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Acute lung injury caused by Pseudomonas aeruginosa is attributed to the translocation of cytotoxin into pulmonary epithelial cells via the P. aeruginosa type III secretion system. This virulence can be blocked with a specific antibody against PcrV in this secretion system. However, because anti-PcrV antibodies do not have bactericidal activity, the treatment of bacteria depends on the phagocytic system of the host. In this study, we investigated the therapeutic effect of combination therapy with an anti-PcrV antibody and bactericidal bacteriophages on acute lung injury and subsequent death in mice compared with a single treatment. After the mice intratracheally received a lethal dose of the cytotoxic P. aeruginosa strain, a second instillation was performed with saline, anti-PcrV IgG, bacteriophages, or a mixture of anti-PcrV and bacteriophages. The survival rates 24 h after infection were as follows: 7.1% in the saline group, 26.7% in the anti-PcrV group, 41.2% in the phage group, and 66.7% in the anti-PcrV + phage group ( P < 0.001 vs saline-treated group). The activity of surviving mice in the anti-PcrV + phage group was significantly greater than that in the saline group. The lung weight in the anti-PcrV + phage group was significantly lower than that in the anti-PcrV group. In conclusion, combination therapy with an anti-PcrV antibody and a bacteriophage reduces acute lung injury and suggests improved survival compared with each treatment alone. This combination therapy, which does not rely on conventional antibiotics, could constitute a new strategy for treating multidrug-resistant P. aeruginosa infections.IMPORTANCECombination therapy with either bacteriophages alone or in combination with anti-PcrV antibodies in a mouse model of Pseudomonas aeruginosa pneumonia may reduce the acute lung injury and improve survival. This combination therapy, which does not rely on conventional antibiotics, may be a new strategy to treat multidrug-resistant Pseudomonas aeruginosa infections.

Background: In contrast to the well-known prognostic values of the cardiorenal linkage, it remains unclear whether impaired cognitive function affects cardiac prognosis in relation to cardiac sympathetic innervation and renal function in patients with heart failure (HF)., Methods and Results: A total of 433 consecutive HF patients with left ventricular ejection fraction (LVEF) <50% underwent the Mini-Mental State Examination (MMSE) and a neuropsychological test for screening of cognition impairment or subclinical dementia. Following metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes with a primary endpoint of lethal cardiac events (CEs) were evaluated for a mean period of 14.8 months. CEs were documented in 84 HF patients during follow-up. MMSE score, estimated glomerular filtration rate (eGFR) and standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in patients with CEs compared with patients without CEs. Furthermore, overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. The cutoff values of MMSE score (<26), sHMR (<1.80) and eGFR (<47.0 mL/min/1.73 m 2 ) determined by receiver operating characteristic (ROC) analysis successfully differentiated HF patients at more increased risk for CEs from other HF patients., Conclusions: Impairment of cognitive function is not only independently related to but also synergistically increases cardiac mortality risk in association with cardiac sympathetic function and renal function in patients with HF.

Mycoplasma bovis mastitisis highly contagious and disrupts lactation, posing a significant threat to the dairy industry. While the mammary gland's defence mechanism involves epithelial cells and mononuclear cells (MNC), their interaction with M. bovis remains incompletely understood. In this study, we assessed the immunological reactivity of bovine mammary epithelial cells (bMEC) to M. bovis through co-culture with MNC. Upon co-culture with MNC, the mRNA expression levels of interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor (TNF)-α in bMEC stimulated by M. bovis showed a significant increase compared to monoculture. Additionally, when stimulated with M. bovis, the culture supernatant exhibited significantly higher concentrations of IL-6 and interferon (IFN)-γ, while IL-1β concentration tended to be higher in co-culture with MNC than in monoculture. Furthermore, the mRNA expression levels of toll-like receptor (TLR) 2 in bMEC stimulated with M. bovis tended to increase, and TLR4 significantly increased when co-cultured with MNC compared to monocultures. However, the surface expression levels in bMEC did not exhibit significant changes between co-culture and monoculture. Overall, our research indicates that the inflammatory response of bMEC is increased during co-culture with MNC, suggesting that the interaction between bMEC and MNC in the mammary gland amplifies the immune response to M. bovis in cows affected by M. bovis mastitis.

