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Phase-locking of two longitudinal oscillating modes of a dual-mode microchip laser that has 101 GHz longitudinal-mode spacing has been successfully demonstrated by using electronic negative-feedback control. Since the two longitudinal modes were oscillating simultaneously in the same laser cavity, the common-mode fluctuation cancels, resulted in the small required control bandwidth of ~4 kHz. This narrow-bandwidth phase-locking technique is useful for generating high-spectral-purity millimetre-wave signals with a considerably simpler setup. [ABSTRACT FROM AUTHOR]

The synthesis of TaSe 3 ring-shaped crystals displaying the coffee ring effect is investigated. By recrystallizing TaSe 3 microcrystals dissolved in droplets of condensed Se gas, ring-shaped crystals were successfully grown. This novel method for ring formation effectively addressed the issue of connecting the edges of the crystal. Consequently, the synthesis method has the capability to grow MX 3 ring-shaped crystals in any location where droplets can condense, can now be grown in specific locations, thus creating opportunities for advancements in electronic component development.

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma., (© 2024 MSD K.K. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT., Objectives: To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose., Materials and Methods: Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5 mg/wk) to a high-dose group (> 62.5 mg/wk)., Results: Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3 mo, P = 0.006, P < 0.001; 6 mo, P = 0.015, P < 0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia., Conclusion: Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass., (© 2024 American Society of Andrology and European Academy of Andrology.)

We previously found that ribosomal protein L9 (RPL9) is a novel advanced glycation end product (AGE)-binding protein that can decrease pro-inflammatory TNF-α expression stimulated by lipopolysaccharide (LPS) plus high-mobility group box 1 (HMGB1), suggesting that RPL9 has a role in regulating LPS+HMGB1-stimulated inflammatory reactions. Among the various ribosomal proteins, it was found that RPS5 reproduced the regulatory activity of RPL9 on LPS+HMGB1-stimulated TNF-α expression in macrophage-like RAW264.7 cells. RPL9 and RPS5 share a common feature as cationic proteins. Polylysine, a cationic polypeptide, and a synthetic peptide of the cationic region from RPL9 also exhibited reducing activity on LPS+HMGB1-induced TNF-α expression. By pull-down assay, RPL9 and RPS5 were confirmed to interact with AGEs. When AGEs coexisted with LPS, HMGB1, plus RPL9 or RPS5, the reducing effect of TNF-α expression by these cationic ribosomal proteins was shown to be abrogated. The results suggest that cationic ribosomal proteins have a regulatory role in the pro-inflammatory response induced by LPS+HMGB1, and in the pathophysiological condition of accumulating AGEs, this regulatory effect is abolished, which exacerbates inflammation., (© 2023 International Union of Biochemistry and Molecular Biology, Inc.)

Post-bariatric hypoglycaemia (PBH) is a metabolic complication of bariatric surgery (BS), consisting of low post-prandial glucose levels in patients having undergone bariatric procedures. While BS is currently the most effective and relatively safe treatment for obesity and its complications, the development of PBH can significantly impact patients' quality of life and mental health. The diagnosis of PBH is still challenging, considering the lack of definitive and reliable diagnostic tools, and the fact that this condition is frequently asymptomatic. However, PBH's prevalence is alarming, involving up to 88% of the post-bariatric population, depending on the diagnostic tool, and this may be underestimated. Given the prevalence of obesity soaring, and an increasing number of bariatric procedures being performed, it is crucial that physicians are skilled to diagnose PBH and promptly treat patients suffering from it. While the milestone of managing this condition is nutritional therapy, growing evidence suggests that old and new pharmacological approaches may be adopted as adjunct therapies for managing this complex condition., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury., Methods and Results: The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R., Conclusions: Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.

Backgrounds: There are limited data on the clinical relevance of transvalvular flow rate (Q mean ) at rest (Q rest) and at peak stress (Q stress ) during dobutamine stress echocardiography (DSE) in patients with low-gradient severe aortic stenosis (LG-SAS)., Methods: We retrospectively analyzed the clinical data of patients with LG-SAS who underwent DSE. LG-SAS was defined as an aortic valve (AV) area index of < .6 cm 2 /m 2 and a mean AV pressure gradient (AVPG) of < 40 mm Hg. The primary endpoint included all-cause death and heart failure hospitalization., Results: Of 100 patients (mean age 79.5 ± 7.3 years; men, 45.0%; resting left ventricular ejection fraction [LVEF] 52.1% ± 15.9%; resting stroke volume index 35.8 ± 7.7 mL/m 2 ; Q rest 171.8 ± 34.9 mL/s), the primary endpoint occurred in 51 patients during a median follow-up of 2.84 (interquartile range 1.01-5.21) years. When the study patients were divided into three subgroups based on Q rest and Q stress , the multivariate analysis showed that Qrest < 200 mL/s and Qstress ≥200 mL/s (hazard ratio 3.844; 95% confidence interval 1.143-12.930; p = .030), as well as Q rest and Qstress < 200 mL/s (hazard ratio 9.444; 95% confidence interval 2.420-36.850; p = .001), were significantly associated with unfavorable outcomes with Q rest and Qstress ≥200 mL/s as a reference after adjusting for resting LVEF, resting mean AVPG, chronic kidney disease, New York Heart Association functional class III/IV, and AV replacement., Conclusions: Flow conditions based on the combination of Q rest and Q stress are helpful for risk stratification in LG-SAS patients., (© 2023 Wiley Periodicals LLC.)

Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt-in-the-mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health., (© 2023 Japanese Dermatological Association.)

The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC)., Aim: To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long-term extension study SELECTIONLTE (NCT02914535)., Methods: Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11-week SELECTION induction study, the 47-week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure-adjusted incidence rates (EAIRs) per 100 censored patient-years of exposure with 95% confidence intervals were reported for treatment-emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status., Results: This interim analysis included 1348 patients representing 3326.2 patient-years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic-experienced than biologic-naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib., Conclusion: FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age., Gov Identifiers (nct Numbers): NCT02914522, NCT02914535., (© 2023 Galapagos NV. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Patients with recurrent adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic cell transplantation (allo-HCT) have a dismal prognosis. We retrospectively evaluated the safety and efficacy of lenalidomide (LEN) in 11 consecutive patients with recurrent ATL after allo-HCT. The median time from allo-HCT to ATL recurrence was 111 days (range, 20-1476), and that from allo-HCT to the initiation of LEN was 162 days (range, 43-1560). The median initial daily dose of LEN was 10 mg (range, 5-25), and the median duration of LEN treatment was 37 days (range, 3-1078). Three patients (27%) achieved complete response and two (18%) achieved partial response (PR). The rates of complete or PR according to the involved site were 57% for skin and 50% for nodal or extranodal lesions. With a median follow-up of 1033 days (range, 601-1465) among survivors, the 1-year probability of overall survival (OS) after ATL recurrence was 55%. Grade ≥3 toxicities included cytopenia (n = 4), superficial vein thrombosis (n = 1), and deep vein thrombosis (n = 1). Graft-versus-host disease (GVHD) newly developed in five patients (45%) and worsened in four patients (36%). The median duration from the initiation of LEN to GVHD onset or worsening was 5 days (range, 1-9). GVHD was manageable in all patients. Seven patients received mogamulizumab (MOG) for recurrent ATL before LEN treatment. The overall response rates to LEN were 57% in patients who had previously received MOG and 25% in those who had not. The 1-year probabilities of OS after recurrent ATL were 71% in patients who had previously received MOG and 25% in those who had not. Although cytopenia and GVHD are common among patients with recurrent ATL after allo-HCT, LEN may improve survival. Administering MOG before LEN may augment treatment efficacy in the allo-HCT population., (© 2022 John Wiley & Sons Ltd.)

The use of anti-SARS-CoV-2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID-19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti-spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV-AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV-AbDab clearly demonstrated the response to mRNA SARS-CoV-2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Aim: To investigate the association between periodontal disease and atherosclerosis and to examine whether the association is modified by hypertension status., Materials and Methods: In this cross-sectional study, 1472 Japanese individuals aged 50-79 years who underwent a medical check-up, dental examination, and carotid ultrasonography were studied. Carotid atherosclerosis was expressed as the maximum and mean carotid intima-media thickness (max-IMT, mean-IMT) and the presence of stenosis (≥75%). Periodontal status was examined by the Community Periodontal Index (CPI, codes 0-4). The participants were divided into three groups according to the periodontal status (CPI0-2, CPI3, CPI4)., Results: A positive correlation was found between mean-IMT and periodontal disease after adjustment for cardiovascular risk factors in the entire cohort (mean-IMT in hypertensives: CPI0-2: 0.848 mm, CPI3: 0.857 mm, CPI4: 0.877 mm; normotensives: 0.782, 0.802, 0.826). In the entire cohort, the multivariable-adjusted odds ratio of stenosis based on mean-IMT significantly increased according to periodontal status in normotensives (odds ratio; CPI0-2: 1, CPI3: 1.39, CPI4: 2.53; p-value for trend = .004) but showed only marginal significant increase in hypertensives (1, 1.15, 1.55; p-value for trend = .063). No significant relationships were observed for max-IMT in all analyses., Conclusion: We observed an association between periodontal disease and atherosclerosis in normotensive and hypertensive participants., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Erectile dysfunction is recognized as one of the complications of diabetes mellitus. To date, a wide gap of knowledge is present on the efficacy of pharmacological treatments of diabetes mellitus on erectile function, acting not only through metabolic control. Similarly, the effects of different diet regimens on erectile dysfunction are still debated., Objectives: We aimed to explore the effects of diet and antihyperglycemic drugs, considering both old and novel therapeutic approaches, on erectile function., Materials/methods: We performed a systematic review, following the PRISMA guidelines. The research was conducted on studies reporting erectile dysfunction assessment in subjects with diabetes and the relationship with diet and antihyperglycemic drugs., Results: The Mediterranean diet was effective in most studies for the protection of erectile function. Furthermore, antihyperglycemic drugs seem to show an overall protective role on erectile function., Discussion/conclusion: Although encouraging results are present for all classes of antihyperglycemic drugs, several studies are needed in humans, mainly on acarbose, pioglitazone, dipeptidyl-peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors., (© 2022 American Society of Andrology and European Academy of Andrology.)

