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There is insufficient evidence that angiotensin-converting enzyme inhibitors (ACEIs) can reduce pneumonia by inducing a dry cough that confers a protective effect on the airway. To increase the evidence base on the clinical use of ACEIs for pneumonia prevention, this retrospective cohort study aimed to comparatively examine the risk of pneumonia-related hospitalization between ACEI initiators and angiotensin II receptor blocker (ARB) initiators using claims data from two Japanese municipalities. We identified persons who were newly prescribed any ACEI or ARB as their first antihypertensive agent between April 2016 and March 2020. The Fine-Gray method was applied to a Cox proportional hazards model to estimate the subdistribution hazard ratio (HR) of ACEI use (reference: ARB use) for pneumonia-related hospitalization, with death treated as a competing risk. Sex, age, comorbidities, medications, and pneumococcal immunization were included as covariates. The analysis was conducted on 1421 ACEI initiators and 9040 ARB initiators, and the adjusted subdistribution HR of ACEI use was estimated to be 1.21 (95% confidence interval: 0.89-1.65; P = 0.22). ACEI initiation did not demonstrate any significant preventive effect against pneumonia-related hospitalization relative to ARB initiation. There remains a lack of strong evidence on the protective effects of ACEIs, and further research is needed to ascertain the benefits of their use in preventing pneumonia. We conducted a large-scale retrospective cohort study using real-world healthcare data from a Japanese population. In this study, ACEI initiation did not indicate a significant preventive effect against pneumonia-related hospitalization., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Purpose: We described clinical outcomes for patients with blunt splenic injuries treated with transarterial embolization (TAE) based on their hemodynamic status., Materials and Methods: This is a retrospective two-center study of adult patients with splenic injuries who underwent emergency TAE between January 2011 and December 2022. Patients were divided into two groups; hemodynamically unstable (HDU) and hemodynamically stable (HDS) patients. HDU patients were defined as transient- or non-responders to fluid resuscitation and HDS as responders. When immediate laparotomy was not possible for HDU patients, angiography and embolization were performed. The primary outcome was the survival discharge rate. Rebleeding and splenectomy rate was also investigated., Results: Of 38 patients underwent emergency TAE for splenic trauma, 17 were HDU patients and 21 were HDS patients. The survival discharge rate was 88.2 % (15/17) in the HDU- and 100 % in HDS patients (p = 0.193). Rebleeding rate was 23.5 % (4/17) in HDU- and 5.0 % (1/21) in HDS patients (p = 0.15). Splenectomy was required for one HDU patient (5.9 %) for rebleeding., Conclusion: The survival discharge rate of TAE for splenic trauma in HDU patients was acceptable with a low rate of splenectomy. Further comparative studies of TAE versus operative management in HDU patients are needed to prove the usefulness of TAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial., Methods and results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133-567) and 170 (72-358) days, respectively, compared with 146 (70-309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50-0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73-0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62-0.76; P<0.001)., Conclusions: This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.

Here we examined the membrane binding and pore formation of amphidinol 3 (AM3) and its truncated synthetic derivatives. Importantly, both of the membrane affinity and pore formation activity were well correlated with the reported antifungal activity. Our data clearly demonstrated that the C1-C30 moiety of AM3 plays essential roles both in sterol recognition and stable pore formation. Based on the current findings, we updated the interacting model between AM3 and sterol, in which the moiety encompassing from C21 to C67 accommodates a sterol molecule with forming hydrogen bonds with the sterol hydroxy group and van der Waals contact between AM3 polyol and sterol skeleton. Although the conformation of the C1-C20 moiety of AM3 is hard to specify due to its flexibility, the region likely contributes to stabilization of pore structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT., Methods: Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o 2 ; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples t tests., Results: V̇o 2 was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; P =0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; P =0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; P =0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; P =0.007)., Conclusions: In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF., Competing Interests: Disclosures None.

Background Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy. Methods and Results Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (V˙O 2 ; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak V˙O 2 by 1.3 mL/kg per min ( P =0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise P =0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL P =0.005). HIT increased left ventricular end-diastolic volume (+17 mL, group×exercise P =0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred. Conclusions This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03335332.

