynthesis models were created using a short femoral nail with a single lag screw or two lag screws and a long femoral nail with a single lag screw or two lag screws. The minimum principal strains of the fracture surfaces were compared when the maximum loads during walking were applied to these models using finite element analysis software. Basicervical fractures accounted for 0.96% of all proximal femur fractures, 67% of which were treated with osteosynthesis; the failure rate was 0%. Transcervical shear fractures accounted for 9.6% of all proximal femur fractures, 24% of which were treated with osteosynthesis; the failure rate was 13%. Finite element analysis showed that transcervical shear fracture has high instability. To perform osteosynthesis, multiple screw insertions into the femoral head and careful postoperative management are required; joint replacement should be considered to achieve early mobility.

Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight., (© 2023. Springer Nature Limited.)

The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients with kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Furthermore, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: The aim of this study was to clarify whether worsening of independence in activities of daily living (ADL) and also difficulties in ADL are triggered by hospitalization in older patients with heart failure (HF) and whether difficulties in ADL can predict readmission for HF regardless of independence in ADL in these patients., Methods and Results: We enrolled 241 HF patients in the present multi-institutional, prospective, observational study. The patients were divided according to age into the non-older patient group (<75 years, n = 137) and the older patient group (≥75 years, n = 104). The Katz index and the Performance Measure for Activities of Daily Living-8 (PMADL-8) were used to evaluate independence and difficulties in ADL, respectively. The endpoint of this study was rehospitalization for HF. Independence as indicated by the Katz index at discharge was significantly lower than that before admission only in the older patient group, and the value of the PMADL-8 at discharge was significantly higher than that before admission (P < 0.001). In all patients, after adjusting for the Katz index and other variables, PMADL-8 score was a significant predictor of rehospitalization for HF (hazard ratio 1.50; 95% confidence interval 1.07-2.13; P = 0.021)., Conclusions: Worsening of both independence and difficulties in ADL was triggered by hospitalization in older HF patients, and difficulties in ADL were relevant factors for risk of rehospitalization regardless of independence in ADL. These findings indicate the importance of preventing not only decreased independence but also increased difficulties in ADL during and after hospitalization., Competing Interests: Conflict of interest: The authors certify that there are no conflicts of interest with any financial organizations regarding the material discussed in this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: No consensus exists on the efficacy of home-based cardiac rehabilitation (CR) in patients who have undergone transcatheter aortic valve implantation (TAVI). Additionally, there are no reports on home-based cardiac telemonitoring rehabilitation (HBTR) in patients after TAVI., Objective: We aimed to investigate the efficacy of HBTR in patients who have undergone TAVI., Methods: This single-center preliminary study introduced HBTR to patients after TAVI, and the efficacy outcomes of the rehabilitation method were compared to that of a historical control cohort. The historical control cohort (control group) consisted of 6 consecutive patients who underwent ordinary outpatient CR after TAVI from February 2016 to March 2020. Patients who participated in the HBTR program were only recruited after the TAVI procedure and before discharge between April 2021 and May 2022. In the first 2 weeks after TAVI, patients underwent outpatient CR and were trained using telemonitoring rehabilitation systems. Thereafter, patients underwent HBTR twice a week for 12 weeks. The control group performed standard outpatient CR at least once a week for 12 to 16 weeks. Efficacy was assessed using peak oxygen uptake (VO 2 ) prior to and after CR., Results: Eleven patients were included in the HBTR group. All patients underwent 24 HBTR sessions during the 12-week training period, and no adverse events were observed. The control group participants performed 19 (SD 7) sessions during the training period, and no adverse events were observed. Participants in the HBTR and control groups had a mean age of 80.4 (SD 6.0) years and 79.0 (SD 3.9) years, respectively. In the HBTR group, preintervention and postintervention peak VO 2 values were 12.0 (SD 1.7) mL/min/kg and 14.3 (SD 2.7) mL/min/kg (P=.03), respectively. The peak VO 2 changes in the HBTR and control groups were 2.4 (SD 1.4) mL/min/kg and 1.3 (SD 5.0) mL/min/kg (P=.64), respectively., Conclusions: Home-based CR using a telemonitoring system is a safe outpatient rehabilitation method. Its efficacy is not inferior to that of standard CR in patients who have undergone TAVI., Trial Registration: Japan Registry of Clinical Trials jRCTs032200122; https://jrct.niph.go.jp/latest-detail/jRCTs032200122., (©Kohei Ashikaga, Shunichi Doi, Kihei Yoneyama, Norio Suzuki, Shingo Kuwata, Masashi Koga, Naoya Takeichi, Satoshi Watanabe, Masaki Izumo, Keisuke Kida, Yoshihiro J Akashi. Originally published in JMIR Rehabilitation and Assistive Technology (https://rehab.jmir.org), 17.05.2023.)