Background The fractional excretion of urea nitrogen (FEUN) has been used as a renal blood flow index related to cardiac output, and the estimated plasma volume status (ePVS) as a body fluid volume index. However, the usefulness of their combination in acute decompensated heart failure (HF) management is unclear. We investigated the effect of 4 hemodynamic categories according to the high and low FEUN and ePVS values at discharge on the long-term prognosis of patients with acute decompensated HF. Methods and Results Between April 2011 and December 2018, we retrospectively identified 466 patients with acute decompensated HF with FEUN and ePVS values at discharge. Primary end point was postdischarge all-cause death. Secondary end points were (1) the composite of all-cause death and HF readmission, and (2) HF readmission in a time-to-event analysis. The patients were divided into 4 groups according to the high/low FEUN (≥35%, <35%) and ePVS (>5.5%, ≤5.5%) values at discharge: high-FEUN/low-ePVS, high-FEUN/high-ePVS, low-FEUN/low-ePVS, and low-FEUN/high-ePVS groups. During a median follow-up period of 28.1 months, there were 173 all-cause deaths (37.1%), 83 cardiovascular deaths (17.8%), and 121 HF readmissions (26.0%). The Kaplan-Meier curve analysis showed that the high-FEUN/low-ePVS group had a better prognosis than the other groups (log-rank test, P <0.001). In the multivariable Cox regression analysis, the low-FEUN/high-ePVS group had a higher mortality than the high-FEUN/low-ePVS group (hazard ratio, 2.92 [95% CIs, 1.73-4.92; P <0.001]). Conclusions The new classification of the 4 hemodynamic profiles using the FEUN and ePVS values may play an important role in improving outcomes in patients with stable acute decompensated HF.

HIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared with individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV-positive subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status, and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased "immunological age" compared with HIV-negative, age-matched cohort (HIV-) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed differential expression in several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Psoriasis and atopic dermatitis are inflammatory skin diseases, and these patients have an increased risk of cardiovascular events and other medical complications. It has been clarified that skin inflammation affects internal organs. Additionally, dental caries tends to occur more frequently in patients with psoriasis and atopic dermatitis. In this study, we aim to investigate the effects of dermatitis on the salivary glands using an inflammation model mouse. Salivary secretion stimulated with pilocarpine was reduced in dermatitis mice. Histologically, dermatitis mice showed amyloid deposition, glandular atrophy, and fibrosis in the salivary glands. Expression of inflammatory cytokines in the salivary glands was higher in dermatitis mice; however, secretion of cytokines in saliva was not significantly different. Dermatitis mice showed decreased salivary secretion and histological changes, which may cause periodontal disease. Therefore, appropriate control of skin inflammation is essential., (© 2022 Japanese Dermatological Association.)

Little information is available regarding whether unrelated cord blood transplantation (CBT) or an HLA 1-3 antigen-mismatched related donor peripheral blood stem-cell transplantation (PBSCT) using low-dose anti-thymocyte globulin (ATG) is superior as an alternative transplantation for patients who lack an HLA-matched sibling or unrelated donor. Therefore, we evaluated 7861 patients with hematologic malignancies (aged 0 to 70 years) who received either a CBT without ATG (CBT-no ATG, n = 7034) or an HLA 1-3 antigen-mismatched related donor PBSCT using low-dose ATG (PBSCT-ATG, n = 827). CBT-no ATG was associated with significantly better overall survival (OS) than the use of a PBSCT-ATG (hazard ratio [HR], 0.77; p < .001), although PBSCT-ATG patients with an HLA 1 antigen-mismatch showed OS comparable to that in the CBT-no ATG group. Neutrophil and platelet engraftment was significantly delayed, whereas the incidences of nonrelapse mortality, and severe graft-versus-host disease (GVHD) were significantly lower in the CBT-no ATG group. The incidences of relapse and chronic GVHD were comparable between these donors. In conclusion, CBT-no ATG may be a better alternative than HLA-mismatched related donor PBSCT using low-dose ATG. Notably, HLA 2-3 antigen mismatch-related transplantation with low-dose ATG had significant adverse effects on transplantation outcomes., (© 2022 Wiley Periodicals LLC.)