To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)+ RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3'-end processing defects of replication-dependent histone mRNAs by Nsp14. These abnormalities were also observed in SARS-CoV-2-infected cells. A mutation introduced at the guanine-N7-methyltransferase active site of Nsp14 diminished these inhibitory activities. Targeted capillary electrophoresis-mass spectrometry analysis (CE-MS) unveiled the production of N7-methyl-GTP in Nsp14-expressing cells. Association of the nuclear cap-binding complex (NCBC) with the mRNA cap and subsequent recruitment of U1 snRNP and the stem-loop binding protein (SLBP) were impaired by Nsp14. These data suggest that the defects in mRNA processing and export arise from the compromise of NCBC function by N7-methyl-GTP, thus exemplifying a novel viral strategy to block host gene expression., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Impaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF., Objectives: This study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects., Methods: Eleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 μg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 μg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography)., Results: Patients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 μg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 μg/kg/min during exercise, PCWP during the 1.0 μg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s', suggesting a mild inotropic effect., Conclusions: Low-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068)., Competing Interests: Funding Support and Author Disclosures This project was supported by the National Institutes of Health (grant RO1 AG17479). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The linker of nucleoskeleton and cytoskeleton (LINC) complex has been implicated in various functions of the nuclear envelope, including nuclear migration, mechanotransduction and DNA repair. We previously revealed that the LINC complex component Sad1 and UNC84 domain containing 1 (SUN1) is required for sublethal-dose X-ray-enhanced cell migration and invasion. This study focused on epithelial-mesenchymal transition (EMT), which contributes to cell migration. Hence, the present study aimed to examine whether sublethal-dose X-irradiation induces EMT and whether LINC complex component SUN1 is involved in low-dose X-ray-induced EMT. This study showed that low-dose (0.5 Gy or 2 Gy) X-irradiation induced EMT in human breast cancer MDA-MB-231 cells. Additionally, X-irradiation increased the expression of SUN1. Therefore, SUN1 was depleted using siRNA. In SUN1-depleted cells, low-dose X-irradiation did not induce EMT. In addition, although the SUN1 splicing variant SUN1&#95;916-depleted cells (containing 916 amino acids [AA] of SUN1) were induced EMT by low-dose X-irradiation like as non-transfected control cells, SUN1&#95;888-depleted cells (which encodes 888 AA) were not induced EMT by low-dose X-irradiation. Moreover, since the Wnt/β-catenin signaling pathway regulates E-cadherin expression via the expression of the E-cadherin repressor Snail, the expression of β-catenin after X-irradiation was examined. After 24 hours of irradiation, β-catenin expression increased in non-transfected cells or SUN1&#95;916-depleted cells, whereas β-catenin expression remained unchanged and did not increase in SUN1- or SUN1&#95;888-depleted cells. Therefore, in this study, we found that low-dose X-irradiation induces EMT, and LINC complex component SUN1, especially SUN1&#95;888, is required for X-ray-induced EMT via activation of the Wnt/β-catenin signaling pathway., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Aerobic exercise is important in the rehabilitation of individuals with prior burn injuries, but no studies have examined whether adult burn survivors demonstrate cardiac remodeling to long-term aerobic exercise training. In this study, we tested the hypothesis that 6 months of progressive exercise training improves cardiac magnetic resonance imaging-based measures of cardiac structure and function in well-healed burn survivors. Secondary analyses explored relations between burn surface area and changes in cardiac structure in the cohort of burn survivors. V̇o 2peak assessments and cardiac magnetic resonance imaging were performed at baseline and following 6 months of progressive exercise training from 19 well-healed burn survivors and 10 nonburned control participants. V̇o 2peak increased following 6 months of training in both groups (Control: Δ5.5 ± 5.8 mL/kg/min; Burn Survivors: Δ3.2 ± 3.6 mL/kg/min, main effect of training, P < 0.001). Left ventricle (LV) mass (Control: Δ1.7 ± 3.1 g/m 2 ; Burn survivors: Δ1.8 ± 2.7 g/m 2 ), stroke volume (Control: Δ5.8 ± 5.2 mL/m 2 ; Burn Survivors: Δ2.8 ± 4.2 mL/m 2 ), and ejection fraction (Control: Δ2.4 ± 4.0%; Burn Survivors: Δ2.2 ± 4.3%) similarly increased following 6 months of exercise training in both cohorts (main effect of training P < 0.05 for all indexes). LV end-diastolic volume increased in the control group (Δ6.5 ± 4.5 mL/m 2 ) but not in the cohort of burn survivors (Δ1.9 ± 2.7 mL/m 2 , interaction, P = 0.040). Multiple linear regression analyses revealed that burn surface area had little to no effect on changes in ventricular mass or end-diastolic volumes in response to exercise training. Our findings provide initial evidence of physiological cardiac remodeling, which is not impacted by burn size, in response to exercise training in individuals with well-healed burn injuries. NEW & NOTEWORTHY Aerobic exercise is important in the rehabilitation of individuals with prior burn injuries, but no studies have examined whether adult burn survivors demonstrate cardiac remodeling to long-term aerobic exercise training. In this study, we tested the hypothesis that 6 months of progressive exercise training would improve cardiac magnetic resonance imaging-based measures of cardiac structure and function in well-healed burn survivors. Our findings highlight the ability of exercise training to modify cardiac structure and function in well-healed burn survivors and nonburned sedentary controls alike.