Self-assemblies of anisotropic colloidal particles into colloidal liquid crystals and well-defined superlattices are of great interest for hierarchical nanofabrications that are applicable for various functional materials. Inorganic nanosheets obtained by exfoliation of layered crystals have been highlighted as the intriguing colloidal units; however, the size polydispersity of the nanosheets has been preventing precise design of the assembled structures and their functions. Here, we demonstrate that the anionic titanate nanosheets with monodisperse size reversibly form very unusual superstructured mesophases through finely tunable weak attractive interactions between the nanosheets. Transmission electron microscopy, polarizing optical microscopy, small-angle x-ray scattering, and confocal laser scanning microscopy clarified the reversible formation of the mesophases (columnar nanofibers, columnar nematic liquid crystals, and columnar nanofiber bundles) as controlled by counter cations, nanosheet concentration, solvent, and temperature.

Phage therapy has re-emerged in modern medicine as a robust antimicrobial strategy in response to the increasing prevalence of antimicrobial-resistant bacteria. However, bacterial resistance to phages can also arise via a variety of molecular mechanisms. In fact, several clinical studies on phage therapy have reported the occurrence of phage-resistant variants, representing a significant concern for the successful development of phage-based therapies. In this context, the fitness trade-offs between phage and antibiotic resistance have revealed new avenues in the field of phage therapy as a countermeasure against phage resistance. This strategy forces to restore the antibiotic susceptibility of antimicrobial-resistant bacteria as compensation for the development of phage resistance. Here, we present the key achievements of these fitness trade-offs, notably focusing on the enhancement of antibiotic sensitivity through the induction of large chromosomal deletions by bacteriophage infection. We also describe the challenges of this strategy that need to be overcome to promote favorable therapeutic outcomes and discuss future directions. The insights gained from the trade-offs between phage and antibiotic sensitivity will help maximize the potential of phage therapy for the treatment of infectious diseases., 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 © 2024 Fujiki, Nakamura, Ishiguro and Iwano.)

Infective endocarditis (IE) is a highly fatal disease in cases of delayed diagnosis and treatment, although its incidence is low. However, there have been few single-center studies in which the risk of in-hospital death from IE was stratified according to laboratory findings on admission and the organism responsible for IE. In this study, a total of 162 patients who were admitted to our hospital during the period from 2009 to 2021, who were suspected of having IE according to the modified Duke classification, and for whom IE was confirmed by transesophageal echocardiography were retrospectively analyzed. Patients were observed for a mean-period of 43.7 days with the primary endpoint being in-hospital death. The in-hospital death group had a lower level of hemoglobin (Hb), higher white blood cell (WBC) count, lower level of estimated glomerular filtration rate (eGFR), and higher frequency of Staphylococcus being the causative agent than those in the non-in-hospital death group. In overall multivariate analysis, Hb, WBC count, eGFR, and Staphylococcus as the causative agent were identified to be significant prognostic determinants. IE patients with Hb < 10.6 g/dL, WBC count > 1.4 × 10 4 /μL, eGFR < 28.1 mL/minute/1.7 m 2 , and Staphylococcus as the causative agent had significantly and synergistically increased in-hospital death rates compared to those in other IE patients. Low level of Hb, high WBC count, low eGFR, and Staphylococcus as the causative agent of IE were independent predictors of in-hospital mortality, suggesting that these 4 parameters may be combined to additively stratify the risk of in-hospital mortality.

We herein report the first case of constrictive pericarditis (CP) induced by long-term pergolide treatment for Parkinson's disease that was assessed using multimodal imaging in a 72-year-old patient with leg edema and dyspnea. The patient was correctly diagnosed with CP using multimodal imaging and successfully treated with pericardiectomy. The treatment history of Parkinson's disease and pathological findings of the removed pericardium suggested that long-term pergolide was the cause of CP. Properly recognizing pergolide as the cause of CP and accurately diagnosing CP using multimodal imaging may contribute to the early detection and treatment of pergolide-induced CP.

The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.

Bacteriophages are expected to be therapeutic agents against infectious diseases. Streptococcus mutans are involved in dental plaque formation related to dental caries and periodontitis. In S. mutans , lytic bacteriophages have been isolated previously, but the isolation of temperate bacteriophage has not been reported although their presence in the genome has been confirmed. Here, we report the isolation of temperate bacteriophage, φKSM96, from S. mutans . φKSM96 has a circular DNA 39,820 bp long and reveals Siphoviridae morphology. φKSM96 shows a broad range of susceptibility against S. mutans strains with different serotypes. By the addition of φKSM96, S. mutans growth and biofilm formation were significantly inhibited. In cocultures of S. mutans with other bacterial species, the proportion of S. mutans significantly decreased in the presence of φKSM96. In summary, φKSM96 shows selective anti- S. mutans activity. The isolation of temperate bacteriophage is important for future genetic manipulation to create more efficient bacteriophages., Competing Interests: The authors declare no competing interests. Patent application No. JP 2022–159774, Filing date 2022/10/03., (© 2023 The Authors.)

