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Proteins overexpressed in early-stage cancers may serve as early diagnosis and prognosis markers as well as targets for cancer therapies. In this study, we examined the expression of an essential amino acid carrier SLC7A5 (LAT1, CD98, or 4F2 light chain) in cancer tissue from two well-annotated cohorts of 575 cases of early-stage and 106 cases of late-stage colorectal cancer patients. Immunohistochemistry showed SLC7A5 overexpression in 72.0% of early-stage and 56.6% of late-stage cases. SLC7A5 expression was not influenced by patient gender, age, location, or mismatch repair status, although it appeared to be slightly less prevalent in tumors of mucinous differentiation or with lymphovascular invasion. Statistical analyses revealed a positive correlation between SLC7A5 overexpression and both overall survival and disease-free survival in early-stage but not late-stage cancers. Co-expression analyses of the TCGA and CPTAC colorectal cancer cohorts identified a network of gene transcripts positively related to SLC7A5, with its heterodimer partner SLC3A2 having the highest co-expression score. Network analysis uncovered the SLC7A network to be significantly associated with ncRNA such as tRNA processing and the mitotic cell cycle. Since SLC7A5 is also a marker of activated lymphocytes such as NK, T, and B lymphocytes, SLC7A5 overexpression in early colorectal cancers might trigger a strong anti-tumor immune response which could results in better clinical outcome. Overall, our study provides clear evidence of differential SLC7A5 expression and its prognostic value for early-stage colorectal cancer, although the understanding of its functions in colorectal tumorigenesis and cancer immunity is currently rather limited and awaits further characterization. [ABSTRACT FROM AUTHOR]

Background: Analysis of omics data that contain multidimensional biological and clinical information can be complex and make it difficult to deduce significance of specific biomarker factors. Methods: We explored the utility of propensity score matching (PSM), a statistical technique for minimizing confounding factors and simplifying the examination of specific factors. We tested two datasets generated from cohorts of colorectal cancer (CRC) patients, one comprised of immunohistochemical analysis of 12 protein markers in 544 CRC tissues and another consisting of RNA-seq profiles of 163 CRC cases. We examined the efficiency of PSM by comparing pre- and post-PSM analytical results. Results: Unlike conventional analysis which typically compares randomized cohorts of cancer and normal tissues, PSM enabled direct comparison between patient characteristics uncovering new prognostic biomarkers. By creating optimally matched groups to minimize confounding effects, our study demonstrates that PSM enables robust extraction of significant biomarkers while requiring fewer cancer cases and smaller overall patient cohorts. Conclusion: PSM may emerge as an efficient and cost-effective strategy for multiomic data analysis and clinical trial design for biomarker discovery. [ABSTRACT FROM AUTHOR]

Aims: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium‐glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods: This was a post‐hoc analysis of the PROCEED trial, which evaluated the effect of 24‐week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post‐treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium‐glucose co‐transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. Results: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3‐0.8; p <.001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3‐3.1; p <.001) and erythropoietin (estimated log‐transformed group difference, 0.1; 95% CI, 0.01‐0.3; p =.036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (β = 0.253, p <.001) or haematocrit (β = 0.278, p <.001). Reductions in estimated plasma volume (estimated group difference, −7.94%; 95% CI, −11.6 to −4.26%; p <.001) and estimated extracellular volume (estimated group difference, −181.6 ml; 95% CI, −275.7 to −87.48 ml; p <.001) were significantly greater in the ipragliflozin group than those in the control group. Conclusions: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. Clinical trial: PROCEED trial (registration number: jRCTs071190054). [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion The diagnosis of drug‐induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM‐J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM‐J 2023 and verify its performance in the context of Japanese patients with DILI.After translation of RECAM into Japanese, modifications were made to develop RECAM‐J 2023 without any alteration to the scores. To examine the validity and performance of RECAM‐J 2023, clinical information on DILI and non‐DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM‐J 2023, and calculated area under curve (AUC) values for identification for DILI.We collected data from 538 DILI and 128 non‐DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM‐J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM‐J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively.RECAM‐J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Although the Fontan procedure has improved the survival of patients with single‐ventricle heart disease, the long‐term consequences of the procedure have been a concern. This study aimed to explore the patients' postoperative clinical characteristics, including a diagnosis of Fontan‐associated liver disease (FALD).A nationwide Japanese epidemiological survey of post‐Fontan patients was undertaken in 2021. The survey targets were selected from all departments of pediatrics, pediatric surgery, cardiology, cardiovascular surgery, and gastroenterology using stratified random sampling by the number of beds. Each department was asked to complete a mail‐back questionnaire on the numbers of patients and their clinical characteristics. The diagnosis of FALD was made by each attending physician.The estimated number of post‐Fontan patients was 7810 (95% confidence interval, 5430−10 200) in 2020, with a period prevalence of 61.9 per million. During the follow‐up of 13.8 years after the Fontan procedure, 40% of patients were diagnosed with FALD. An elevated γ‐glutamyl transpeptidase level was the most common finding leading to the FALD diagnosis (41%), and 45% of the patients also showed liver fibrosis. Compared with non‐FALD patients, FALD patients were older, had longer duration since the Fontan procedure, and had more severe cardiac or liver conditions. However, more than half of the non‐FALD patients had elevated liver enzyme levels, suggesting underestimation of the number of FALD patients.In 2020, approximately 40% of post‐Fontan patients underwent follow‐up with a diagnosis of FALD, although the lack of established diagnostic criteria for FALD could affect the reported prevalence of FALD. [ABSTRACT FROM AUTHOR]

This article discusses the uric acid-lowering effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes. The study, called the PROTECT trial, examined the effects of ipragliflozin therapy on carotid intima-media thickness in patients with type 2 diabetes. The results showed that SGLT2 inhibition with ipragliflozin led to a reduction in serum uric acid (SUA) levels over a 24-month period. The study also found that patients with mildly impaired renal function and elevated SUA levels at baseline experienced a greater uric acid-lowering effect. These findings suggest that SGLT2 inhibitors may be beneficial for reducing uric acid levels in patients with type 2 diabetes, particularly those with lower renal function and higher SUA levels. [Extracted from the article]