Background: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown., Objectives: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension., Method: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint., Results: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584)., Conclusions: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified., Methods: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding., Results: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients., Conclusions: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Compared with younger adults, passive heating induced increases in cardiac output are attenuated by ∼50% in older adults. This attenuated response may be associated with older individuals' inability to maintain stroke volume through ionotropic mechanisms and/or through altered chronotropic mechanisms. The purpose of this study was to identify the interactive effect of age and hyperthermia on cardiac responsiveness to dobutamine-induced cardiac stimulation. Eleven young (26 ± 4 yr) and 8 older (68 ± 5 yr) participants underwent a normothermic and a hyperthermic (baseline core temperature +1.2°C) trial on the same day. In both thermal conditions, after baseline measurements, intravenous dobutamine was administered for 12 min at 5 µg/kg/min, followed by 12 min at 15 µg/kg/min. Primary measurements included echocardiography-based assessments of cardiac function, gastrointestinal and skin temperatures, heart rate, and mean arterial pressure. Heart rate responses to dobutamine were similar between groups in both thermal conditions ( P > 0.05). The peak systolic mitral annular velocity (S'), i.e., an index of left ventricular longitudinal systolic function, was similar between groups for both thermal conditions at baseline. While normothermic, the increase in S' between groups was similar with dobutamine administration. However, while hyperthermic, the increase in S' was attenuated in the older participants with dobutamine ( P < 0.001). Healthy, older individuals show attenuated inotropic, but maintained chronotropic responsiveness to dobutamine administration during hyperthermia. These data suggest that older individuals have a reduced capacity to increase cardiomyocyte contractility, estimated by changes in S', via β1-adrenergic mechanisms while hyperthermic.