Background: The MitraClip G4 system is the latest version of the transcatheter edge-to-edge repair (TEER) system for mitral regurgitation (MR). We aimed to investigate the impact of the new system on routine clinical practice and patient outcomes in the treatment of primary MR., Methods: Consecutive patients with primary MR who underwent TEER with either the MitraClip G2 or G4 between 2018 and 2021 were enrolled from a single center registry. Baseline clinical and echocardiographic characteristics as well as procedural and clinical outcomes up to 1 year were compared between groups. Technical and device success were defined in accordance with the Mitral Valve Academic Research Consortium criteria., Results: Among 71 patients with primary MR, 34 were treated with G2 and 37 were treated with G4. Patients treated with G4 had lower surgical risk (7.74 [5.04, 14.97] vs. 5.26 [3.98, 6.40]; p < 0.01) than those with G2. There were no significant differences in other baseline clinical variables between groups. On baseline echocardiography, MR volume and flail gap were significantly greater in the G4 group than in the G2 group (regurgitant volume: 63 [41-76] mL vs. 68 [62-84] mL; p = 0.04, flail gap: 4.5 [3.5-5.5] mm vs. 5.4 [4.5-7.1] mm; p = 0.04). Technical success was achieved in over 95% of both groups with no significant difference ( p > 0.99). Device success was achieved in 61.8% of the G2 group, while in 70.3% of the G4 group ( p = 0.47). Post-procedural MR severity was comparable ( p = 0.42) and there was no significant difference in the occurrence of mitral stenosis ( p = 0.61) between groups. Among patients who reached 1-year follow-up (n = 54), there was no significant difference between groups in a composite endpoint of death or heart failure rehospitalization (10.5% vs. 20.2%; HR 0.61; 95% CI 0.17-2.22; p = 0.45). Residual heart failure symptoms (NYHA ≥ 3) at 1 year were observed in 3.7% of the G2 group, while no patient in the G4 group ( p > 0.99)., Conclusions: The MitraClip G4 system achieved comparable device outcomes to the early-generation device (G2), despite treating more severe primary MR with a larger flail gap., Competing Interests: T. Okuno reports personal fees from Abbott and Medtronic, outside the submitted work. M Izumo is a clinical proctor of Abbott Medical Japan and a screening proctor of Edwards Lifesciences. S Kuwata is a clinical proctor of Abbott Medical Japan. All other authors have no conflicts of interest to declare., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Nutrition in the cardiovascular field to date has focused on improving lifestyle-related diseases such as hypertension and diabetes from the viewpoint of secondary prevention. For these conditions, "nutrition for weight loss" is recommended, and nutritional guidance that restricts calories is provided. On the other hand, in symptomatic Stage C and D heart failure, it is known that underweight patients who manifest poor nutrition, sarcopenia, and cardiac cachexia have a poor prognosis. This is referred to as the "Obesity paradox". In order to "avoid weight loss" in patients with heart failure, a paradigm shift to nutritional management to prevent weight loss is needed. Rather than prescribing uniform recommendation for salt reduction of 6 g/day or less, awareness of the behavior change stage model is attracting attention. In this setting, the value of salt restriction will need to be determined to determine the priority level of intervention for undernutrition versus the need to prevent congestive signs and symptoms. In the Intensive Care Unit (ICU)/Cardiac Care Unit (CCU) for acute heart failure, nutritional intervention should be considered within 48 h of admission. Key points are selection of access route, timing of intervention, and monitoring of side effects. In nutritional management at home and in end-of-life care, food is a reflection of an individual's values, as well as a source of joy and encouragement. The importance of digestive tract should also be recognized in heart failure from oral flail to intestinal edema, constipation, and the intestinal bacteria called the heart-gut axis. Finally, we would like to propose a new term "heart nutrition" for nutritional management in patients with heart failure in this review. Compared to the evidence for exercise therapy in heart failure, studies assessing nutritional management remain scarce and there is a need for research in this area in the future., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Treatment methods for proximal femoral fractures, when the fractures run from the femoral basal neck to the subtrochanteric area, have not yet been fully reported. Thus, we aimed to clarify osteosynthesis methods based on the fracture frequency and clinical results. We classified the proximal femoral fractures using the Area classification method based on the location (area) of the fracture line. The proximal femur has 4 areas with 3 boundaries; the center of the femoral neck, the boundary between femoral neck and trochanter, and the plane connecting the lower ends of the greater trochanter and the lesser trochanter. Fractures occurring only in Area-1 (proximal from the center of the femoral neck) were classified as Type 1; those in both Areas 1 and 2 (base of the femoral neck) were classified as Type 1-2. Therefore, fractures running from femoral basal neck to the subtrochanteric area were classified as Type 2-3-4. We targeted 60 Type 2-3-4 cases (average age 81 years, 10 men, 50 women) out of 1042 proximal femoral fracture cases who visited 8 hospitals in 2 years. We investigated the presence or absence of lateral trochanteric wall fractures, the selection of internal fixator, and the proportion of poor results. The lateral trochanteric wall fracture was observed in 48% of subjects. Long nails were selected to treat 46% cases, and nails with 2 or 3 proximal lag screws were used in 58% cases. Long nails and those with 2 or 3 lag screws were also used in 59% and 69% of lateral trochanteric wall fractures. Poor results such as cutout or excessive telescoping of lag screw occurred in 11.7% of cases and 17.2% of lateral trochanteric wall fractures. Even in cases where long nails and multiple lag screws were used for femoral trochanteric fractures whose fracture line ran from the femoral basal neck to subtrochanteric area were used, the failure rate was high in the presence of a lateral wall fracture. Therefore, it is necessary to consider careful post-operative treatment for proximal femoral fractures with lateral wall fracture, whose fracture line runs from femoral basal neck to subtrochanteric area., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hypoxia-inducible factor (HIF) activators aid the treatment of renal anemia and ischemia. Recently, PyrzA (5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid), a HIF activator by PHD inhibition without a 2-oxoglutarate moiety was reported. However, PyrzA has low lipophilicity, and it was necessary to improve its solubility by synthesizing derivatives. In this study, we synthesized and evaluated a higher lipophilic derivative of PyrzA and found that it exhibited higher HIF activity and stabilizing ability at low concentrations compared to Roxadustat, a commercially available HIF activator., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.U. is a chief operation officer, and S-i.K. and T.T. are advisory members for Tetra Create Co., Ltd. All other authors declare no conflicts of interest. Compounds 1a and 9c are available from Tetra Create Co., Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Lower leg strength at hospital discharge is strongly associated with poor prognosis in older patients with acute decompensated heart failure (ADHF). Improving leg strength is important in acute-phase cardiac rehabilitation (CR)., Aims: This study aimed to clarify whether a change in leg strength occurs during hospitalization of older ADHF patients receiving CR and whether it affects leg strength at discharge., Methods and Results: We enrolled 247 ADHF patients who underwent CR during hospitalization. They were divided into the non-older patient group (&lt;75 years; n = 142) and older patient group (≥75 years; n = 105). Quadriceps isometric strength (QIS), body mass-corrected QIS (%BM QIS), and change in QIS during hospitalization (QIS ratio) were evaluated in all patients. Physical function in the stable phase was measured by the Performance Measure for Activities of Daily Living-8 (PMADL-8). The QIS value increased during hospitalization in the non-older patient group (30.0 ± 11.1 vs. 31.6 ± 10.9 kgf, P &lt; 0.001) but did not increase in the older patient group (19.1 ± 6.3 vs. 19.5 ± 6.1 kgf, P = 0.275). Multiple regression analysis revealed that PMADL-8 significantly predicted %BM QIS at discharge in the non-older patient group (β = -0.254, P = 0.004), whereas in the older patient group, QIS ratio and PMADL-8 significantly predicted %BM QIS at discharge (β = 0.264, P = 0.008 for QIS ratio and β = -0.307, P = 0.003 for PMADL-8)., Conclusions: Leg strength was not improved in older ADHF patients during hospitalization even if they received CR, and this affected leg strength at discharge, suggesting that careful skeletal muscle intervention should be provided during hospitalization, and patients need to continue exercise after discharge., Competing Interests: Conflicts of interest: The authors declare that there is no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: We present results of a 24-week comparative study of the effects of the sodium−glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m2 vs. BMI < 25 kg/m2. Results: A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 (p = 0.940) for the subgroup with BMI ≥ 25 kg/m2 and 0.85 (p = 0.075) for the subgroup with BMI < 25 kg/m2, respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m2 showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group (p = 0.295); that difference was not seen among patients with BMI ≥30 kg/m2 (p = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. Conclusion: There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669.