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that can progress to cirrhosis and hepatic failure if left untreated. Ursodeoxycholic acid (UDCA) was introduced as a first-line drug for PBC around 1990; it remarkably improved patient outcomes, leading to the nomenclature change of PBC in 2015, from primary biliary "cirrhosis" to primary biliary "cholangitis." Nevertheless, 20–30% of patients exhibit an incomplete response to UDCA, resulting in significantly worse outcomes compared to those with a complete response. Therefore, improving the long-term outcomes of patients with an incomplete response to UDCA has been recognized as an unmet need. In addition, patients with PBC often suffer from a variety of debilitating symptoms, such as pruritus, fatigue and sicca syndrome, which significantly impair their health-related quality of life. Thus, appropriate management of these symptoms is currently regarded as another unmet need for PBC treatment. In this review, several compounds and drugs under clinical trials that can potentially solve these unmet needs are comprehensively discussed, and future directions of treatment policy of PBC are proposed for significantly improving long-term outcome as well as health-related quality of life of patients. [ABSTRACT FROM AUTHOR]

Background: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. Methods: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. Discussion: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 (https://clinicaltrials.gov/ct2/show/NCT05887817) and jRCTs021230011 (https://jrct.niph.go.jp/latest-detail/jRCTs021230011). [ABSTRACT FROM AUTHOR]

Backgrounds/Aim: Recent studies have shown that the addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors gradually reduces the estimated fluid volume parameters in a broad range of patient populations, suggesting that this mediates the clinical benefits of SGLT2 inhibitors in preventing heart failure. Here, we sought to examine the long-term (24 months) effect of the SGLT2 inhibitor ipragliflozin on the estimated fluid volume parameters in patients with type 2 diabetes mellitus (T2DM). Methods: In this prespecified sub-analysis of the PROTECT (Prevention of Atherosclerosis by SGLT2 Inhibitor: Multicenter, Randomized Controlled Study) trial, which was an investigator-initiated, multicenter, prospective, randomized, open-label, clinical trial primarily designed to evaluate the effect of ipragliflozin treatment administered for 24 months on carotid atherosclerosis in patients with T2DM, we evaluated serial changes in estimated plasma volume (ePV, %) calculated using the Straus formula and estimated extracellular volume (eEV, mL) calculated by the body surface area by 24 months following the initiation of 50-mg ipragliflozin once daily and compared them with those following standard care for T2DM (non-SGLT2 inhibitor use). Results: This sub-analysis included 464 patients (ipragliflozin, n = 232; control, n = 232), a full analysis set of the PROTECT trial. In an analysis using mixed-effects models for repeated measures, relative to the control group, ipragliflozin significantly reduced ePV by − 10.29% (95% confidence interval [CI] − 12.47% to − 8.11%; P < 0.001) at 12 months and − 10.76% (95% CI − 12.86% to − 8.67%; P < 0.001) at 24 months. Additionally, ipragliflozin significantly reduced eEV by − 190.44 mL (95% CI − 249.09 to − 131.79 mL; P < 0.001) at 12 months and − 176.90 mL (95% CI − 233.36 to − 120.44 mL; P < 0.001) at 24 months. The effects of ipragliflozin on these parameters over 24 months were mostly consistent across various patient clinical characteristics. Conclusions: This prespecified sub-analysis from the PROTECT trial demonstrated that ipragliflozin treatment, compared with the standard care for T2DM, reduced two types of estimated fluid volume parameters in patients with T2DM, and the effect was maintained for 24 months. Our findings suggest that SGLT2 inhibitor treatment regulates clinical parameters incorporated into the calculating formulas analyzed and consequently fluid volume status for the long-term, and this may be at least partly associated with clinical benefits from chronic use of SGLT2 inhibitors. Trial registration Japan Registry of Clinical Trials, ID jRCT1071220089 [ABSTRACT FROM AUTHOR]

Hyperuricemia is reportedly associated with the progression of carotid intima-media thickness (IMT), a surrogate of cardiovascular risks and events. However, factors associated with carotid IMT progression in patients with asymptomatic hyperuricemia are largely unknown. In this post-hoc analysis of the multicenter, randomized PRIZE study, we analyzed data from a total of 326 patients who underwent carotid ultrasonography in a blind manner at baseline and 24 months to evaluate carotid IMT. Mean and maximum IMT at the common carotid artery (CCA) were measured at a central core laboratory. Factors related to the absolute change in mean and maximum IMT from baseline to 24 months were explored. Overall, the adjusted mean [0.0032 (− 0.0214 to 0.0278) mm] and maximum [0.0011 (− 0.0327 to 0.0351) mm] CCA-IMT increased numerically from baseline to 24 months. Multivariable analysis identified higher body mass index, history of atherosclerotic cardiovascular disease (ASCVD), and lower mean CCA-IMT at baseline as significant factors associated with the increase in mean CCA-IMT. In addition, older age and lower mean CCA-IMT at baseline were significant factors for an increased absolute change in the maximum CCA-IMT at 24 months. The present sub-analysis of the PRIZE study showed higher body mass index, history of ASCVD, and older age as significant factors associated with CCA-IMT progression in patients with asymptomatic hyperuricemia. These factors may be considered when identifying the possible risk of atherosclerotic progression in this specific patient population of hyperuricemia. Trial registration: UMIN000012911 and UMIN000041322. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate changes in muscle strength and functional outcome before and after surgery for soft-tissue sarcoma of the thigh and to examine the timing of recovery. Methods: From 2014 to 2019, 15 patients who underwent multiple resections of the thigh muscle for soft-tissue sarcoma of the thigh were included in this study. The muscle strength was measured with an isokinetic dynamometer for the knee joint and with a hand-held dynamometer for the hip joint. The functional outcome assessment was based on the Musculoskeletal Tumor Society (MSTS) score, Toronto Extremity Salvage Score (TESS), European Quality of Life-5 Dimensions (EQ-5D), and maximum walking speed (MWS). All measurements were conducted preoperatively and at 3, 6, 12, 18, and 24 months postoperatively, and the ratio of postoperative to preoperative value was used. A repeated-measures analysis of variance was performed to compare changes over time and to investigate the recovery plateau. Correlations between changes in muscle strength and functional outcomes were also examined. Results: The muscle strength of the affected limb, MSTS score, TESS, EQ-5D, and MWS were significantly decreased at 3 months postoperatively. The recovery plateau was subsequently reached at 12 months postoperatively. The changes in muscle strength of the affected limb and functional outcome showed a significant correlation. Conclusions: The estimated postoperative recovery for soft-tissue sarcoma of the thigh is 12 months after surgery. [ABSTRACT FROM AUTHOR]