Patients with hypertrophic cardiomyopathy (HCM) often have reduced exercise capacity, and it is unclear whether cardiovascular regulation during exercise is intact in these patients. We aimed to determine the relationship between cardiac output (Q̇ c ) and oxygen uptake (V̇o 2 ), and stroke volume (SV) reserve in HCM compared with healthy participants and participants with left ventricular hypertrophy (LVH) but not HCM. Sixteen patients with HCM (48 ± 7 yr, 44% female), 16 participants with LVH (49 ± 5 yr, 44% female), and 61 healthy controls (CON: 52 ± 5 yr, 52% female) completed submaximal steady-state treadmill exercise followed by a maximal exercise test. V̇o 2 , Q̇ c , SV, and arteriovenous oxygen difference were measured during rest and exercise, and Q̇ c /V̇o 2 slopes were constructed, The Q̇ c /V̇o 2 slope was blunted in HCM compared with CON and LVH [HCM 4.9 ± 0.7 vs. CON 5.5 ± 1.0 ( P = 0.027) vs. LVH 6.0 ± 1.0 AU ( P = 0.002)] and participants with HCM had a lower SV reserve (HCM 53 ± 33%, controls 83 ± 33%, LVH 82 ± 22%; HCM vs. controls P = 0.002; HCM vs. LVH P = 0.015). Despite a blunted Q̇ c /V̇o 2 slope, 75% of patients with HCM achieved ≥80% predicted V̇o 2max by augmenting a-vo 2 difference at maximal exercise (16.0 ± 0.8 mL/100 mL vs. 13.8 ± 2.7 mL/100 mL, P = 0.021). Patients with HCM do not appropriately match Q̇ c to metabolic demand, primarily due to inadequate stroke volume augmentation. Despite this central limitation, many patients achieve normal exercise capacities by significantly increasing peripheral oxygen extraction. NEW & NOTEWORTHY Through state-of-the-art hemodynamic and oxygen uptake methodologies, this study found the cardiac output response to increasing metabolic demand is blunted among patients with hypertrophic cardiomyopathy (HCM), primarily due to a reduced stroke volume reserve. Many patients with HCM augment their peripheral oxygen extraction during maximal exercise to achieve normal exercise capacity and overcome ineffective matching of cardiac output. Peripheral adaptations that compensate for cardiac limitations may contribute to the heterogeneity of functional limitations observed within this patient population.

The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the inner nuclear membrane-spanning SUN proteins and the outer nuclear membrane-spanning nesprin proteins. The LINC complex physically connects the nucleus and plasma membrane via the actin cytoskeleton to perform diverse functions including mechanotransduction from the extracellular environment to the nucleus. Mammalian somatic cells express two principal SUN proteins, namely SUN1 and SUN2. We have previously reported that SUN1, but not SUN2, is essential for directional cell migration; however, the underlying mechanism remains elusive. Because the balance between adhesive force and traction force is critical for cell migration, in the present study, we focused on focal adhesions (FAs) and the actin cytoskeleton. We observed that siRNA-mediated SUN1 depletion did not affect the recruitment of integrin β1, one of the ubiquitously expressed focal adhesion molecules, to the plasma membrane. Consistently, SUN1-depleted cells normally adhered to extracellular matrix proteins, including collagen, fibronectin, laminin, and vitronectin. In contrast, SUN1 depletion reduced the activation of integrin β1. Strikingly, the depletion of SUN1 interfered with the incorporation of vinculin into the focal adhesions, whereas no significant differences in the expression of vinculin were observed between wild-type and SUN1-depleted cells. In addition, SUN1 depletion suppressed the recruitment of zyxin to nascent focal adhesions. These data indicate that SUN1 is involved in the maturation of focal adhesions. Moreover, disruption of the SUN1-containing LINC complex abrogates the actin cytoskeleton and generation of intracellular traction force, despite the presence of SUN2. Thus, a physical link between the nucleus and cytoskeleton through SUN1 is required for the proper organization of actin, thereby suppressing the incorporation of vinculin and zyxin into focal adhesions and the activation of integrin β1, both of which are dependent on traction force. This study provides insights into a previously unappreciated signaling pathway from the nucleus to the cytoskeleton, which is in the opposite direction to the well-known mechanotransduction pathways from the extracellular matrix to the nucleus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ueda, Maekawa, Matsui, Deguchi, Takata, Katahira, Higashiyama and Hieda.)