Background: D-dimer levels can predict ischemic stroke in patients with acute heart failure (AHF). However, the effects of direct oral anticoagulants on D-dimer levels have not been investigated during admission for AHF in patients with atrial fibrillation (AF). This study examined D-dimer levels immediately after admission and following edoxaban initiation as a sub-analysis of a multi-center study that investigated the pharmacokinetics and pharmacodynamics of edoxaban in patients with nonvalvular AF (NVAF) and AHF., Methods: Hospitalized patients with NVAF and AHF received edoxaban according to the label. The primary measure was the change in D-dimer levels on 7 consecutive days after admission for AHF. We also investigated differences according to prior edoxaban use (de novo at the time of admission or continuation)., Results: In 10/13 (76.9%) de novo patients, D-dimer levels exceeded the reference value (1.0 µg/mL) at admission (mean, 2.12 µg/mL) and subsequently decreased in 9 patients (at final blood sampling: mean, 1.12 µg/mL); 1 patient did not fall below the reference value due to stasis dermatitis. In the continuation group, most patients had D-dimer levels below the reference value from Day 1 (mean, 0.93 µg/mL), and levels remained stable or decreased (at final blood sampling: mean, 0.49 µg/mL). No events of stroke were observed., Conclusions: D-dimer levels may be elevated in patients with NVAF and AHF, particularly in those without prior anticoagulant treatment. Edoxaban may be effective for lowering and keeping D-dimer levels, a biomarker for predicting ischemic stroke, below the reference value in patients with NVAF and AHF., (Copyright © 2022. Published by Elsevier Ltd.)