Aim: To compare patient characteristics and outcomes between the overall and Japanese populations of GLIMMER. Methods: GLIMMER was a multicenter, double‐blind, randomized, placebo‐controlled, Phase IIb study evaluating linerixibat for the treatment of pruritus in patients with primary biliary cholangitis. Results: In total, 147 patients were randomized in the GLIMMER overall population with 38 patients comprising the Japanese population. Demographics and baseline clinical characteristics were similar across treatment groups and between both populations. A reduction in mean worst daily itch score from baseline to week 16 (primary endpoint) was seen in all groups, with the largest reduction observed with linerixibat 40 mg twice daily (BID; −2.92 [95% confidence interval: −5.07, −0.76] and −2.86 [95% confidence interval: −3.76, −1.95] for Japanese and overall populations, respectively). The highest proportion of responders was generally in the 40 mg BID group in both populations regardless of the responder definition applied. Improvements in health‐related quality of life were generally consistent in both populations. In the Japanese and overall populations, on‐treatment drug‐related adverse events were reported in 25% and 19% of patients in the placebo group and 0%–86% and 31%–78% of patients in the linerixibat groups, respectively. Consistent with the mechanism of action, the most common events were gastrointestinal in nature. The effects of linerixibat on pharmacodynamic biomarkers favored BID dosing. Conclusions: Therapeutic responses and safety of linerixibat were consistent between the Japanese and overall populations of GLIMMER. Linerixibat may provide an effective treatment option for cholestatic pruritus in patients with primary biliary cholangitis. Clinical Trial Registration: NCT02966834. [ABSTRACT FROM AUTHOR]

Wood-based paper fibers are inherently biodegradable. In contact with moist soil and in compost, papermaking fibers are readily broken down by soil microbes. Resistance to biodegradation is needed, as paper is used for special applications such as mulching in agriculture and forestry, the coating of construction materials, and for packing and wrapping under conditions where packaging materials may be exposed to contact with moist soil or other type microbial active contamination. A preceding study showed that paper chemical crosslinking with glyoxal, citric acid (CA), or methylated 1,3-dimethylol-4,5-dihydroxyethylene urea (mDMDHEU) results in substantially improved paper wet strength and lower paper water absorbency. The present study examined the efficiency of chemical crosslinking treatments with CA and with mDMDHEU to decrease the biodegradation rate of laboratory paper sheets and a sack paper, both made of kraft fibers. The biodegradation was examined using a 48-h enzymatic degradation test and a 2-month soil burial test. The results indicate that chemical crosslinking is an effective non-biocidal method for making sulphate kraft paper more resistant to biodegradation. In some end-uses, improved resistance to biodegradation, along with improved paper wet performance, can enhance paper performance comparable to plastic films. [ABSTRACT FROM AUTHOR]

Purpose: Patients with diffuse idiopathic skeletal hyperostosis (DISH) that extends to the lumbar segments (L-DISH) have a high risk of further surgery after lumbar decompression. However, few studies have focused on the ankylosis status of the residual caudal segments, including the sacroiliac joint (SIJ). We hypothesized that patients with more ankylosed segments beside the operated level, including the SIJ, would be at a higher risk of further surgery. Methods: A total of 79 patients with L-DISH who underwent decompression surgery for lumbar stenosis at a single academic institution between 2007 and 2021 were enrolled. The baseline demographics and radiological findings by CT imaging focusing on the ankylosing condition of the residual lumbar segments and SIJ were collected. Cox proportional hazard analysis was conducted to investigate the risk factors for further surgery after lumbar decompression. Results: The rate of further surgery was 37.9% during an average of 48.8 months of follow-up. Cox proportional hazard analysis demonstrated that the presence of fewer than three segments of non-operated mobile caudal segments was an independent predictor for further surgery (including both the same and adjacent levels) after lumbar decompression (adjusted hazard ratio 2.53, 95%CI [1.12–5.70]). Conclusions: L-DISH patients with fewer than three mobile caudal segments besides index decompression levels are at a high risk of further surgery. Ankylosis status of the residual lumbar segments and SIJ should be thoroughly evaluated using CT during preoperative planning. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are abundant in tumor tissues, raising a question of whether immunosuppressive tumor-infiltrating Tregs (TI-Tregs) can be selectively depleted or functionally attenuated to evoke effective anti-tumor immune responses by conventional T cells (Tconvs), without perturbing Treg-dependent immune homeostasis in healthy organs and causing autoimmunity. Here, we review current cancer immunotherapy strategies, including immune checkpoint blockade (ICB) antibodies against CTLA-4 and PD-1 and discuss their effects on TI-Tregs. We also discuss approaches that exploit differentially regulated molecules on the cell surface (e.g., CTLA-4) and intracellularly (e.g., T cell receptor signaling molecules) between TI-Tregs and Tconvs as well as their dependence on cytokines (e.g., IL-2) and metabolites (e.g., lactate). We envisage that targeting TI-Tregs could be effective as a monotherapy and/or when combined with ICB antibodies. Tay et al. discuss the potential of targeting TI-Tregs as an effective cancer therapy strategy. They review the effect of current cancer immunotherapies on TI-Tregs and the approaches that exploit differentially regulated molecules between TI-Tregs and Tconvs as well as their dependence on cytokines and metabolites for cancer therapy. [ABSTRACT FROM AUTHOR]