Objective: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients., Methods: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT., Results: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m 2 ) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type., Conclusions: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A)., Background: It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors., Methods: High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide >40 pg/mL or high-sensitivity cardiac troponin T >0.6 pg/mL; visceral fat >2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.O 2 ), left ventricular (LV) mass, LV volume, myocardial triglyceride content (magnetic resonance spectroscopy), arterial stiffness/function (central pulsed-wave velocity; augmentation index), and body composition (dual x-ray absorptiometry scan)., Results: Fifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.O 2 : 4.46 mL/kg per minute, 95% CI: 3.18 to 5.56; P < 0.0001), increased LV mass (Δ: 9.40 g, 95% CI: 4.36 to 14.44; P < 0.001), and volume (Δ: 12.33 mL, 95 % CI: 5.61 to 19.05; P < 0.001) and reduced augmentation index (Δ: -4.81%, 95% CI: -8.63 to -0.98; P = 0.009). There was no independent or interaction effect of n-3 FA on any outcome., Conclusions: One-year HIIT improved exercise capacity, cardiovascular structure/function, and adiposity in stage A HF with no independent or additive effect of n-3 FA administration. (Improving Metabolic Health in Patients With Diastolic Dysfunction [MTG]; NCT03448185)., Competing Interests: Funding Support and Author Disclosures Supported by the American Heart Association Strategically Focused Research Network (14SFRN20600009-03). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Erythrocytes are oxygen carriers and exposed to redox cycle in oxygenation and deoxygenation of hemoglobin. This indicates that circulating erythrocytes are vulnerable to the oxidative injury occurring under the imbalance of redox homeostasis. In this review article, two topics are presented concerning the human erythrocytes exposed to the oxidative inflammation including septic and sterile conditions. First, we demonstrate rheological derangement of erythrocytes subjected to acute oxidative injury caused by exogenous generators of reactive oxygen species (ROS). Erythrocyte filterability as whole-cell deformability has been estimated by the gravity-based nickel mesh filtration technique in our laboratory and was dramatically impaired in a time-dependent manner after starting exposure to the ROS generators, that is associated with concurrent progression of membrane protein degradation, phospholipid peroxidation, erythrocyte swelling, methemoglobin formation, and oxidative hemolysis. Second, we introduce an impairment of erythrocyte filterability confirmed quantitatively in diabetes mellitus and hypertension of animal models and patients under treatment. Among the cell geometry, internal viscosity, and membrane property as the three major determinants of erythrocyte deformability, erythrocyte membrane alteration is supposed to be the primary cause of this impairment in these lifestyle-related diseases associated with persistent oxidative inflammation. Excessive ROS trigger the inflammatory responses and reduce the erythrocyte membrane fluidity. Oxidative inflammation increasing erythrocyte membrane rigidity underlies the impaired systemic microcirculation, which is observed in diabetic and/or hypertensive patients. On the other hand, elevated internal viscosity caused by sickle hemoglobin polymerization is a primary cause of impaired erythrocyte filterability in sickle cell disease (SCD). However, oxidative inflammation is also involved in the pathophysiology of SCD. The physiologic level of ROS acts as signaling molecules for adaptation to oxidative environment, but the pathological level of ROS induces suicidal erythrocyte death (eryptosis). These findings provide further insight into the ROS-related pathophysiology of many clinical conditions., Competing Interests: SM and TF was employed by Institute of Rheological Function of Foods Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maruyama, Hieda, Mawatari and Fujino.)

The hemodynamic effects of aortic stenosis (AS) consist of increased left ventricular (LV) afterload, reduced myocardial compliance, and increased myocardial workload. The LV in AS patients faces a double load: valvular and arterial loads. As such, the presence of symptoms and occurrence of adverse events in AS should better correlate with calculating the global burden faced by the LV in addition to the transvalvular gradient and aortic valve area (AVA). The valvulo-arterial impedance (Zva) is a useful parameter providing an estimate of the global LV hemodynamic load that results from the summation of the valvular and vascular loads. In addition to calculating the global LV afterload, it is paramount to estimate the stenosis severity accurately. In clinical practice, the management of low-flow low-gradient (LF-LG) severe AS with preserved LV ejection fraction requires careful confirmation of stenosis severity. In addition to the Zva, the dimensionless index (DI) is a very useful parameter to express the size of the effective valvular area as a proportion of the cross-section area of the left ventricular outlet tract velocity-time integral (LVOT-VTI) to that of the aortic valve jet (dimensionless velocity ratio). The DI is calculated by a ratio of the sub-valvular velocity obtained by pulsed-wave Doppler (LVOT-VTI) divided by the maximum velocity obtained by continuous-wave Doppler across the aortic valve (AV-VTI). In contrast to AVA measurement, the DI does not require the calculation of LVOT cross-sectional area, a major cause of erroneous assessment and underestimation of AVA. Hence, among patients with LG severe AS and preserved LV ejection fraction, calculation of DI in routine echocardiographic practice may be useful to identify a subgroup of patients at higher risk of mortality who may derive benefit from aortic valve replacement. This article aims to elucidate the Zva and DI in different clinical situations, correlate with the standard indexes of AS severity, LV geometry, and function, and thus prove to improve risk stratification and clinical decision making in patients with severe AS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mantha, Futami, Moriyama and Hieda.)