Diagnostic reasoning is the thought process used to arrive at a diagnosis based on symptoms, examination findings, and laboratory values. Diagnosis is categorized as nonanalytic reasoning (intuition) and analytic reasoning (analysis). Rehabilitation nutrition involves the diagnosis of nutritional disorders, sarcopenia, and excess or deficient nutrient intake. There is usually only one correct answer for the presence or absence of these. On the other hand, there may be no single correct answer for the causes of anorexia, weight loss, or sarcopenia, and analytical reasoning is required. In this case, diagnostic reasoning involves hypotheses. Simply using nutritional supplements without performing diagnostic reasoning about these causes is like prescribing antipyretic analgesics to a patient with a headache without diagnosing the cause of the headache. To maximize function and quality of life in rehabilitation nutrition, it is necessary to suspect the common causes of anorexia, weight loss, and sarcopenia in all cases., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Hypoxia-inducible factor-α (HIF-α) activation has shown promising results in the treatment of ischemia, such as stroke, myocardial infarction, and chronic kidney disease. A number of HIF-α activators have been developed to improve the symptoms of these diseases. Many feature 2-oxoglutarate (2-OG) scaffolds that interact with the active centers of prolyl hydroxylase domain-containing proteins (PHDs), displacing the coenzyme 2-OG. This stabilizes HIF-α. Therefore, the specificity of the 2-OG analogs is not high. Here, we identified 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid (PyrzA) among over 10 000 compounds as a novel HIF activator that does not contain a 2-OG scaffold. In cultured cells, PyrzA enhanced HIF-α stability and upregulated the expression of HIF target genes. Interestingly, PyrzA decreased HIF-1α prolyl hydroxylation, suggesting that PyrzA may activate HIF to prevent the degradation of HIF-α. These results indicate that PyrzA stabilizes HIF via a novel mechanism and could be a potential HIF activator candidate., Competing Interests: The authors declare the following competing financial interest(s): S-i.K. and T.T. are advisory members for Tetra Create Co., Ltd. All other authors declare no conflicts of interest., (© 2022 American Chemical Society.)

Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: It is recommended that patients with myocardial infarction (MI) be prescribed exercise by target heart rate (HR) at the anaerobic threshold (AT) via cardiopulmonary exercise testing (CPX). Although percent HR reserve using predicted HRmax (%HRRpred) is used to prescribe exercise if CPX or an exercise test cannot be performed, %HRRpred is especially difficult to use when patients take β-blockers. We devised a new formula to predict HR at AT (HRAT) that considers β-blocker effects in MI patients and validated its accuracy., Methods: The new formula was created using the data of 196 MI patients in our hospital (derivation sample), and its accuracy was assessed using the data of 71 MI patients in other hospitals (validation sample). All patients underwent CPX 1 mo after MI onset, and resting HR, resting systolic blood pressure (SBP), and HRAT were measured during CPX., Results: The results of multiple regression analysis in the derivation sample gave the following formula (R2 = 0.605, P < .001): predicted HRAT = 2.035 × (≥65 yr:-1, <65 yr:1) + 3.648 × (body mass index <18.5 kg/m2:-1, body mass index ≥18.5 kg/m2:1) + 4.284 × (β1-blocker(+):-1, β1-blocker(-):1) + 0.734 × (HRrest) + 0.078 × (SBPrest) + 36.812. This formula consists entirely of predictors that can be obtained at rest. HRAT and predicted HRAT with the new formula were not significantly different in the validation sample (mean absolute error: 5.5 ± 4.1 bpm)., Conclusions: The accuracy of the new formula appeared to be favorable. This new formula may be a practical method for exercise prescription in MI patients, regardless of their β-blocker treatment status, if CPX is unavailable., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The aim of this study was to examine the neuropsychological factors that may be related to the impaired gesture imitations in patients with dementia., Methods: The imitation of unilateral finger and bimanual gestures was evaluated in 162 patients with Alzheimer's disease (AD) and 103 patients with dementia with Lewy bodies (DLB). The relationships of gesture imitation performance to global cognition, semantic fluency, phonemic fluency, figure copying, clock drawing, and trail-making test part A (TMT-A) scores were examined., Results: Mean scores for unilateral finger imitation were significantly lower in DLB patients than in AD patients, and significantly more DLB patients showed impaired performance in unilateral finger imitation than AD patients. In contrast, the percentage of patients with impaired bimanual gesture imitation was not significantly different between AD and DLB patients. Unilateral finger imitation performance was predicted by pentagon copying in the AD patients, and was predicted by cube copying in the DLB patients. Bimanual gesture imitation performance was predicted by TMT-A scores and phonemic fluency in the AD patients but was predicted by TMT-A scores, cube copying, and parkinsonism severity in the DLB patients., Discussion: Our study suggested that bimanual gesture imitation is a complex task that is supported by a wide range of neuropsychological processes, such as visuospatial attention, executive function, and visuomotor control, and therefore, it was easily impaired in early dementia. Unilateral finger imitation was more similar to constructional tasks, such as figure drawing, and was impaired more often in DLB patients than in AD patients., (© 2021 John Wiley & Sons Ltd.)

Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses., (© 2021. The Author(s).)

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Heme oxygenase 1 (HO-1) is the key enzyme for heme catabolism and cytoprotection. Whereas HO-1 gene expression in response to various stresses has been investigated extensively, the precise mechanisms by which HO-1 gene expression is regulated by the HO-1 substrate heme remain elusive. To systematically examine whether stress-mediated induction and substrate-mediated induction of HO-1 utilize similar or distinct regulatory pathways, we developed an HO-1-DsRed-knock-in reporter mouse in which the HO-1 gene is floxed by loxP sites and the DsRed gene has been inserted. Myeloid lineage-specific recombination of the floxed locus led to fluorescence derived from expression of the HO-1-DsRed fusion protein in peritoneal macrophages. We also challenged general recombination of the locus and generated mice harboring heterozygous recombinant alleles, which enabled us to monitor HO-1-DsRed expression in the whole body in vivo and ex vivo . HO-1 inducers upregulated HO-1-DsRed expression in myeloid lineage cells isolated from the mice. Notably, analyses of peritoneal macrophages from HO-1-DsRed mice lacking NRF2, a major regulator of the oxidative/electrophilic stress response, led us to identify NRF2-dependent stress response-mediated HO-1 induction and NRF2-independent substrate-mediated HO-1 induction. Thus, the HO-1 gene is subjected to at least two distinct levels of regulation, and the available lines of evidence suggest that substrate induction in peritoneal macrophages is independent of CNC family-based regulation.

Background: Atrial fibrillation (AF) is a common arrhythmia in patients with acute heart failure (AHF). Heart rate (HR) also changes significantly over time. However, the association between changes in HR in AF patients and prognosis is uncertain., Methods and results: We investigated the association between HR reduction in AF achieved within 48 h of admission and 60-day mortality in patients with AHF from the REALITY-AHF study. The percentage HR (%HR) reduction was calculated as (baseline HR-HR at 48 h) / baseline HR × 100. The primary endpoint was 60-day all-cause mortality. In 468 patients with confirmed AF at both admission and 48 h after admission, the median HR at these time points was 105±31 and 84±18 beats/min, respectively. The median %HR reduction was 15.4% (interquartile range 2.2-31.4%). During the 60 days of admission, 39 deaths (8.3%) were recorded, and the %HR reduction within 48 h was significantly associated with 60-day mortality in the unadjusted model (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.77-0.95; P=0.005) and after adjusting for other covariates (HR 0.81; 95% CI 0.68-0.96; P=0.016).Furthermore, the %HR reduction was associated with a significant reduction in 60-day mortality in patients with higher baseline HR., Conclusions: %HR reduction is associated with a better short-term prognosis in patients with AHF presenting with AF, particularly in those with a rapid ventricular response.

Renal interstitial fibroblasts are responsible for producing the erythroid growth factor Epo and the vasopressor renin in addition to kidney fibrosis, in which they are transformed into myofibroblasts. Therefore, analyses of fibroblasts may elucidate the complex mechanisms of kidney diseases. However, the fragility of these cells makes their isolation for in vitro analyses and ex vivo cultivation difficult. We have overcome these difficulties by mildly dissociating mouse kidneys and coculturing fibroblasts with other kidney cells in semisolid medium. For complete details on the use and execution of this protocol, please refer to Sato et al. (2019a) and Miyauchi et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. Aims/Objectives: This study aims to identify a mechanism to target for the future treatment of AERD via the elucidation of the effect of systemic steroids on the expression of hematopoietic prostaglandin D 2 synthase (HPGDS) and chemotaxic prostaglandin D 2 (DP2) receptor relative to eosinophil activation in the nasal polyps of patients with AERD., Materials and Methods: Among 37 patients undergoing endoscopic sinus surgery, 28 received systemic steroids preoperatively. Nasal polyps were harvested from all 37 patients. After routine processing of paraffin sections, immunohistochemistry was performed using specific antibodies for HPGDS, eosinophil peroxidase (EPX), and DP2., Results: Expression of HPGDS, DP2, and EPX by eosinophils was higher and more frequent in patients with non-preoperative steroid therapy. Likewise, HPGDS and DP2 were highly expressed in activated eosinophils in the nasal polyps, but not in normal eosinophils., Conclusion and Significance: This study provides clear evidence that systemic steroid therapy inhibits eosinophil activation and decreases HPGDS and DP2 expression in patients with AERD, indicating a reduction in prostaglandin D 2 production and hence control hyperplasia of nasal polyps.