Aims: To investigate if extra virgin olive oil (EVOO) or palm oil enriched chocolate spreads consumption leads to different results in terms of plasma ceramides concentration, glucose and lipid metabolism, inflammatory markers and appetite regulation in young healthy subjects., Methods: In a 2-week, double-blind, cross-over, randomised controlled trial, 20 healthy, normal-weight subjects with a mean age of 24.2 years (SD: 1.2), consumed chocolate spread snacks (73% of energy [%E] from fat, 20% from carbohydrates and 7% from proteins), providing 570 Kcal/day added to an isocaloric diet. The chocolate spreads were identical, except for the type of fat: EVOO oil, rich in monounsaturated fatty acids (MUFAs), or palm oil, rich in Saturated Fatty Acids (SFAs)., Results: EVOO-enriched chocolate spread consumption led to better circulating sphingolipids and glucose profile, with reduced plasma ceramide C16:0, ceramide C16:0/ceramide C22:0-ceramide C24:0 ratio and sphingomyelin C18:0 (P = 0.030, P= 0.032 and P = 0.042, respectively) compared to the palm oil-enriched chocolate spread diet. HOMA-IR and plasma insulin were lower, while the Quicki and the McAuley Index were higher after the EVOO diet compared to the palm oil diet (P = 0.046, P = 0.045, P = 0.018 and P = 0.039 respectively). Subjects maintained a stable weight throughout the study. No major significant changes in total cholesterol, triglycerides, HDL, inflammatory markers, and appetite-regulating hormones/visual analogue scale were observed between the groups., Conclusions: Partially replacing SFAs with MUFAs in a chocolate-based snack as part of a short-term isocaloric diet in healthy individuals may limit SFAs detrimental effects on insulin sensitivity and decrease circulating harmful sphingolipids in young adults., (© 2021 VENCHI SpA. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Individuals with trisomy 18 (T18) usually have congenital heart disease, often with pulmonary hypertension, which is associated with poor outcomes. This study aimed to explore the characteristics of pulmonary circulation including pulmonary vascular resistance (Rp) and compliance (Cp) among them. We retrospectively reviewed cardiac catheterization data in subjects with T18, trisomy 21 (T21), and without chromosomal anomaly (control group) who were referred due to heart failure associated with ventricular septal defect between 2000 and 2020. Pulmonary hemodynamic parameters including Rp and Cp were compared between these groups. We studied 20 subjects with T18, 88 subjects with T21, and 240 control subjects. There was no significant difference in age (T18: 4.6 [3.0-6. 9] vs. T21: 2.8 [1.9-4.0] vs. control: 2.9 [1.6-3.2] months, p = 0.06) and mean pulmonary arterial pressure (T18: 41 [33-49] vs. T21: 35 [30-41] vs. control: 36 [28-43] mmHg, p = 0.121) between the groups. The pulmonary to systemic blood flow ratio (Qp/Qs) (p = 0.983), Rp (p = 0.449), and Cp (p = 0.195) did not differ between T18 and control groups. However, Qp/Qs and Cp in T18 group were significantly greater than that in T21 group (T18: Qp/Qs: 3.4 [2.3-5.2] vs. T: 21 2.3 [1.7-3.7], p = 0.001. Cp: 3.5 [2.3-5.5] vs. 2.3 [1.6-3.1] mmHg/mL/m 2 , p = 0.007), while Rp was identical between the groups (T18: 2.0 [1.6-3.3] vs. T21: 2.3 [1.7-3.7], p = 0.386). The pulmonary circulation in T18 subjects differed from that observed in T21 subjects, and identical to that observed in control subjects. Pulmonary hypertension is expected to be normalized after reasonable corrective surgery in T18 patients with congenital heart disease., (© 2021 Wiley Periodicals LLC.)

Aims: To explore variables associated with the serological response following COVID-19 mRNA vaccine., Methods: Eighty-six healthcare workers adhering to the vaccination campaign against COVID-19 were enrolled in January-February 2021. All subjects underwent two COVID-19 mRNA vaccine inoculations (Pfizer/BioNTech) separated by 3 weeks. Blood samples were collected before the 1st and 1-4 weeks after the second inoculation. Clinical history, demographics, and vaccine side effects were recorded. Baseline anthropometric parameters were measured, and body composition was performed through dual-energy-X-ray absorptiometry., Results: Higher waist circumference was associated with lower antibody (Ab) titres (R = -0.324, p = 0.004); smokers had lower levels compared to non-smokers [1099 (1350) vs. 1921 (1375), p = 0.007], as well as hypertensive versus normotensive [650 ± 1192 vs. 1911 (1364), p = 0.001] and dyslipideamic compared to those with normal serum lipids [534 (972) vs 1872 (1406), p = 0.005]. Multivariate analysis showed that higher waist circumference, smoking, hypertension, and longer time elapsed since second vaccine inoculation were associated with lower Ab titres, independent of BMI, age. and gender., Conclusions: Central obesity, hypertension, and smoking are associated with lower Ab titres following COVID-19 vaccination. Although it is currently impossible to determine whether lower SARS-CoV-2 Abs lead to higher likelihood of developing COVID-19, it is well-established that neutralizing antibodies correlate with protection against several viruses including SARS-CoV-2. Our findings, therefore, call for a vigilant approach, as subjects with central obesity, hypertension, and smoking could benefit from earlier vaccine boosters or different vaccine schedules., (© 2021 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: Mitral annular calcification (MAC) is increasingly observed in elderly population. The purpose of this study was to investigate incidence of MAC and its association with mitral valvular disease (MVD)., Methods: A total of 13,483 consecutive patients who underwent echocardiography were enrolled. MAC was defined as an echo-dense, shelf-like structure with an irregular, lumpy appearance involving the mitral valve annulus, with acoustic shadowing. Prevalence of MAC and its association with significant mitral stenosis (MS) or mitral regurgitation (MR) were studied. Significant (≥moderate) MS was defined as mean transmitral valvular pressure gradient > 5 mm Hg and significant MR was defined as ≥moderate MR based on quantitative or semi-quantitative Doppler methods., Results: MAC was present in 1881 of 13,483 patients (14%). Patients with MAC (MAC group) was older and more female gender than those without MAC (non-MAC group). Significant MS was present in 2.2% of MAC and in .6% of the non-MAC group (p < 0.0001). Significant MR was present in 11.9% of MAC and in 5.0% of the non-MAC group (p < 0.0001). Co-existence of MAC and aortic valve replacement (AVR) was associated with increased prevalence of MVD (MS:11.4%, MR:17.2%, respectively)., Conclusion: MAC was present in 14% of the patients and was associated with significant MVD. Co-existence of MAC and AVR may increase the risk of MVD., (© 2021 Wiley Periodicals LLC.)