We describe a wet creping approach, applicable not only for softwood kraft papers in the grammage range of 30–120 g/m2 but also for 300 g/m2 CTMP board. Creping of board requires a certain level of deformability in the material, which is controlled by its solids content. The concept was tested at laboratory scale using a device on which temperature, blade angle and line load could be adjusted. The sample density was decreased by creping due to small-scale delamination of the structure, leading to separate inner layers with a wavy appearance. The strain at break was remarkably increased and agreed well with the theoretical estimate based on the crepe ratio and the breaking strain of the uncreped sample. Simultaneously, tensile strength was reduced by creping. In terms of tensile strength and stretch, 60–70 % solids content during creping was optimal for the tested board. [ABSTRACT FROM AUTHOR]

Background: First successful human round spermatid injection (ROSI) was conducted by Tesarik et al. in 1996 for the sole treatment of nonobstructive azoospermic men whose most advanced spermatogenic cells were elongating round spermatids. Nine offsprings from ROSI were reported between 1996 and 2000. No successful deliveries were reported for 15 years after that. Tanaka et al. reported 90 babies born after ROSI and their follow‐up studies in 2015 and 2018 showed no significant differences in comparison with those born after natural conception in terms of physical and cognitive abilities. However, clinical outcomes remain low. Method: Clinical and laboratory data of successful cases in the precursor ROSI groups and those of Tanaka et al. were reviewed. Results: Differences were found between the two groups in terms of identification of characteristics of round spermatid and oocyte activation. Additionally, epigenetic abnormalities were identified as underlying causes for poor ROSI results, besides correct identification of round spermatid and adequate oocyte activation. Correction of epigenetic errors could lead to optimal embryonic development. Conclusion: Correction of epigenetic abnormalities has a probability to improve the clinical outcome of ROSI. [ABSTRACT FROM AUTHOR]

Chemical crosslinking is an established method for improving the wet performance of paper. In the chemical crosslinking process, covalent bonds are formed between cellulosic surfaces. The formed intra- and interfiber bonds increase the paper's wet strength and reduce its water absorptivity. The majority of published studies concern crosslinking treatments with glyoxal, citric acid (CA), or with 1,2,3,4-butanetetracarboxylic acid (BTCA). The most severe disadvantage of the crosslinking treatments with glyoxal, CA, and BTCA is that the formed crosslinks make the fibers and the paper more brittle. This downside effect has largely impeded the utilization of crosslinking in paper and paperboard making. In the present study, handsheets made from Nordic bleached softwood kraft pulp (NBSK) were crosslinked with methylated 1,3-dimethylol-4,5-dihydroxyethylene urea (mDMDHEU), which is commonly used in cotton fabric finishing. Similar to using glyoxal and citric acid, crosslinking with mDMDHEU notably increased the handsheet wet strength and decreased the water absorption. Compared to the use of glyoxal or CA, the crosslinking with mDMDHEU did not make the handsheets that brittle. These results suggest that mDMDHEU could be a more viable crosslinking agent for improving the wet performance of paper products. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Clinical evidence is lacking about the influence of sodium–glucose cotransporter 2 inhibitors on white blood cell (WBC) counts, a commonly used and widely available marker of inflammation. The aim of the present analysis was to assess the effect of canagliflozin relative to glimepiride on WBC counts. Materials and Methods: This was a post‐hoc subanalysis of the CANDLE trial (Effects of Canagliflozin in Patients with Type 2 Diabetes and Chronic Heart Failure: A Randomized Trial; UMIN000017669), an investigator‐initiated, multicenter, open‐label, randomized, controlled trial. A total of 233 patients with type 2 diabetes and concomitant heart failure were randomly assigned to either canagliflozin (n = 113) or glimepiride (n = 120) treatment for 24 weeks. Overall, patient baseline characteristics were as follows: mean ± standard deviation age, 68.6 ± 10.1 years; hemoglobin A1c, 7.0 ± 0.9%; left ventricular ejection fraction, 56.7 ± 14.4%; and median N‐terminal pro‐brain natriuretic peptide, 252 pg/mL (interquartile range 96–563 pg/mL). The mean baseline WBC counts were 6704 cells/μL (95% confidence interval 6,362–7,047) in the canagliflozin group and 6322 cells/μL (95% confidence interval 5,991–6,654) in the glimepiride group. There were no significant differences between treatment groups in terms of changes in WBC counts from baseline to weeks 4 and 12. In contrast, a group difference (canagliflozin minus glimepiride) from baseline to week 24 was significant (mean difference − 456 cells/μL [95% confidence interval −774 to −139, P = 0.005]). Conclusions: Our findings suggest that 24 weeks of treatment with canagliflozin, relative to glimepiride, reduced WBC counts in patients with type 2 diabetes and heart failure. [ABSTRACT FROM AUTHOR]

Since an elevation of pulmonary artery pressure (PAP) often precedes clinical worsening of heart failure (HF), early and non-invasive detection of this sign is useful in HF care. This study aimed to assess whether cardiac acoustic biomarkers (CABs) are associated with the elevation of PAP in patients with HF. Patients with HF scheduled to undergo right heart catheterization were prospectively enrolled. CABs were concurrently recorded during catheterization at rest (baseline) and while applying a handgrip (exercise). Forty-nine patients were included in the analysis, and their mean PAP significantly increased after exercise compared to baseline. Several CABs correlated significantly with mean PAP by absolute values, among which S2 Width (r = 0.354; p = 0.014 and r = 0.363; p = 0.010) and S3 Strength (r = 0.375; p = 0.009 and r = 0.386; p = 0.007) were consistent throughout baseline and exercise. The response of CABs to exercise-induced PAP elevation was divided into two patterns: increasing and decreasing. The frequency of cardiac index below 2.2 mL/m2 was significantly higher in the decreasing pattern. CABs related to S2 and S3 showed significant correlations with absolute PAP values both at baseline and after exercise in patients with HF, but no significant correlations between their changes from baseline to post-exercise were observed in this study population. Further research is therefore needed to assess whether CABs can sensitively reflect changes in PAP according to HF status and underlying phenotypes. [ABSTRACT FROM AUTHOR]