Pericytes play an important role in the recovery process after ischemic injury of many tissues. Brain pericytes in the peri-infarct area express macrophage markers in response to injury stimuli and are involved in neovascularization. In the kidney, nerve/glial antigen 2 (NG2) + pericytes have been found to accumulate after renal injury. These accumulated NG2 + cells are not involved in scar formation. However, the role of accumulated NG2 + cells in injured kidneys remains unknown. Here, using a reversible ischemia-reperfusion (I/R) model, we found that renal NG2 + cells were increased in injured kidneys and expressed macrophage markers (CD11b or F4/80) on day 3 after reperfusion. Isolated NG2 + cells from I/R kidneys also had phagocytic activity and expressed anti-inflammatory cytokine genes, including mannose receptor and IL-10. These macrophage-like NG2 + cells did not likely differentiate into myofibroblasts because they did not increase α-smooth muscle actin expression. Intravenous transfusion of renal NG2 + cells isolated from donor mice on day 3 after reperfusion into recipient mice on day 1 after I/R surgery revealed that NG2 + cell-injected mice had lower plasma blood urea nitrogen, reduced kidney injury molecule-1 mRNA expression, ameliorated renal damage, and reduced cellular debris accumulation compared with PBS-injected mice on day 5 after reperfusion. In conclusion, these data suggest that renal NG2 + cells have an M2 macrophage-like ability and play a novel role in facilitating the recovery process after renal I/R injury. NEW & NOTEWORTHY Brain pericytes have macrophage-like activities after injury. However, such properties of pericytes in peripheral tissues have not been investigated. Here, we provide evidence that nerve/glial antigen 2-positive cells increase after renal injury. The population of nerve/glial antigen 2-positive cells, which does not increase expression of myofibroblast-associated gene, express macrophage markers and anti-inflammatory cytokine genes, have phagocytic activity, and play a role in renal recovery after kidney injury.

Objective: The objective of this study was to assess the pharmacokinetic and pharmacodynamic profiles and safety of edoxaban in patients with nonvalvular atrial fibrillation (NVAF) who were hospitalized with acute heart failure (AHF)., Methods: The trough plasma concentrations of edoxaban, and the coagulation biomarkers prothrombin fragments 1 and 2 (F1+2) and D-dimer, were determined. Twenty-six patients received edoxaban 60 mg (30 mg when dose adjustment was required) and blood samples were collected immediately before oral edoxaban administration for 7 consecutive days after hospitalization and on the day of discharge., Results: The mean observation period was 13 (range 7-46) days. Trough plasma concentrations of edoxaban were constant from day 2 onwards. On day 1, the variation was greater owing to the differing intervals between the last edoxaban dose and day 1 blood collection. Trough plasma concentrations were higher in patients with reduced creatinine clearance (≤ 50 mL/min). Median values for F1+2 and D-dimer remained within normal ranges throughout the study. There were no drug discontinuations, and no serious adverse events were reported., Conclusions: This is the first study of edoxaban pharmacokinetics and pharmacodynamics in patients with NVAF and AHF, and shows that the pharmacokinetic and pharmacodynamic profiles of edoxaban were constant during hospitalization. Thus, even in patients with NVAF and AHF, edoxaban anticoagulation therapy with guided dose adjustment is considered to be a safe and appropriate intervention. In particular, patients with reduced creatinine clearance should adhere to dose adjustment criteria., Clinical Trial Registration: jRCTs031190006 (Japan Registry of Clinical Trials), 5 April, 2019 retrospectively registered., (© 2021. The Author(s).)

Preoperative frailty diminishes the potential for functional recovery after transcatheter aortic valve implantation (TAVI). However, perioperative changes in physical status and their impact on prognosis after TAVI have not previously been reported. Therefore, this study aimed to investigate whether perioperative changes in physical function affect prognosis in patients undergoing TAVI. We retrospectively reviewed 257 patients who underwent TAVI. The Short Physical Performance Battery (SPPB), an objective physical status assessment tool, was evaluated pre- and post-TAVI. Patients were divided into two groups: (i) patients whose SPPB score declined in the perioperative period (the decline group) and (ii) patients whose SPPB score did not decline in the perioperative period (the non-decline group). The primary endpoint was unplanned hospitalization owing to heart failure or cardiovascular death following TAVI. The mean follow-up period was 385 ± 151 days, mean age was 83.2 ± 5.8 years, and 67% of the patients were women. Sixteen patients required readmission owing to heart failure, and seven experienced cardiovascular-related death. Kaplan-Meier analysis revealed that the event-free rate was significantly lower in the decline group (log-rank, p = 0.006). A stepwise multivariate logistic regression analysis showed that a perioperative change in SPPB was significantly associated with primary endpoints (odds ratio, 1.51; 95% confidence interval, 1.12-2.04). Perioperative change in physical function was an independent risk factor for heart failure, hospitalization, or cardiovascular death following TAVI.