Background: Several studies have reported a positive correlation between serum drug concentrations and endoscopic remission in patients with Crohn's disease., Aim: To examine the association between the concentrations of cytokine blockers (infliximab, adalimumab and ustekinumab) and endoscopic remission of small bowel lesions., Method: This was a cross-sectional study conducted at a single tertiary referral centre. Patients with Crohn's disease who received maintenance cytokine blocker therapy were recruited from April 2018 to May 2020. We performed balloon-assisted enteroscopy and collected serum samples to measure drug concentrations. The primary endpoint was the relationship between the concentrations of cytokine blockers and endoscopic remission in the small bowel., Results: We enrolled 143 patients, 66, 44 and 33 of whom were receiving infliximab, adalimumab and ustekinumab, respectively. Enteroscopic findings showed that the rate of endoscopic remission of small bowel lesions was significantly lower than that of colonic lesions (P < 0.01). For each agent, the mean drug concentration in patients exhibiting endoscopic remission in the small bowel was higher than that observed in patients with endoscopic remission in the colon (but not in the small bowel) or with any active disease (either in the small bowel, colon or both). Patients with infliximab, adalimumab and ustekinumab concentrations >5, 14 and 4 µg/mL were nearly 5.3-, 9.4- and 14.7-times more likely to exhibit endoscopic remission of the small bowel, respectively., Conclusions: Cytokine blocker treatment was less efficacious for small bowel inflammation than colonic inflammation. Higher serum concentrations were needed to achieve endoscopic remission of small bowel lesions., (© 2021 John Wiley & Sons Ltd.)

Objective: Dobutamine stress echocardiography (DSE) is not always feasible in patients with low-gradient severe aortic stenosis (LG-SAS), and there are limited data available on the resting echocardiographic predictors for true-severe aortic stenosis (TSAS). This study investigated resting echocardiographic predictors for TSAS., Methods: Clinical data of 106 LG-SAS patients who underwent DSE were retrospectively analyzed. LG-SAS was defined as an aortic valve area index (AVAi) < .6 cm 2 /m 2 , and a mean AV pressure gradient < 40 mm Hg. The velocity ratio (VR) was calculated as the peak left ventricular outflow tract velocity/peak AV velocity. TSAS was defined as a projected AVAi < .6 cm 2 /m 2 ., Results: The mean age was 79.3 ± 7.3 years, and 45 (42.5%) were men. The resting AV data were as follows: AVAi, .50 ± .07 cm 2 /m 2 ; mean AV pressure gradient, 23.0 ± 7.4 mm Hg; and VR, .25 ± .05. The projected AVAi was .58 ± .09 cm 2 /m 2 , and TSAS was documented in 65 (61.3%) patients. In multivariate analysis, the independent predictors of TSAS were AVAi (p = 0.012) and VR (p = 0.004) with respective best cut-off values of .52 cm 2 /m 2 and .25 on receiver-operating characteristic curve analysis. According to incremental numbers of the predictors, correct classification percentages of TSAS significantly increased with the Cochran-Armitage trend test (16.2% in no predictors, 65.2% in one predictor, and 95.7 % in two predictors; p < 0.001)., Conclusions: Resting AVAi and VR were independent predictors of TSAS in LG-SAS patients. The true severity might be predictable using the combination of resting parameters., (© 2021 Wiley Periodicals LLC.)

Aim: We aimed to clarify the association between deterioration of periodontal status and masticatory performance in a longitudinal follow-up study of a general urban population., Materials and Methods: This study investigated 663 participants in the Suita study with no changes in the number of functional teeth or occlusal support areas during a 5-year follow-up period. Participants were classified into three groups according to changes in periodontal status during the survey period: a recovered group; a stable group; and a deteriorated group. Rate of masticatory performance change was calculated by subtracting the value at baseline from the value at follow-up and dividing the resulting value by the baseline value., Results: Median rates of masticatory performance change were -11.7% in the recovered group, -19.2% in the stable group, and -30.8% in the deteriorated group, and these values were significantly different (p < .001). Multiple regression analysis revealed periodontal status group (recovered group: reference; stable group: p = .029; deteriorated group: p = .006) as an independent variable was significantly associated with the rate of masticatory performance change., Conclusion: The present results suggest that deterioration of periodontal status increases the risk of age-related declines in masticatory performance., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D)., Materials and Methods: Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption., Results: GLP-1 and oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend., Conclusions: In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period., (© 2020 John Wiley & Sons Ltd.)