Background: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy., Methods: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V 0 )}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V 0 " is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness., Results: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min -1 ·kg -1 , P <0.0001, interaction P =0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min -1 ·kg -1 , P =0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P =0.001)., Conclusions: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

Amphidinol 3 (AM3), a polyhydroxy-polyene metabolite from the dinoflagellate Amphidinium klebsii , possesses potent antifungal activity. AM3 is known to interact directly with membrane sterols and permeabilize membranes by forming pores. Because AM3 binds to sterols such as cholesterol and ergosterol, it can be assumed that AM3 has some impact on lipid rafts, which are membrane domains rich in sphingolipids and cholesterol. Hence, we first examined the effect of AM3 on phase-separated liposomes, in which raft-like ordered and non-raft-like disordered domains are segregated. Consequently, AM3 disrupted the phase separation at 22 μM, as in the case of methyl-β-cyclodextrin, a well-known raft-disrupter that extracts sterol from membranes. The surface plasmon resonance measurements and dye leakage assays show that AM3 preferentially recognizes cholesterol in the disordered membrane, which may reflect a weaker lipid-cholesterol interaction in disordered membrane than in ordered membrane. Finally, to gain insight into the AM3-induced coalescence of membrane phases, we measured membrane fluidity using fluorescence correlation spectroscopy, demonstrating that AM3 significantly increases the order of disordered phase. Together, AM3 preferentially binds to the disordered phase rather than the ordered phase, and enhances the order of the disordered phase, consequently blending the separated phases., Competing Interests: We do not have any conflict of interest., (© 2021 The Authors.)

Background: Patients with continuous-flow left ventricular assist devices (CF-LVADs) experience limitations in functional capacity and frequently, right ventricular (RV) dysfunction. We sought to characterize RV function in the context of global cardiopulmonary performance during exercise in this population., Methods: A total of 26 patients with CF-LVAD (aged 58 ± 11 years, 23 males) completed a hemodynamic assessment with either conductance catheters (Group 1, n = 13) inserted into the right ventricle to generate RV pressure‒volume loops or traditional Swan‒Ganz catheters (Group 2, n = 13) during invasive cardiopulmonary exercise testing. Hemodynamics were collected at rest, 2 sub-maximal levels of exercise, and peak effort. Breath-by-breath gas exchange parameters were collected by indirect calorimetry. Group 1 participants also completed an invasive ramp test during supine rest to determine the impact of varying levels of CF-LVAD support on RV function., Results: In Group 1, pump speed modulations minimally influenced RV function. During upright exercise, there were modest increases in RV contractility during sub-maximal exercise, but there were no appreciable increases at peak effort. Ventricular‒arterial coupling was preserved throughout the exercise. In Group 2, there were large increases in pulmonary arterial, left-sided filling, and right-sided filling pressures during sub-maximal and peak exercises. Among all participants, the cardiac output‒oxygen uptake relationship was preserved at 5.8:1. Ventilatory efficiency was severely abnormal at 42.3 ± 11.6., Conclusions: Patients with CF-LVAD suffer from limited RV contractile reserve; marked elevations in pulmonary, left-sided filling, and right-sided filling pressures during exercise; and severe ventilatory inefficiency. These findings explain mechanisms for persistent reductions in functional capacity in this patient population., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The nucleolar structure is highly dynamic and strictly regulated in response to internal cues, such as metabolic rates, and to external cues, such as mechanical forces applied to cells. Although the multilayered nucleolar structure is largely determined by the liquid-like properties of RNA and proteins, the mechanisms regulating the morphology and number of nucleoli remain elusive. The linker of the nucleoskeleton and cytoskeleton (LINC) complex comprises inner nuclear membrane Sad1/UNC-84 (SUN) proteins and outer nuclear membrane-localized nesprins. We previously showed that the depletion of SUN1 proteins affects nucleolar morphologies. This study focuses on the function of SUN1 splicing variants in determining nucleolar morphology. An RNA interference strategy showed that the predominantly expressed variants, SUN1&#95;888 and SUN1&#95;916, were crucial for nucleolar morphology but functionally distinct. In addition, the depletion of either SUN1&#95;888 or SUN1&#95;916 altered the chromatin structure and affected the distribution of histone modifications. Based on these results, we propose a model in which the LINC complex plays a role in modulating nucleolar morphology and numbers via chromatin., (© 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