Background: Individuals undergoing rehabilitation often experience nutritional problems such as malnutrition, but there are no clinical practice guidelines (CPGs) specifically tailored to the combination of rehabilitation and nutritional care for these patients. The Japanese Association for Rehabilitation Nutrition aimed to develop CPGs for rehabilitation nutrition to support clinical decision making in daily practice., Methods: A CPG committee and development process based on the Grading of Recommendations Assessment, Development and Evaluation system and the Minds Handbook for Clinical Practice Guideline Development 2014 was established. Four clinical questions were defined for patients undergoing rehabilitation for cerebrovascular disease, hip fracture, cancer, and acute illness. Literatures of randomised control trials (RCTs) up to April 2020 were searched for using the MEDLINE, EMBASE, CENTRAL, and Ichushi-web databases. After screening, full-text papers were assessed for eligibility for analysis. Subsequently, studies included in the systematic review were examined regarding their risk of bias, and underwent meta-analyses. A CPG development committee drafted the guidelines based on the systematic review report. Final recommendations were determined by the panel members., Results: Four recommendations were made based on 4 to 9 RCTs for each disease/condition. The certainty of the evidence ranged from very low to low. Overall, the enhanced nutritional care was weakly recommended for rehabilitation patients with cerebrovascular disease, hip fracture, cancer, and acute illnesses., Conclusions: This CPG provides tentative recommendations for nutritional care of individuals undergoing rehabilitation. Due to low certainty of evidence and small sample sizes of the included studies, more high-quality and larger RCTs are needed to develop more practical CPGs., Competing Interests: Declaration of competing interest All members of the CPG Committee declare having a conflict of interest (COI) prior to developing this CPG. This includes both financial and academic COIs. The financial COIs included: employment and/or advisory roles; shareholdings and their profits; patent royalties; honoraria; payment for the manuscript; scholarship; research funding; donations for the course of the university; and others, including travel expenses and gifts not connected to research. Academic COIs included: affiliations; side jobs; specialties; affiliated academic societies; authorship of published articles regarding rehabilitation nutrition CPG; and experience developing a CPG other than the current CPG. The following COIs were reported: 1) Financial COIs. Hidetaka Wakabayashi received honoraria from Clinico Co. Ltd. and Nestle Japan Co. Ltd. Kenji Omura received honoraria from Otsuka Pharmaceutical Factory Co. Ltd. Committee of Clinical Practice Guideline, Japanese Association of Rehabilitation Nutrition, involved a member employed by the Department of Disaster and Comprehensive Medicine, Fukushima Medical University, endowed by Kowa Yakuhin Co. Ltd. and Toshiba Corporation. The other authors have no financial conflicts of interest to declare. 2) Academic COIs. Shinta Nishioka, Ryo Momosaki, Atsushi Fujimoto, Hidetaka Wakabayashi, and five other members of the Committee of Clinical Practice Guidelines, Japanese Association of Rehabilitation Nutrition have authorship of published articles regarding nutritional rehabilitation CPGs. Yayoi Kanehisa, Hideki Aragane, Yuki Iida, Yoshimasa Ishii, Hidetaka Wakabayashi, and 11 other members of the Committee of Clinical Practice Guideline, Japanese Association of Rehabilitation Nutrition, and 2 external reviewers had prior experience of developing CPGs other than the current CPG. The other authors have no academic conflicts of interest to declare., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Erythropoietin (EPO) is an essential growth factor for erythroid cells and is mainly secreted from the kidneys and subsidiarily from the livers of adult mammals in an anemia/hypoxia-inducible manner., Aim and Method: To elucidate the regulatory mechanisms of stress-inducible and cell type-specific Epo gene transcription, the rate-limiting step of EPO production, we investigated the sufficiency of a 180-kb genomic fragment flanking the mouse Epo gene locus for recapitulating endogenous Epo gene function by a transgene complementation strategy., Key Findings: While Epo gene-deficient mice exhibited lethal anemia in utero with defects in erythroblast proliferation and maturation, Epo-knockout mice integrated with the 180-kb Epo transgene showed normal erythropoiesis throughout life. In the transgene-rescued mice, liver-specific deletion of the transgene by the Cre-loxP recombination system caused neonatal anemia with erythropoietic defects in the liver but not in the spleen, indicating the essential function of hepatic EPO on normal erythropoiesis in the liver, which is the major erythropoietic site in late embryonic and neonatal stages., Significance: These results demonstrate that the 180 kb Epo gene flanking region contains the fully functional Epo gene unit and that EPO from the liver dominantly stimulates hepatic erythropoiesis but contributes less to erythropoiesis in other organs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown., Methods and Findings: We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure., Interpretation: Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin., Funding: Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation., Competing Interests: Declaration of Competing Interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Teriparatide is sometimes used in the treatment of atypical femoral fracture (AFF). Even if bone union is achieved, orthopedic physicians must consider the risk of relapse. This study aimed to investigate the factors affecting AFF recurrence, and to determine the appropriate treatment for osteoporosis after bone union., Methods: One hundred thirty-one consecutive AFFs in 113 Japanese patients were included. Eleven patients had AFF in the unaffected limb (9 patients) after the first AFF or re-fracture at the original fracture site (2 