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long-term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post-discharge all-cause death. Patients were divided into two groups according to a FEUN cut-off value of 35%, commonly used in pre-renal failure. The FEUN <35% (low-FEUN) group included 224 patients (48.1%), and the all-cause mortality rate for the total cohort was 37.1%. The log-rank test revealed that the low-FEUN group had a significantly higher rate of all-cause death compared to the FEUN equal to or greater than 35% (high-FEUN) group ( P <0.001). Multivariate Cox proportional hazards model analysis revealed that low-FEUN was associated with post-discharge all-cause death, independently of other heart failure risk factors (hazard ratio, 1.467; 95% CI, 1.030-2.088, P =0.033). The risk of low-FEUN compared to high-FEUN in post-discharge all-cause death was consistent across all subgroups; however, the effects tended to be modified by renal function (threshold: 60 mL/min/1.73 m 2 , interaction P =0.069). Conclusions Our study suggests that FEUN may be a novel surrogate marker of volume status in patients with ADHF requiring diuretics.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34 + , CD203c - , CD117 + , CD123dim + ) and basophils (CD34 - , CD203c + , CD117 ± , CD123 + ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33 + , CD34 + , CD123 - ) and basophils (CD33 + , CD34 + , CD123 + ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: The risk stratification of hypertrophic cardiomyopathy (HCM) without left ventricular outflow tract (LVOT) obstruction and the utility of exercise stress echocardiography (ESE) remains unclear. We investigated the value of right ventricular (RV) function and RV-pulmonary artery (PA) coupling during exercise in asymptomatic/minimally symptomatic patients with nonobstructive HCM (nHCM)., Method and Results: This retrospective study evaluated 74 HCM patients (age 63 ± 13 years, 65% men) without LVOT obstruction (≥30 mmHg) who underwent​ ESE. Eight patients (11%) suffered from HCM-related cardiac events during a median 2.5 years follow-up. During exercise, tricuspid annular plane systolic excursion (Ex-TAPSE) and Ex-TAPSE/systolic pulmonary artery pressure [SPAP] ratio were more impaired in patients with than in those without events (22 ± 4 vs 26 ± 4 mm, P = .005; and 0.45 [0.41, 0.47] vs 0.56 [0.47, 0.82] mm/mmHg, P = .002). In Cox regression analysis, Ex-TAPSE (HR: 1.397, P = .002) and the Ex-TAPSE/SPAP ratio (HR: 2.737, P = .006) were associated with cardiac events. In Kaplan-Meier analysis, patients with a low Ex-TAPSE (<24 mm) and Ex-TAPSE/SPAP ratio (<0.50 mm/mmHg) had a higher incidence of adverse outcomes than those with high Ex-TAPSE (Log rank, P < .001 and =.001, respectively)., Conclusions: A low Ex-TAPSE and Ex-TAPSE/SPAP ratio were associated with adverse outcomes in nHCM. Evaluation of RV functional performance during exercise may play a crucial role in the risk stratification of nHCM., (© 2021 Wiley Periodicals LLC.)

New Findings: What is the central question of this study? Recently, an internal jugular venous thrombus was identified during spaceflight: does microgravity induce venous and/or coagulation pathophysiology, and thus an increased risk of venous thromboembolism (VTE)? What is the main finding and its importance? Whilst data are limited, this systematic review suggests that microgravity and its analogues may induce an enhanced coagulation state due to venous changes most prominent in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability in microgravity and its analogues. However, whether such changes precipitate an increased VTE risk in spaceflight remains to be determined., Abstract: Recently, an internal jugular venous thrombus was identified during spaceflight, but whether microgravity induces venous and/or coagulation pathophysiology, and thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore, a systematic (Cochrane compliant) review was performed of venous system or coagulation parameters in actual spaceflight (microgravity) or ground-based analogues in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which 26 were included for evaluation with 21 evaluating venous, and five coagulation parameters. Nine articles contained spaceflight data, whereas the rest reported ground-based analogue data. There is substantial variability in study design, objectives and outcomes. Yet, data suggested cephalad venous system dilatation, increased venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen levels, presence of thrombin generation markers and endothelial damage were also reported. Limited human venous and coagulation system data exist in spaceflight, or its analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation state in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability. Whether such changes precipitate an increased VTE risk in spaceflight remains to be determined., (© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Mucosal healing is an important treatment target in patients with ulcerative colitis., Aims: To explore the optimal colonoscopic strategy to determine the risk for clinical relapse in patients with ulcerative colitis., Methods: We enrolled 325 consecutive patients with ulcerative colitis in clinical and biochemical remission from April 2018 to March 2019. Five colonic segments were endoscopically and histologically assessed systematically. For endoscopic evaluation, we used three different modes of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS): "original," "worst affected," and "pancolonic." The Geboes score was used for histological evaluation. We prospectively followed up the patients and defined clinical relapse as the primary endpoint., Results: Within 1 year after colonoscopy, 18.2% of patients experienced a clinical relapse. Receiver operating characteristic curve analysis showed areas under the curve of 0.755, 0.817, and 0.852 for the "original," "worst affected," and "pancolonic" groups, respectively; hence, pancolonic UCEIS obtained the highest predictive value. Using the pancolonic UCEIS cutoff value of 3, Kaplan-Meier curve analysis showed that patients with endoscopic activity had a significantly lower relapse-free rate than those with endoscopic remission (P < 0.01). Multivariate analysis demonstrated endoscopic (pancolonic UCEIS >3) and histological (Geboes >3.0) activities as independent risks for relapse (HR: 3.96 and 3.48, respectively). Combining pancolonic UCEIS ≤3 and Geboes score ≤3.0 to provide 1-year relapse avoidance was 92.0% sensitive and 97.0% specific., Conclusion: Evaluating disease remission by complete colonoscopy is relevant, and the combination of pancolonic endoscopic and histological evaluations may appropriately evaluate mucosal healing., (© 2021 John Wiley & Sons Ltd.)