New Findings: What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals., Abstract: This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 μmol l -1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Background Accurate assessment of cardiac output is critical to the diagnosis and management of various cardiac disease states; however, clinical standards of direct Fick and thermodilution are invasive. Noninvasive alternatives, such as closed-circuit acetylene (C 2 H 2 ) rebreathing, warrant validation. Methods and Results We analyzed 10 clinical studies and all available cardiopulmonary stress tests performed in our laboratory that included a rebreathing method and direct Fick or thermodilution. Studies included healthy individuals and patients with clinical disease. Simultaneous cardiac output measurements were obtained under normovolemic, hypovolemic, and hypervolemic conditions, along with submaximal and maximal exercise. A total of 3198 measurements in 519 patients were analyzed (mean age, 59 years; 48% women). The C 2 H 2 method was more precise than thermodilution in healthy individuals with half the typical error (TE; 0.34 L/min [ r =0.92] and coefficient of variation, 7.2%) versus thermodilution (TE=0.67 [ r =0.70] and coefficient of variation, 13.2%). In healthy individuals during supine rest and upright exercise, C 2 H 2 correlated well with thermodilution (supine: r =0.84, TE=1.02; exercise: r =0.82, TE=2.36). In patients with clinical disease during supine rest, C 2 H 2 correlated with thermodilution ( r =0.85, TE=1.43). C 2 H 2 was similar to thermodilution and nitrous oxide (N 2 O) rebreathing technique compared with Fick in healthy adults (C 2 H 2 rest: r =0.85, TE=0.84; C 2 H 2 exercise: r =0.87, TE=2.39; thermodilution rest: r =0.72, TE=1.11; thermodilution exercise: r =0.73, TE=2.87; N 2 O rest: r =0.82, TE=0.94; N 2 O exercise: r =0.84, TE=2.18). The accuracy of the C 2 H 2 and N 2 O methods was excellent ( r =0.99, TE=0.58). Conclusions The C 2 H 2 rebreathing method is more precise than, and as accurate as, the thermodilution method in a variety of patients, with accuracy similar to an N 2 O rebreathing method approved by the US Food and Drug Administration.