Obesity is characterized by visceral fat accumulation and various metabolic disturbances that cause metabolic syndrome and obesity-related cardiovascular diseases (ORCVDs). Hence, treatments targeting obesity should also prevent ORCVDs. Nonetheless, lifestyle modification therapy alone is still insufficient to reduce the risk of ORCVDs, although most cardiovascular guidelines still list it as the only treatment for obesity. Additionally, conventional anti-obesity drugs, such as orlistat, phentermine-topiramate, and naltrexone-bupropion, can reduce body weight but have not demonstrated a clear reduction in the risk of ORCVDs. To overcome this unmet clinical need, newer anti-obesity drugs must exhibit not only sufficient and long-lasting weight loss but also obvious cardiovascular benefits. Given recent clinical findings and evidences, in this context glucagon-like peptide-1 receptor agonist is currently available as a candidate that is clinically positioned as a first-line anti-obesity agent for the effective prevention of ORCVDs in people with obesity. [ABSTRACT FROM AUTHOR]

When there are many non-intersecting paths between two vertices on a network, the connectivity is fault-tolerant. Because of no common vertices on these paths, they can be emergently used in avoiding destroyed parts on the usual paths by any disasters or attacks. It gives a tolerance index whether the combination of non-intersecting paths is many or few. However, to enumerate such paths is an intractable combinatorial problem, no practical algorithm has been known. On the other hand, many socio-technological infrastructure networks are embedded on the surface of Earth. Thus, as an approximate solution, we extendedly apply the counting method based on a path matrix with our proposed mapping to directed acyclic graphs from a planar network according to each pair of source and terminal vertices. The tendency of many or few combinations of the paths is clearly investigated through computer simulations for realistic networks. This approach will be useful for evaluating the existence of substitutive paths to improve the tolerance in risk management. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. Methods: This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. Results: Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was − 3.52 mU/L (95% confidence interval, − 4.85 to − 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin. Conclusion: Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status. Trial registration: University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015. [ABSTRACT FROM AUTHOR]

The high post-discharge mortality rate of acute myocardial infarction (AMI) survivors is concerning, indicating a need for reliable, easy-to-use risk prediction tools. We aimed to examine if a combined pre-procedural blood testing risk model predicts one-year mortality in AMI survivors. Overall, 1355 consecutive AMI patients who received primary coronary revascularization were divided into derivation (n = 949) and validation (n = 406) cohorts. A risk-score model of parameters from pre-procedural routine blood testing on admission was generated. In the derivation cohort, multivariable analysis demonstrated that hemoglobin < 11 g/dL (odds ratio (OR) 4.01), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (OR 3.75), albumin < 3.8 mg/dL (OR 3.37), and high-sensitivity troponin I > 2560 ng/L (OR 3.78) were significantly associated with one-year mortality after discharge. An increased risk score, assigned from 0 to 4 points according to the counts of selected variables, was significantly associated with higher one-year mortality in both cohorts (p < 0.001). Receiver-operating characteristics curve analyses of risk models demonstrated adequate discrimination between patients with and without one-year death (area under the curve (95% confidence interval) 0.850 (0.756–0.912) in the derivation cohort; 0.820 (0.664–0.913) in the validation cohort). Our laboratory risk-score model can be useful for predicting one-year mortality in AMI survivors. [ABSTRACT FROM AUTHOR]

As a newly developed technique to slice GaN substrates, which are currently very expensive, with less loss, we previously reported a laser slicing technique in this journal. In the previous report, from the perspective of GaN substrate processing, we could only show that the GaN substrate could be sliced by a laser and that the sliced GaN substrate could be reused. In this study, we newly investigated the applicability of this method as a device fabrication process. We demonstrated the thinning of GaN-on-GaN high-electron-mobility transistors (HEMTs) using a laser slicing technique. Even when the HEMTs were thinned by laser slicing to a thickness of 50 μm after completing the fabrication process, no significant fracture was observed in these devices, and no adverse effects of laser-induced damage were observed on electrical characteristics. This means that the laser slicing process can be applied even after device fabrication. It can also be used as a completely new semiconductor process for fabricating thin devices with thicknesses on the order of 10 μm, while significantly reducing the consumption of GaN substrates. [ABSTRACT FROM AUTHOR]

As a newly developed technique to slice GaN substrates, which are currently very expensive, with less loss, we previously reported a laser slicing technique in this journal. In the previous report, from the perspective of GaN substrate processing, we could only show that the GaN substrate could be sliced by a laser and that the sliced GaN substrate could be reused. In this study, we newly investigated the applicability of this method as a device fabrication process. We demonstrated the thinning of GaN-on-GaN high-electron-mobility transistors (HEMTs) using a laser slicing technique. Even when the HEMTs were thinned by laser slicing to a thickness of 50 mm after completing the fabrication process, no significant fracture was observed in these devices, and no adverse effects of laser-induced damage were observed on electrical characteristics. This means that the laser slicing process can be applied even after device fabrication. It can also be used as a completely new semiconductor process for fabricating thin devices with thicknesses on the order of 10 mm, while significantly reducing the consumption of GaN substrates. [ABSTRACT FROM AUTHOR]

Evidence has established that sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment reduces the risk of hospitalization for heart failure (HF) and cardiovascular death. Herein, we conducted a post hoc mediation analysis to explore potential mediators that could influence the true NT-proBNP response to canagliflozin treatment and to estimate the identified mediator-adjusted treatment effect of canagliflozin on the NT-proBNP concentration, using data from the CANDLE trial. According to the beneficial impact obtained in recent large-scale randomized clinical trials of SGLT2i treatment and relevant guidelines,12 the use of SGLT2i in the setting of HF care is expected to increase, and it is therefore clinically important to understand the current evidence gap and resolve it to improve the quality of HF care. More recently, it has also been shown that these agents reduce the total burden of cardiovascular and hospitalization events in Asian as well as non-Asian patients.1 However, the natriuretic peptide (NP) response to SGLT2i treatment observed in several mechanistic clinical studies is conflicting; in particular, short-term SGLT2i intervention often failed to reduce NP levels.2 There seems to be a discrepancy between the NP response and the clinical benefits of SGLT2i treatment. [Extracted from the article]