Aim: To examine the effects of an enteropeptidase inhibitor, SCO-792, on kidney function in rats., Materials and Methods: The pharmacological effects of SCO-792 were evaluated in Wistar fatty (WF) rats, a rat model of diabetic kidney disease (DKD)., Results: Oral administration of SCO-792 increased faecal protein content and improved glycaemic control in WF rats. SCO-792 elicited a rapid decrease in urine albumin-to-creatinine ratio (UACR). SCO-792 also normalized glomerular hyperfiltration and decreased fibrosis, inflammation and tubular injury markers in the kidneys. However, pioglitazone-induced glycaemic improvement had no effect on kidney variables. Dietary supplementation of amino acids (AAs), which bypass the action of enteropeptidase inhibition, mitigated the effect of SCO-792 on UACR reduction, suggesting a pivotal role for enteropeptidase. Furthermore, autophagy activity in the glomerulus, which is impaired in DKD, was elevated in SCO-792-treated rats. Finally, a therapeutically additive effect on UACR reduction was observed with a combination of SCO-792 with irbesartan, an angiotensin II receptor blocker., Conclusions: This study is the first to demonstrate that enteropeptidase inhibition is effective in improving disease conditions in DKD. SCO-792-induced therapeutic efficacy is likely to be independent of glycaemic control and mediated by the regulation of AAs and autophagy. Taken together with a combination effect of irbesartan, SCO-792 may be a novel therapeutic option for patients with DKD., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Although 5-aminosalicylate (5-ASA) is the therapy of first choice in ulcerative colitis (UC), some patients cannot tolerate it because of side effects. Previous reports have not investigated whether 5-ASA intolerance is associated with the risk of colectomy., Aim: To investigate the associations between 5-ASA tolerance and colectomy among UC patients METHODS: The data of UC patients who visited any of three hospitals during 2014-2018 in and around Tokyo, Japan, were retrospectively obtained from the medical records. Patients were categorized as (a) tolerant to any 5-ASA compounds ("tolerant to 5-ASA") and (b) patients who were intolerant to one or more 5-ASA compounds leading to refrainment from their further use ("intolerant to 5-ASA"). The association between 5-ASA tolerance and colectomy was examined by Cox proportional hazards model adjusted for sex, age, smoking and extent of colitis., Results: Of 1788 patients, 1684 were "tolerant to 5-ASA" while 104 were "intolerant to 5-ASA". Colectomy was performed in 43 (2.6%) of the patients tolerant to 5-ASA and 12 (11.5%) of the patients intolerant to 5-ASA. After adjusting for all covariates, the risk of undergoing colectomy was higher in the "intolerant to 5-ASA" group than in the "tolerant to 5-ASA" group (hazard ratio: 4.92; 95% confidence interval: 2.58-9.38)., Conclusion: Patients in whom 5-ASA was discontinued due to intolerance had a higher risk of undergoing colectomy than patients tolerant to their first, second or third 5-ASA compounds., (© 2020 John Wiley & Sons Ltd.)

Background: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C 2 H 5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant.", Methods/results: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts., Conclusions: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues., (© 2020 by the Research Society on Alcoholism.)

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium-dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium-dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium-dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium-dependent hyperpolarization (EDH)-mediated vasodilation was prominent in small distal PAs (fourth-fifth order). Chronic hypoxia abolished EDH-mediated relaxation in small distal PAs without affecting smooth muscle-dependent relaxation. RNA-sequencing data revealed that, among genes related to EDH, the levels of Cx37 , Cx40 , Cx43 , and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH-mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH-mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia-induced downregulation of endothelial Cx40 results in impaired EDH-mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension.