patients) after bone union of the first AFF was confirmed. We divided all patients into two groups: the second fracture group (22 AFFs in 11 patients) and non-second fracture group (109 AFFs in 102 patients). We compared clinical information between the 2 groups and investigated the factors affecting AFF recurrence using the Student t-, Welch t-, and chi-square tests., Results: Although there was no significant difference in clinical characteristics between the 2 groups, multivariate analysis of factors associated with AFF recurrence identified short duration of treatment with teriparatide and active vitamin D 3 (p = 0.0408 and 0.0366, respectively) as risk factors. Even in the analysis excluding subtrochanteric AFF, short periods of teriparatide and active vitamin D 3 administration were observed as risk factors (p = 0.0484 and 0.0346, respectively)., Conclusion: The administration of teriparatide for as long as possible after occurrence first AFF and the use of active vitamin D 3 after completion of teriparatide therapy may be the most effective strategy to prevent the recurrence of AFF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Differences in mechanisms of subtrochanteric and diaphyseal atypical femoral fractures (AFFs) are speculated in studies that analyzed differences in the patients' background. However, the etiologies of each type of AFF have not been studied in detail. This study aimed to investigate the nature and etiologies of the risk factors for diaphyseal AFFs., Materials and Methods: Eighty consecutive Japanese patients with 91 diaphyseal AFFs (AFF group) and 110 age-matched women with osteoporosis (non-AFF control group) were included. Their clinical data were compared; factors affecting AFFs were investigated, and the etiologies of the risk factors for diaphyseal AFFs were examined., Results: Multivariate analysis revealed that femoral serrated changes, bisphosphonate or denosumab usage, and lateral and anterior femoral curvatures were risk factors for diaphyseal AFFs (p < 0.0011, p = 0.0137, and p < 0.0001, respectively). Multivariate analyses revealed that serrated changes and low serum 25(OH)D levels affected the lateral curvature (p = 0.0088 and 0.0205, respectively), while serrated changes affected the anterior curvature (p = 0.0006), each significantly affected the femoral curvature. High serum calcium (Ca) levels, lateral femoral curvature, and anterior femoral curvature were predictors of serrated changes (p = 0.0146, 0.0002, and 0.0098, respectively)., Conclusion: Risk factors for diaphyseal AFFs were bone resorption inhibitor usage, a strong femoral curvature, and serrated changes. Low serum 25(OH)D levels and serrated changes are risk factors for lateral curvature, while a high serum Ca level is a risk factor for serrated changes., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Activation of cellular antioxidative signaling is expected to be a silver bullet against kidney diseases, and clinical trials of compounds activating the antioxidant transcription factor Nrf2 have revealed their renoprotective effects. However, cardiac events have been observed in some cases with elevated urinary albumin excretion in these trials. Therefore, elucidating the negative effects of Nrf2 activation is essential. Rush and colleagues demonstrated that Nrf2 activation aggravates podocyte injury, a factor related to proteinuria and cardiac failure., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Although the reported clinical outcomes of total hip arthroplasty (THA) for hip osteoarthritis are satisfactory, not all patients are completely satisfied. Thus, there is interest in predicting postoperative satisfaction before surgery. The influence of comorbidities and preoperative medications on the incidence of complications and duration of hospitalization following THA has become apparent. However, studies about the associations of preoperative medication with clinical outcomes of THA are limited. Therefore, this study aimed to clarify the relationship between preoperative medications and postoperative patient-reported outcomes. This retrospective cross-sectional multicenter study enrolled post-THA patients (79 patients, 90 hips) who were examined from February to March 2019 in eight general hospitals. Outcome measures included patient-reported outcome as Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) score. Preoperative medications were investigated from medical records. Medications were categorized, and analgesics were categorized into non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, pregabalin, duloxetine, neurotropin (an extract from inflammatory rabbit skin inoculated by vaccinia virus), and opioid. To identify the factors associated with JHEQ score, the patients were divided into lower (<55 score) and higher (≥55) JHEQ score groups. Spearman rank correlation coefficient (r) showed significant difference between the total number of preoperative medications and postoperative JHEQ movement subscale (r = -0.37, p < 0.01), mental subscale (r = -0.29, p < 0.01), and JHEQ (r = -0.30, p < 0.01) scores. In the multiple logistic regression analysis, only the total number of preoperative medications was identified as a risk factor for lower JHEQ score (p < 0.01). This study clarified an inverse correlation between the total preoperative medication count and postoperative outcomes and found that larger total count of preoperative medications is a risk factor of poor postoperative patient-reported outcomes of THA., Competing Interests: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2020 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

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., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function., Competing Interests: Declaration of competing interest This study was sponsored by Bayer Yakuhin, Ltd., and molidustat was supplied by Bayer Pharma AG. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The manuscript has not been published previously, nor is it under consideration for publication elsewhere, in whole or in part, in any language, except as an abstract., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)