In recent decades, phage therapy has been overshadowed by the widespread use of antibiotics in Western countries. However, it has been revitalized as a powerful approach due to the increasing prevalence of antimicrobial-resistant bacteria. Although bacterial resistance to phages has been reported in clinical cases, recent studies on the fitness trade-offs between phage and antibiotic resistance have revealed new avenues in the field of phage therapy. This strategy aims to restore the antibiotic susceptibility of antimicrobial-resistant bacteria, even if phage-resistant variants develop. Here, we summarize the basic virological properties of phages and their applications within the context of antimicrobial resistance. In addition, we review the occurrence of phage resistance in clinical cases, and examine fitness trade-offs between phage and antibiotic sensitivity, exploring the potential of an evolutionary fitness cost as a countermeasure against phage resistance in therapy. Finally, we discuss future strategies and directions for phage-based therapy from the aspect of fitness trade-offs. This approach is expected to provide robust options when combined with antibiotics in this era of phage 're'-discovery.

Background Prognostic implications of transcatheter aortic valve implantation (TAVI) in low-gradient (LG) aortic stenosis (AS) remain controversial. The authors hypothesized that differences in cardiac functional recovery may solve this ongoing controversy. The aim was to evaluate clinical outcomes and the response of left ventricular (LV) function following TAVI in patients with LG AS. Methods and Results This multicenter retrospective study included 1742 patients with severe AS undergoing TAVI between January 2015 and March 2019. Patients were subdivided into low-flow (LF) LG, normal-flow (NF) LG, LF high-gradient, and NF high-gradient AS groups according to the mean gradient of the aortic valve (LG <40 mm Hg) and LV stroke volume index (LF <35 mL/m 2 ). Outcomes and changes in echocardiographic parameters after TAVI were compared between the groups. A total of 227 patients (13%) had reduced ejection fraction, and 486 patients (28%) had LG AS (LF-LG 143 [8%]; NF-LG 343 [20%]). During a median follow-up period of 747 days, 301 patients experienced a composite end point of cardiovascular death and rehospitalization for cardiovascular events, which was higher in the LF-LG and NF-LG groups than in the high-gradient groups. LG AS was independently associated with the primary outcome (hazard ratio, 1.69; P <0.001). Among 1239 patients with follow-up echocardiography, LG AS showed less improvement in the LV mass index and LV end-diastolic volume compared with high-gradient AS after 1 year, while LV recovery was similar between the LF AS and NF AS groups. Conclusions LG AS was associated with poorer outcomes and LV recovery, regardless of flow status after TAVI. Careful evaluation of AS severity may be required in LG AS to provide TAVI within the appropriate time and advanced care afterward.