In a quest for prognostic biomarkers in early-stage colorectal cancer, we investigated NNMT (nicotinamide N-methyltransferase) in large cohorts of patients. Immunohistochemical examination of 679 patients illustrates that NNMT protein is predominantly expressed in the cancer stroma at varying levels, and about 20% of cancer tissues overexpress NNMT when compared to levels observed in normal colorectal mucosa. Clinical correlation analyses of 572 patients with early-stage cancers reveal that NNMT protein overexpression is significantly associated with shorter overall and disease-free survival, but no such correlation is found in late-stage colorectal cancer. Analyses of TCGA and CPTAC colorectal cancer cohorts show that NNMT mRNA expression is positively correlated with protein levels, is significantly higher in CIMP-high or MSI subtypes than in CIMP-low or MSS subtypes, and is positively correlated with its paralog INMT but not with its interaction partners such as PNMT, ADK, APP, ATF6, BMF, BRD4, CDC37, or CRYZ. In early-stage cancers, NNMT expression is higher in BRAF-mutated than in BRAF wild type tumors but is not affected by KRAS or PIK3CA mutation status. As a cancer stromal protein with important roles in metabolism and cancer epigenetics, NNMT is emerging as a promising biomarker for risk stratification of early-stage cancers. [ABSTRACT FROM AUTHOR]

Background: To assess the points of consideration when performing surgical procedures for proximal femoral bone metastasis.Methods: Fourty patients who underwent surgery for proximal femoral bone metastasis from 2009 to 2019 were included. Prognostic assessments were performed based on the Katagiri scoring system. The low-risk group underwent endoprosthetic replacement (EPR) following resection, while the high-risk group underwent internal fixation (IF). For the intermediate-risk group, one of the surgical procedures was chosen depending on general and local condition. Survival period, walking ability, and treatment failure were evaluated.Results: Sixteen and 24 patients underwent EPR and IF, respectively. Although walking reacquisition rate was 94% (15 of 16 patients) for EPR and 75% (18 of 24 patients) for IF (p = 0.210), the median time to walking was shorter in IF compared to EPR (EPR, 29 days, interquartile range [IQR] 23-40; IF, 14 days, IQR 9-24; p = 0.014). Neither EPR nor IF resulted in treatment failure for those with survival periods of <1 year. The treatment failure rate for those with survival periods of ≥1 year was significantly different between EPR (9%, 1 of 11 patients) and IF (50%, 5 of 10 patients) (p = 0.038). All five patients of treatment failure for IF were renal cancer with no bone formation in the intermediate-risk group. Of the 13 patients who underwent IF for the intermediate-risk group, treatment failure did not occur in 5 patients with bone formation.Conclusions: Although EPR is a more reliable treatment than IF, patients with life expectancy of <1 year are sufficiently manageable with IF. For the intermediate-risk group, EPR should be selected for cases without expected bone formation, and IF can be considered for cases with expected bone formation due to the risk of treatment failure for IF at ≥ 1 year after surgery. [ABSTRACT FROM AUTHOR]

Although molecular dynamics (MD) simulation is a powerful tool for investigating the atomic-scale structures of complex materials, several challenges limit their reliable and accurate application to multi-component glass systems. The available force fields (FFs) that can treat many elements in a multi-component glass are limited, and even if such a FF exists, its accuracy is suspicious due to the large variety and complexity of chemical environments in these materials. First-principles calculations based on the density functional theory (DFT) are reliable, but prohibitively expensive with conventional methods. In this study, we use large-scale DFT techniques and demonstrate that it is possible to perform efficient and accurate DFT calculations of multi-component glass systems, such as (SiO 2) 0.70 (Al 2 O 3) 0.13 (X O) 0.17 (X = Mg, Ca, Sr, Ba), containing about 1000–5000 atoms. From the results of large-scale DFT calculations, we evaluate the accuracy of some classical FFs, and show that the accuracy for non-bridging oxygen atoms is very low especially when the Si O distance is short. Large differences in the distribution of Si O Si angles observed in the FF-MD and DFT-MD simulations and the unique electronic structure in the case of X = Mg are also discussed. • Large-scale DFT calculations of multi-component glass systems were performed. • Benchmark tests of classical force fields revealed a low accuracy for NBOs. • Structure factor from the DFT-MD simulation agreed well with the experimental result. [ABSTRACT FROM AUTHOR]

We have investigated the possibility of applying lasers to slice GaN substrates. Using a sub-nanosecond laser with a wavelength of 532 nm, we succeeded in slicing GaN substrates. In the laser slicing method used in this study, there was almost no kerf loss, and the thickness of the layer damaged by laser slicing was about 40 µm. We demonstrated that a standard high quality homoepitaxial layer can be grown on the sliced surface after removing the damaged layer by polishing. [ABSTRACT FROM AUTHOR]

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents. Methods: This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents. Results: Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup. Conclusion: The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015 [ABSTRACT FROM AUTHOR]

A beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) has been reported in patients with an incomplete response to ursodeoxycholic acid (UDCA), but long-term effects on survival remain unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort. All consecutively registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT). Of 3,908 eligible patients, 3,162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17,360 and 3,932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 LT were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936–0.5466 and 0.2748, 95% CI 0.1336–0.5655, respectively; p < 0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent 1 additional death or LT over 5, 10, and 15 years were 29 (95% CI 22–46), 14 (10–22), and 8 (6–15), respectively. In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis. The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) – free survival in patients with PBC and an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with a lower risk of all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes. [Display omitted] • Long-term efficacy of second-line therapies for PBC (obeticholic acid, bezafibrate) remains to be established. • In Japan, bezafibrate has been used since 2000 as a de facto second-line treatment for UDCA-resistant PBC. • In this large Japanese retrospective cohort study (n = 3,908), addition of bezafibrate to UDCA was associated with improved transplant-free survival. • Bezafibrate is currently the only drug in PBC demonstrating efficacy in improving symptoms, biochemical markers, and prognosis. [ABSTRACT FROM AUTHOR]