Aims: The safety and pharmacokinetics of single and multiple doses of a novel mGlu 2/3 receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects., Methods: Phase 1 single-ascending dose (5-20 mg) and multiple-ascending dose titration (5-80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double-blinded and placebo-controlled. In one cohort of single-ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose., Results: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (C max ) in plasma within 4 hours postdose and declined with a terminal half-life (t 1/2 ) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma C max and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma C max ratio of 3.66%, and was eliminated with a t 1/2 of approximately 16 hours. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting., Conclusion: TS-134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS-134 was safe and generally well-tolerated; hence, TS-134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia., (© 2020 Taisho Pharmaceutical R&D Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Evidence has lately emerged regarding an increased risk of SARS-CoV-2 with worse prognosis in patients with obesity, especially among the young. Weight excess is a well-established respiratory disease risk factor, and the newly reported correlation is therefore unsurprising. The underlying pathophysiology is likely multi-stranded, ranging from complement system hyperactivation, increased Interleukin-6 secretion, chronic inflammation, presence of comorbidities such as diabetes and hypertension, and a possible local, detrimental effect within the lung. Further understanding the link between obesity and SARS-CoV-2 is crucial, as this could aid proper tailoring of immunomodulatory treatments, together with improving stratification among those possibly requiring critical care., (© 2020 John Wiley & Sons Ltd.)

BACKGROUND Vascular healing response associated with adjunctive n-3 polyunsaturated fatty acid therapy therapy in patients receiving strong statin therapy remains unclear. The aim of this study was to evaluate the effect of polyunsaturated fatty acid therapy with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in addition to strong statin therapy on coronary atherosclerotic plaques using optical coherence tomography. METHODS AND RESULTS This prospective multicenter randomized controlled trial included 130 patients with acute coronary syndrome treated with strong statins. They were assigned to either statin only (control group, n=42), statin+high-dose EPA (1800 mg/day) (EPA group, n=40), statin+EPA (930 mg/day)+DHA (750 mg/day) (EPA+DHA group, n=48). Optical coherence tomography was performed at baseline and at the 8-month follow-up. The target for optical coherence tomography analysis was a nonculprit lesion with a lipid plaque. Between baseline and the 8-month follow-up, fibrous cap thickness (FCT) significantly increased in all 3 groups. There were no significant differences in the percent change for minimum FCT between the EPA or EPA+DHA group and the control group. In patients with FCT <120 µm (median value), the percent change for minimum FCT was significantly higher in the EPA or EPA+DHA group compared with the control group. CONCLUSIONS EPA or EPA+DHA therapy in addition to strong statin therapy did not significantly increase FCT in nonculprit plaques compared with strong statin therapy alone, but significantly increased FCT in patients with thinner FCT. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN 000012825.

Use of antimicrobials for acne treatment is correlated with an increased occurrence of antimicrobial-resistant Cutibacterium acnes. To clarify the role of antimicrobial use on the resistance and to investigate the characteristics of resistant strains, we conducted a multicenter study in dermatological clinics frequently visited by new patients with acne vulgaris. We collected specimens in 264 acne patients and tested 164 C. acnes strains isolated from 164 patients visiting 13 dermatological clinics. Antimicrobial susceptibility testing showed that the rates of resistance for tetracyclines, macrolides and clindamycin were significantly higher in C. acnes strains isolated from patients using antimicrobials for acne treatment than patients not using them. In particular, clindamycin-resistant strains were frequently isolated from patients with older median age (≥24 years) and severe/moderate acne. After investigating the resistance mechanism of 15 high-level clindamycin-resistant strains, the transposable clindamycin resistance genes, erm(X) or erm(50), were detected in 14 strains. Using single-locus sequence typing for C. acnes, the strains with erm(X) or multidrug resistance plasmid pTZC1 coding erm(50) and tetracycline resistance gene tet(W) were classified into clade F, which were specifically isolated from Japanese patients with acne, except for one strain. Our data showed that patients' information, such as antimicrobial use, age and acne severity, are valuable in estimating whether a patient carries antimicrobial-resistant C. acnes. Additionally, our results suggest that the clade F strains have a high risk of acquiring multidrug resistance., (© 2020 Japanese Dermatological Association.)

Background Insulin beneficially affects myocardial functions during myocardial ischemia. It increases glucose-derived ATP production, decreases oxygen consumption, suppresses apoptosis of cardiomyocytes, and promotes the survival of cardiomyocytes. Patients with chronic heart failure generally have high insulin resistance, which is correlated with poor outcomes. The role of insulin in acute decompensated heart failure (ADHF) remains unclear. This study aimed to investigate the prognostic value of serum insulin level at the time of admission for long-term outcomes in patients with ADHF. Methods and Results We enrolled 1074 consecutive patients who were admitted to our department for ADHF. Of these 1074 patients, we studied the impact of insulin on the prognosis of ADHF in 241 patients without diabetes mellitus. The patients were divided into groups according to low, intermediate, and high tertiles of serum insulin levels. Primary end points were all-cause death and cardiovascular death. During a mean follow-up of 21.8 months, 71 all-cause deaths and 38 cardiovascular deaths occurred. Kaplan-Meier analysis showed that all-cause and cardiovascular mortality was significantly higher in the low-insulin group than those in the intermediate- and high-insulin groups (log-rank P =0.0046 and P =0.038, respectively). Moreover, according to the multivariable analysis, low serum insulin was an independent predictor of all-cause and cardiovascular mortality (hazard ratio, 2.37 [95% CI, 1.24-4.65; P =0.009] and 2.94 [95% CI, 1.12-8.19; P =0.028], respectively). Conclusions Low serum insulin levels were associated with increased risk of all-cause and cardiovascular death in ADHF patients without diabetes mellitus.