Background: Dyspnea is a common symptom in acute heart failure (AHF) patients. Although an accurate and rapid diagnosis of AHF is essential to improve prognosis, estimation of left ventricular (LV) filling pressure (FP) remains challenging, especially for noncardiologists. We evaluated the usefulness of a recently-proposed parameter of LV FP, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, to detect AHF in patients complaining of dyspnea., Methods: Echocardiography and lung ultrasonography (LUS) were performed in 121 consecutive patients (68 ± 14 years old, 75 males) presenting with dyspnea. The VMT score was determined from the atrioventricular valve opening phase (tricuspid valve first: 0, simultaneous: 1, mitral valve first: 2) and inferior vena cava dilatation (absent: 0, present: 1), and VMT ≥2 was judged as positive. LUS was performed with the 8 zones method and judged as positive if 3 or more B-lines were observed in bilateral regions. The AHF diagnosis was performed by certified cardiologists according to recent guidelines., Results: Of the 121 patients, 33 were diagnosed with AHF. The sensitivity and specificity for diagnosing AHF were 64 % and 84 % for LUS and 94 % and 88 % for VMT score. In logistic regression analysis, VMT score showed a significantly higher c-index than LUS (0.91 vs 0.74, p = 0.002). In multivariable analyses, VMT score was associated with AHF independently of clinically relevant covariates and LUS. In addition, serial assessment of VMT score followed by LUS provided a diagnostic flow chart to diagnose AHF (VMT 3: AHF definitive, VMT 2 and LUS positive: AHF highly suspicious; VMT 2 and LUS negative: further investigation is needed; VMT ≤ 1: AHF rejected)., Conclusions: VMT score showed high diagnostic accuracy in diagnosing AHF. Combined assessment of the VMT score and LUS could become a reliable strategy for diagnosis of AHF by non-cardiologists., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Although left ventricular (LV) cardiac power output (CPO) is a powerful prognostic indicator in heart failure (HF), the significance of right ventricular (RV) CPO is unknown. In contrast, RV pulsatile load is a key prognostic marker in HF. We investigated the impact of RV-CPO and pulsatile load on cardiac outcome and the prognostic performance of the combined systemic and pulmonary circulation parameters in HF., Methods: Right heart catheterization and echocardiography were performed in 231 HF patients (62 ± 16 years, LV ejection fraction 42 ± 18 %). Invasive and noninvasive CPOs were calculated from mean systemic or pulmonary arterial pressure and cardiac output. LV-CPO was then normalized to LV mass (LV-P/M). Pulmonary arterial capacitance and the ratio of acceleration time to ejection time (AcT/ET) of RV outflow were used as parameters of RV pulsatile load. The primary endpoints, defined as a composite of cardiac death, HF hospitalization, ventricular arrythmia, and LVAD implantation after the examination, were recorded., Results: Noninvasive CPOs were moderately correlated with invasive ones (LV: ρ = 0.787, RV: ρ = 0.568, and p < 0.001 for both). During a median follow-up period of 441 days, 57 cardiovascular events occurred. Lower LV-P/M and higher RV pulsatile load were associated with cardiovascular events; however, RV-CPO was not associated with the outcome. Echocardiographic LV-P/M and AcT/ET showed significant incremental prognostic value over the clinical parameters., Conclusions: RV pulsatile load assessed by AcT/ET may be a predictor of clinical events in HF patients. The combination of echocardiographic LV-P/M and AcT/ET could be a novel noninvasive prognostic indicator in HF patients., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

This study aimed to examine the antimicrobial susceptibility of bovine mastitis pathogens in Japan and develop criteria for testing antimicrobial susceptibility using the simplified agar disk diffusion (ADD) method that is currently being used in clinical practice. Milk samples from 1,349 dairy cows with clinical mastitis were collected and cultured. The minimum inhibitory concentrations (MICs) of the antimicrobials were determined for 504 strains of 28 bacteria. Of the gram-positive bacteria, most Staphylococcus spp. were susceptible to penicillin G (PCG), kanamycin (KM), oxytetracycline (OTC), cefazolin (CEZ), pirlimycin, enrofloxacin, and marbofloxacin. Streptococcus spp. and Trueperella pyogenes showed resistance to OTC and KM. Most gram-negative bacteria were resistant to OTC and CEZ and particularly susceptible to fluoroquinolones. To develop the criteria for a disk diffusion test of the simplified ADD method, the relationships between MICs and diameters of inhibition zones (DIZs) were analyzed and compared with the conventional method. The susceptibility breakpoints of several antimicrobials were lower for both gram-positive and gram-negative bacteria. Particularly for gram-positive bacteria, the application of the new criteria lowers the breakpoint for PCG, suggesting that the use of PCG instead of CEZ may increase. The results suggest that use of these criteria for the simplified ADD method may lead to appropriate antimicrobial choice and consequently the appropriate use of antimicrobials in clinical practice.