Gallium nitride (GaN)-based devices surpass the traditional silicon-based power devices in terms of higher breakdown voltage, faster-switching speed, higher thermal conductivity, and lower on-resistance. However, heteroepitaxial GaN growths like GaN on sapphire are not suitable for power devices due to the threading dislocation densities as high as 108/cm2. Recently, homoepitaxial GaN growth has become possible thanks to the native GaN substrates with dislocation densities in the order of 104/cm2 but the extremely high cost of the GaN substrates makes the homoepitaxy method unacceptable for industrial applications, and the slicing of wafers for reusing them is an effective solution for cost reduction. In this study, we will investigate a route for slicing the GaN single crystal substrate by controlling the laser pulse energy and changing the distance between each laser shot. The 2D and 3D crack propagations are observed by a multiphoton confocal microscope, and the cross section of samples is observed by a scanning electron microscope (SEM). The results showed that two types of radial and lateral cracking occurred depending on the pulse energy and shot pitch, and controlling them was of importance for attaining a smooth GaN substrate slicing. Cross-sectional SEM images showed that at suitable pulse energy and distance, crack propagation could be controlled with respect to the irradiation plane. [ABSTRACT FROM AUTHOR]

Immunoglobulin G4 (IgG4)‐related disease (IgG4‐RD) is a chronic inflammatory disease that simultaneously or consecutively involves multiple organs of the body. It is characterized by elevated serum IgG4 levels and massive infiltration of IgG4+ plasma cells in the damaged tissues. IgG4‐related autoimmune hepatitis (IgG4‐AIH) and IgG4‐hepatopathy are relatively new entities that have been proposed as a phenotype of IgG4‐RD in the liver. Immunoglobulin G4‐AIH is defined as a disorder with serological, histopathological, and clinical features of both IgG4‐RD and AIH, simultaneously satisfying the diagnostic criteria of both classical AIH and IgG4‐RD. Although there are several case reports and studies of IgG4‐AIH among the published works, no consensus regarding the histopathological characteristics of IgG4‐AIH has been established, and its clinical implications remain obscure. Immunoglobulin G4‐hepatopathy is defined as a comorbidity of IgG4‐RD in the liver, and patients not meeting the diagnostic criteria of classical AIH could be diagnosed with IgG4‐hepatopathy. Numerous issues regarding these diseases, especially their epidemiology, histopathological and clinical characteristics, and treatment response to corticosteroids, remain unsolved, and need to be determined to establish the disease concepts of IgG4‐AIH and IgG4‐hepathopathy. [ABSTRACT FROM AUTHOR]

Background: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. Methods: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. Results: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference − 8.5 [95% confidence interval (CI) − 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (− 0.54 [95% CI − 1.07 to − 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. Conclusion: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502 [ABSTRACT FROM AUTHOR]

A combination of direct SARS-CoV-2 infection of endothelial cells and a cytokine storm originating in the lungs synergistically causes endothelial cell injury, resulting in endothelial dysfunction and subsequent cardiovascular complications. Two years have passed since the unprecedented breakout of the global pandemic of the coronavirus disease COVID-19, which began at the end of 2019. In particular, the authors emphasized the diverse mechanisms of cardiovascular injury in COVID-19 and the need to urgently establish treatment strategies for the multifaceted and complex pathophysiology of the disease. [Extracted from the article]

Backgrounds/Aim: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). Methods: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. Results: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by − 2.23% (95% CI − 5.72 to 1.25) at week 4, − 8.07% (− 12.76 to − 3.37) at week 12, and − 5.60% (− 9.87 to − 1.32) at week 24; eEV by − 70.3 mL (95% CI − 136.8 to − 3.8) at week 4, − 135.9 mL (− 209.6 to − 62.3) at week 12, and − 144.4 mL (− 226.3 to − 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. Conclusions: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502 [ABSTRACT FROM AUTHOR]

Traditional particle board can generate harmful indoor air emissions due to the volatile resin-based compounds present. This study investigated the preparation of sawdust particle board using the novel ionic liquid based fusion approach with [EMIM]OAc. The dissolution parameters were investigated using the thermal optical microscopy technique. The particle board sheets were prepared by hot pressing sawdust in the presence of ionic liquid (IL) ([EMIM]OAc) and subsequently purifying the fusion sawdust matrix from the IL with methanol. The fusion process of the sawdust particles was analysed with SEM and mechanical testing. The raw materials and the produced materials were investigated with elemental analysis, FTIR, and 13C-SS-NMR. IL fusion of the sawdust required a temperature above 150 °C, similar to the glass transition temperature (tg) of lignin. At lower temperatures, strong particle fusion was not obtained. It was observed that the sawdust/IL weight ratio was an important parameter of the fusion process, and a 1:3 weight ratio resulted in the strongest particle boards with a tensile strength of up to 10 MPa, similar to commercial particle boards. The particle fusion process was also studied with a twin-screw extruder. The extrusion enhanced the fusion of the sawdust particles by increasing dissolution of the sawdust particles, which was subsequently seen in elevated tensile strength (20 MPa). The study provides a practical view of how sawdust-based particle board can be manufactured using ionic liquid-based fusion. [ABSTRACT FROM AUTHOR]

Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication. [ABSTRACT FROM AUTHOR]