Acute myocardial infarction (AMI) results in significant changes in cardiac structure and functions, leading to left ventricular remodeling and subsequent systolic and diastolic dysfunction. To improve current approaches in diagnoses, treatments, and prevention of cardiovascular diseases, a better understanding of cardiac mechanoenergetics, including systolic performance and energy demand, becomes paramount. In this review, we summarize cardiac mechanics, cardiac energetics, and their relationship in complications related to AMI using 2 important physiologic frameworks, pressure-volume loops and the Vo 2 -pressure-volume area relationship diagram, as they are powerful tools for understanding physiologic behavior and mechanoenergetics of the left ventricle., Competing Interests: Conflict of interest None. Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Noninvasive positive pressure ventilation (NIPPV), which can be applied without endotracheal airway or tracheostomy, has been used as the first-line device for patients with acute decompensated heart failure (ADHF) and cardiogenic pulmonary edema. Positive airway pressure (PAP) devices include continuous PAP, bilevel PAP, and adaptive servoventilation. NIPPV can provide favorable physiologic benefits, including improving oxygenation, respiratory mechanics, and pulmonary and systemic hemodynamics. It can also reduce the intubation rate and improve clinical symptoms, resulting in good quality of life and mortality., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The incidence of cardiogenic shock and the utilization of mechanical circulatory support devices are increasing in the US. In this review we discuss the pathophysiology of cardiogenic shock through basic hemodynamic and myocardial energetic principles. We also explore the commonly used platforms for temporary mechanical circulatory support, their advantages, disadvantages and practical considerations relating to implementation and management. It is through the translation of underlying physiological principles that we can attempt to maximize the clinical utility of circulatory support devices and improve outcomes in cardiogenic shock., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hyperbaric oxygen therapy (HBOT) is a well-established treatment for a variety of conditions. Hyperbaric oxygen therapy is the administration of 100% oxygen breathing in a pressure vessel at higher than atmospheric pressure (1 atmosphere absolute = 101 kPa). Typically, treatment is given daily for between 1 and 2 h at pressures of 2.0 to 2.8 ATA, depending on the indication. Sporting injuries are often treated over 3 to 10 sessions. Hyperbaric oxygen therapy has been documented to be effective and is approved in 14 medical indications by the Undersea and Hyperbaric Medical Society, including, but not limited to, carbon monoxide poisoning, compromised skin grafts and flaps, crush injuries, necrotizing soft tissue infections, and nonhealing ulcers with arterial insufficiencies. Recently, HBOT for sports musculoskeletal injuries is receiving increased attention. Hyperbaric oxygen therapy may allow injured athletes to recover faster than normal rehabilitation methods. Any reduction in collegiate and professional athletes' rehabilitation period can be financially significant for top-level sports teams; however, further research is required to confirm HBOT's benefits on sports musculoskeletal injuries. The purpose of this review to discuss the current understanding of HBOT as a treatment modality for common musculoskeletal injuries in sport medicine. Moreover, we will highlight the advantages and disadvantages of this modality, as well as relevant clinical and research applications.

The evolutionarily conserved multiprotein complex THO/TREX is required for pre-mRNA processing, mRNA export and the maintenance of genome stability. In this study, we analyzed the genome-wide distribution of human THOC7, a component of human THO, by chromatin immunoprecipitation sequencing. The analysis revealed that human THOC7 occupies repetitive sequences, which include microsatellite repeats in genic and intergenic regions and telomeric repeats. The majority of the THOC7 ChIP peaks overlapped with those of the elongating form of RNA polymerase II and R-loops, indicating that THOC7 accumulates in transcriptionally active repeat regions. Knocking down THOC5, an RNA-binding component of human THO, by siRNA induced the accumulation of γH2AX in the repeat regions. We also observed an aberration in the telomeres in the THOC5-depleted condition. These results suggest that human THO restrains the transcription-associated instability of repeat regions in the human genome., (© 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

This article reviews treatment and management of common cardiovascular emergencies in critically ill patients, focusing on acute decompensated heart failure, cardiogenic shock, pulmonary embolism, and hypertensive crisis management with inotropes, vasopressors, diuretics, and antiarrhythmic drugs. Clinicians frequently come across challenging clinical scenarios, and there is a gap between evidence-based medicine and clinical practice. Inotropic and vasopressor agents are useful in the acute setting but must be weaned off or used as a bridge for mechanical circulation support devices. Clinicians should aim to lower complications by choosing medications with respect to comorbidities and close the gap between evidence-based medicine and clinical practice., Competing Interests: Disclosure The authors have nothing to disclose. Conflict of interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Heart failure (HF) is a leading cause of hospitalization. Suitable pharmacologic management is critical. Distinct physical findings such as congestion and peripheral hypoperfusion need to be considered in selecting pharmacologic therapy. By applying the pretest probability and likelihood ratios of unique physical findings of HF to a Markov model, a definite posttest probability can be obtained. This article focuses on the findings of S3, jugular venous pressure, proportional pulse pressure, bendopnea, trepopnea, and various heart murmurs. Incorporating statistical precision in physical assessments, diagnoses of HF can be further refined, providing a sophisticated approach to evaluate patients hemodynamics status noninvasively., Competing Interests: Conflict of interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)