Background: Determinants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated., Methods: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO 2 ). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s') and early diastolic mitral annular velocities (e'), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s') were measured at rest and exercise. E/e' and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively., Results: During exercise, CO, LV-s', RV-s', e', and SPAP were significantly increased (p < 0.05 for all), whereas E/e' remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO 2 . In univariable analyses, LV-s' (R = 0.35, p = 0.022), SPAP (R = -0.40, p = 0.008), RV-s' (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO 2 . In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO 2 even after the adjustment for clinically relevant parameters., Conclusions: In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure., Competing Interests: Declaration of competing interest There is no conflict of interest to disclose relating to the present study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Staphylococcus virus ΦSA012 has a wide host range and efficient lytic activity. Here, we assessed the biological stability of ΦSA012 against temperature, freeze-thawing, and pH to clinically apply the phage. In addition, inoculation of ΦSA012 through i.p. and i.v. injections into mice revealed that phages were reached the limit of detection in serum and accumulated notably spleens without inflammation at 48 h post-inoculation. Furthermore, inoculation of ΦSA012 through s.c. injections in mice significantly induced IgG, which possesses neutralizing activity against ΦSA012 and other Staphylococcus viruses, ΦSA039 and ΦMR003, but not Pseudomonas viruses ΦS12-3 and ΦR18 or Escherichia viruses T1, T4, and T7 in vitro. Immunoelectron microscopic analysis showed that purified anti-phage IgG recognizes the long-tail fiber of staphylococcus viruses. Although S. aureus inoculation resulted in a 25% survival rate in a mouse i.p. model, ΦSA012 inoculation (i.p.) improved the survival rate to 75%; however, the survival rate of ΦSA012-immunized mice decreased to less than non-immunized mice with phage i.v. injection at a MOI of 100. These results indicated that ΦSA012 possesses promise for use against staphylococcal infections but we should carefully address the appropriate dose and periods of phage administration. Our findings facilitate understandings of staphylococcus viruses for phage therapy., (© 2022. The Author(s).)

Background: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry., Methods and Results: From 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %)., Conclusions: Although the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Although the left ventricular (LV) dysfunction in pre-capillary pulmonary hypertension (PH) has been recently recognized, the mechanism of LV dysfunction in this entity is not completely understood. We thus aimed to elucidate the determinants of intraventricular pressure difference (IVPD), a measure of LV suction, in pre-capillary PH., Methods and Results: Right heart catheterization and echocardiography were performed in 86 consecutive patients with pre-capillary PH (57 ± 18 years, 85% female). IVPD was determined using colour M-mode Doppler to integrate the Euler equation. In overall, IVPD was reduced compared to previously reported value in normal subjects. In univariable analyses, QRS duration (P = 0.028), LV ejection fraction (P = 0.006), right ventricular (RV) end-diastolic area (P < 0.001), tricuspid annular plane systolic excursion (P = 0.004), and LV early-diastolic eccentricity index (P = 0.009) were associated with IVPD. In the multivariable analyses, RV end-diastolic area and LV eccentricity index independently determined the IVPD., Conclusion: Aberrant ventricular interdependence caused by RV enlargement could impair the LV suction. This study first applied echocardiographic IVPD, a reliable marker of LV diastolic suction, to investigate the mechanism of LV diastolic dysfunction in pre-capillary PH., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: The predictive value of echocardiographic parameters for early worsening heart failure (WHF), worsening of symptoms of heart failure requiring intensification of therapy during an admission for acute decompensated heart failure (ADHF), has not been elucidated., Methods: Sixteen centers in Japan prospectively enrolled 303 ADHF hospitalized patients who did not receive positive inotropic agents as an initial therapy. Physical and Doppler echocardiographic examinations were performed before the initial therapy and the association of low output findings and occurrence of early WHF were tested., Results: Early WHF occurred in 63 patients with a median duration of 6 (IQR: 2-23) hours from the administration of the initial therapy. In patients with left ventricular (LV) ejection fraction <40% (N = 153), echocardiographic stroke volume index, and cardiac index showed greater c-index [95% confidence interval, 0.71 (0.61-0.79) and 0.72 (0.63-0.80), respectively] compared to single low perfusion finding (symptomatic hypotension, reduced pulse pressure, and impaired mentation) other than cool extremities. When physical findings were combined (low perfusion score), the predictive ability improved to the similar levels of echocardiographic LV output parameters [c-index: 0.69 (0.60-0.76)]. However, addition of cardiac index significantly improved the prognostic ability when added to low perfusion score [0.82 (0.74-0.87), p < 0.001]. In contrast, in patients with LV ejection fraction ≥40% (N = 150), low perfusion score, rather than LV output parameters, was predictive of early WHF [c-index: 0.73 (0.56-0.85)]., Conclusions: We demonstrated the predictive value of echocardiographic LV output indices for early WHF in ADHF patients with LV systolic dysfunction. These data support the motivation for routine use of echocardiography for initial assessment of ADHF., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of thrombi on the heart valves without bacteremia and predominantly affects patients with hypercoagulable state. Since the lesion of NBTE often exists in the left-sided valves, involvement of the tricuspid valve (TV) is rare. We herein report a 34-year-old woman with advanced ovarian cancer and pulmonary embolization showing NBTE on the TV. Plasma D-dimer level was markedly elevated and echocardiography showed highly mobile masses on the TV with moderate to severe regurgitation. After the initiation of heparin therapy, reduction of plasma D-dimer levels along with shrinkage of the TV vegetations was observed. However, she was forced to discontinue the heparin because its supply was interrupted in association with coronavirus disease 2019. Coupled with systemic metastasis of ovarian cancer, elevated plasma D-dimer level and exacerbation of NBTE were observed. Thereafter, she resumed subcutaneous injection of heparin, resulting in re-improvement., Learning Objective: Involvement of tricuspid valve (TV) by nonbacterial thrombotic endocarditis (NBTE) is rare, especially when they are associated with advanced cancer. Our case underlines the importance of listing the NBTE as a differential diagnosis in cancer patients showing valve vegetations even in the TV., Competing Interests: The authors have nothing to be disclosed regarding this case report., (© 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. All rights reserved.)