Refractory angina is an independent predictor of adverse events in patients with vasospastic angina (VSA). The aim of this study was to investigate the relationship between coronary lumen complexity and refractory symptoms in patients with VSA. Seventeen patients with VSA underwent optical coherence tomography. The patients were divided into the refractory VSA group (n = 9) and the stable VSA group (n = 8). A shoreline development index was used to assess the coronary artery lumen complexity. Shear stress was estimated using a computational fluid dynamics model. No difference was observed in the baseline characteristics between the two groups. The refractory VSA group showed the higher shoreline development index (refractory VSA 1.042 [1.017–1.188] vs stable VSA 1.003 [1.006–1.025], p = 0.036), and higher maximum medial thickness (refractory VSA 184 ± 17 μm vs stable VSA 148 ± 31 μm, p = 0.017), and higher maximum shear stress (refractory VSA 14.5 [12.1–18.8] Pa vs stable VSA 5.6 [3.0–10.5] Pa, p = 0.003). The shoreline development index positively correlates with shear stress (R2 = 0.46, P = 0.004). Increased medial thickness of the coronary arteries provokes lumen complexity and high shear stress, which might cause refractory symptoms in patients with VSA. The shoreline index could serve as a marker for irritability of the medial layer of coronary arteries and symptoms. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is a mosquito-borne RNA virus that causes Chikungunya fever in humans. In this study, we generated two DNA-based CHIKV infectious clones derived from an Indian Ocean Lineage SL11131 strain and a prototype Ross strain. When the replication capabilities of the infectious CHIKV in various cell lines were evaluated, the SL11131 strain was found to replicate more efficiently than the Ross strain in Aedes albopictus C6/36 cells, whereas SL11131 underwent limited replication in a BHK-21-derivative cell line named BHK-DRV. Infection experiments using chimeric CHIKV between SL11131 and Ross revealed that these different replication activities of SL11131 in C6/36 and BHK-DRV cells were determined by structural and nonstructural genes, respectively. Therefore, the infectious clones created in this study will be a useful tool for investigating the virological features of a recent epidemic strain of CHIKV and benefit the development of effective prevention and treatment of CHIKV infection. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease and cancer often share risk factors and influence each other's pathological features. In addition to the unfavorable effects of cancer on the cardiovascular system, the adverse effects of cancer therapies, such as chemotherapy and radiation, have also been determined. In particular, vascular toxic effects associated with cancer therapy (vasospasm, thrombosis formation, and promotion of arteriosclerosis), which are the second most common complications after myocardial adverse effects, are usually managed after the onset of vascular diseases, because screening and predictive methods are yet to be fully established. However, the onset of these vascular complications has a major influence on the implementation of cancer therapy, resulting in worsening of the quality of cancer care and prognosis of patients with cancer. It is therefore necessary to establish clinical strategies for detecting the vascular adverse effects of cancer therapy and evaluating vascular function during cancer care. In this article, we discuss the expected role of vascular function assessment using physiological testing tools for early detection of vascular adverse effects caused by cancer therapy and also preemptive assessment of vascular function prior to this treatment being initiated. [ABSTRACT FROM AUTHOR]

DEAD-box RNA helicase DDX21 (also named nucleolar RNA helicase 2) is a nuclear autoantigen with undefined roles in cancer. To explore possible roles of autoimmune recognition in cancer immunity, we examined DDX21 protein expression in colorectal cancer tissue and its association with patient clinical outcomes. Unbiased deep proteomic profiling of two independent colorectal cancer cohorts using mass spectrometry showed that DDX21 protein was significantly upregulated in cancer relative to benign mucosa. We then examined DDX21 protein expression in a validation group of 710 patients, 619 of whom with early stage and 91 with late stage colorectal cancers. DDX21 was detected mostly in the tumor cell nuclei, with high expression in some mitotic cells. High levels of DDX21 protein were found in 28% of stage I, 21% of stage II, 30% of stage III, and 32% of stage IV colorectal cancer cases. DDX21 expression levels correlated with non-mucinous histology in early stage cancers but not with other clinicopathological features such as patient gender, age, tumor location, tumor grade, or mismatch repair status in any cancer stage. Kaplan–Meier analyses revealed that high DDX21 protein levels was associated with longer survival in patients with early stage colorectal cancer, especially longer disease-free survival in patients with microsatellite instability (MSI) cancers, but no such correlations were found for the microsatellite stable subtype or late stage colorectal cancer. Univariate and multivariate analyses also identified high DDX21 protein expression as an independent favorable prognostic marker for early stage MSI colorectal cancer. [ABSTRACT FROM AUTHOR]

It has been widely documented that circannual variation has an impact on the incidence and prognosis of cardiovascular diseases. It is unclear why cold ambient temperature increase the incidence of acute myocardial infarction (AMI). We investigated the relationship between the ambient temperature at the onset of AMI, the morphology of the culprit lesion in patients with AMI. We investigated 202 consecutive patients with AMI who underwent optical coherence tomography (OCT). The participants were divided into lower (n = 100) and higher (n = 102) temperature groups based on the ambient temperature. The culprit lesion morphology was compared between the two groups. The median temperature at the onset of AMI was 16.6 °C. The prevalence of plaque ruptures was higher at lower temperatures (lower 66% vs. higher 45%, p =.003), whereas OCT-erosion was more frequent in the higher temperature group (lower 13% vs. higher 26%, p =.021). The lower temperature group showed more cholesterol crystals (lower 71% vs. higher 54%, p =.014). The peak incidence of AMI in the winter is formed by increased plaque rupture, suggesting environmental temperature has an influence on the pathogenesis of AMI. • The onset of AMI demonstrates a bimodal distribution according to the ambient temperature. • AMI is most likely to occur at two specific temperatures: ~10 and ~ 20 °C. • Plaque rupture was more frequent in the colder ambient temperature. • OCT-erosion was more frequent in the higher ambient temperature. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Recent clinical trials on sodium–glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear. Materials and Methods: The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post‐hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non‐responders to treatment. Results: Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log‐transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters. Conclusions: Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium–glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials. [ABSTRACT FROM AUTHOR]

The present study concerns a practical approach to survey water sorption properties of ionic liquid ([EMIM]OAc) treated papers with and without chemical crosslinking. Ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([EMIM]OAc) can be used to transform sulfate pulp paper to regenerated cellulose film-like material. The fusion process increases both the dry and wet strength of the paper, improves oxygen and grease barrier properties, and increases paper transparency. The transformation is brought about by dissolution of the surfaces of the cellulosic fibers followed by precipitation and fusion of the fiber surfaces. Treatment conditions can be adjusted to produce partial dissolution of the fibers resulting in paper-like materials with improved wet-strength, or to achieve substantial or full dissolution resulting in transparent, regenerated cellulose film-like materials. From the industrial feasibility point of view, understanding the water sorption properties of IL-treated paper and the process parameters to control it are crucial. Results show that the treatment makes the paper more sensitive to both liquid water and water vapor, the magnitude depending on the degree of fiber dissolution and restraint of sheet shrinking during the treatment. Decreased water absorption and improved sheet dimensional stability were achieved by use of chemical crosslinking. [ABSTRACT FROM AUTHOR]

Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre‐eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non‐alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up‐to‐date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes. [ABSTRACT FROM AUTHOR]