This case report describes a fatal outcome due to delayed perforation after cold snare polypectomy in a patient with bullous pemphigoid receiving oral corticosteroids. Cold snare polypectomy has become the standard treatment for small colorectal polyps because of the procedure's safety and simplicity. In this case, however, corticosteroid therapy and vasculitis may have caused local necrosis and tearing of the intestinal wall. Corticosteroids are widely used, and perforation after cold snare polypectomy is extremely rare. However, some patients on corticosteroid therapy may have special pathologies, such as in this case, and we advise physicians to use appropriate judgment and extreme caution in determining the indication for endoscopic therapy., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Bovine pneumonia is a disease that causes significant economic losses in livestock industries and is vital for animal welfare. The whole-genome sequence of Pasteurella multocida strain Pm1, isolated from a calf suffering from pneumonia in Japan, is reported here.

Aims: Elevated left ventricular filling pressure (LVFP) is a powerful indicator of worsening clinical outcomes in heart failure with preserved ejection fraction (HFpEF); however, detection of elevated LVFP is often challenging. This study aimed to determine the association between the newly proposed echocardiographic LVFP parameter, visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score, and clinical outcomes of HFpEF., Methods and Results: We retrospectively investigated 310 well-differentiated HFpEF patients in stable conditions. VMT was scored from 0 to 3 using two-dimensional echocardiographic images, and VMT ≥2 was regarded as a sign of elevated LVFP. The primary endpoint was a composite of cardiac death or heart failure hospitalization during the 2 years after the echocardiographic examination. In all patients, Kaplan-Meier curves showed that VMT ≥2 (n = 54) was associated with worse outcomes than the VMT ≤1 group (n = 256) (P < 0.001). Furthermore, VMT ≥2 was associated with worse outcomes when tested in 100 HFpEF patients with atrial fibrillation (AF) (P = 0.026). In the adjusted model, VMT ≥2 was independently associated with the primary outcome (hazard ratio 2.60, 95% confidence interval 1.46-4.61; P = 0.001). Additionally, VMT scoring provided an incremental prognostic value over clinically relevant variables and diastolic function grading (χ2 10.8-16.3, P = 0.035)., Conclusions: In patients with HFpEF, the VMT score was independently and incrementally associated with adverse clinical outcomes. Moreover, it could also predict clinical outcomes in HFpEF patients with AF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Right-sided filling pressure is elevated in some patients with heart failure (HF) and preserved ejection fraction (HFpEF). We hypothesized that right atrial pressure (RAP) would represent the cumulative burden of abnormalities in the left heart, pulmonary vasculature, and the right heart., Methods and Results: Echocardiography was performed in 399 patients with HFpEF. RAP was estimated from inferior vena cava morphology and its respiratory change [estimated right atrial pressure (eRAP)], and patients were divided according to eRAP (3 or ≥8 mmHg). Patients with higher eRAP displayed more severe abnormalities in LV diastolic function as well as right heart structure and function than those with normal eRAP. Cardiac deaths or HF hospitalization occurred in 84 patients over a median follow-up of 19.0 months (interquartile range 6.7-36.9). The presence of higher eRAP was independently associated with an increased risk of the composite outcome (adjusted hazard ratio 2.20 vs. normal eRAP group, 95% confidence interval 1.34-3.62, P = 0.002). Kaplan-Meier curves separating the patients into four groups based on eRAP and E/e' ratio showed that event-free survival varied among the groups, providing an incremental prognostic value of eRAP over E/e' ratio. The classification and regression tree analysis demonstrated that eRAP was the strongest predictor of the outcome followed by right ventricular dimension, E/e' ratio, and estimated right ventricular systolic pressure, stratifying the patients into four risk groups (incident rate 8.8-72.2%)., Conclusions: These data may provide new insights into the prognostic role of RAP in the complex pathophysiology of HFpEF and suggest the utility of eRAP for the risk stratification in patients with HFpEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Although Escherichia coli is a commensal bacterium of the bovine vaginal microbiota, it is an important pathogenic bacterium that causes diseases of the reproductive tract and sub-fertility. Recent studies have focused on virulence factors (VFs) of intrauterine E. coli; however, actual endometrial VFs have not been clearly identified. The purpose of this study was to identify the VFs of E. coli associated with clinical metritis and endometritis. Thirty-two strains of E. coli and four mixed Trueperella pyogenes (TP) strains were detected in the uterus of 19 Holstein dairy cows with obvious clinical signs (between 8 and 66 days postpartum). The presence of six E. coli VFs (fimH, fyuA, kpsMTII, hra1, csgA, and astA) was examined by PCR, and clinical signs and reproductive performance (mixed TP, the percentage of polymorphonuclear neutrophils [PMN%], days to uterine involution, etc.) were evaluated. Four VFs (fimH, hra1, csgA, and astA) were detected in all E. coli strains, whereas fyuA and kpsMTII were detected in 94% and 50% of strains, respectively. Cows with E. coli strains harboring kpsMTII exhibited significantly severe clinical scores (vaginal discharge score, PMN%, uterine involution), suggesting that kpsMTII is a key VF for progression of clinical metritis and endometritis. In the present study, we clearly identified six VFs associated with clinical metritis and endometritis. In addition, E. coli strains with kpsMTII probably play a crucial role in the progression of clinical metritis and endometritis.

Background: Cardiac power output is a measure of cardiac performance, and its prognostic significance has been shown in heart failure (HF) with reduced ejection fraction. Patients with HF with preserved ejection fraction may have altered cardiac performance, but the prognostic relevance of cardiac power output is unknown. This study sought to determine the association between cardiac power output and clinical outcomes in HF with preserved ejection fraction and to compare its prognostic effect to other measures of cardiac performance including ventricular-arterial coupling and mechanical efficiency., Methods: Cardiac power output normalized to left ventricular mass was assessed by echocardiography in 408 patients with HF with preserved ejection fraction. Load-independent contractility (end-systolic elastance), arterial elastance, its coupling (arterial elastance/end-systolic elastance), left ventricular global longitudinal strain, and mechanical efficiency (stroke work/pressure-volume area) were also estimated noninvasively. The primary end point was a composite of cardiovascular mortality or HF hospitalization., Results: The primary composite outcome occurred in 84 patients during a median follow-up of 19.4 months. There was a dose-dependent association between cardiac power output and the composite outcomes, in which patients with the lowest tertile of cardiac power output had >3-fold risk than those with the highest tertile (hazard ratio, 3.04 [95% CI, 1.66-5.57]; P =0.0003). In a multivariable model, lower cardiac power output was independently associated with adverse outcomes (hazard ratio, 0.70 per 1 SD [95% CI, 0.49-0.97]; P =0.03). In contrast, left ventricular size, end-systolic elastance, arterial elastance, arterial elastance/end-systolic elastance ratio, and left ventricular mechanical efficiency were not associated with outcomes. Cardiac power output provided an incremental prognostic effect over the model based on clinical (age, gender, diastolic blood pressure, and atrial fibrillation) and echocardiographic markers (left atrial size, pulmonary pressures, global longitudinal strain, and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity; P =0.03)., Conclusions: In patients with HF with preserved ejection fraction, cardiac power output was independently and incrementally associated with adverse outcomes whereas other markers of cardiac performance were not.

Objectives: This study aimed to assess, among Japanese patients with cardiac sarcoidosis (CS), the implantable cardioverter-defibrillator (ICD) recommendations from the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death (SCD)., Background: Although ICDs are used to prevent SCD from ventricular tachycardia or ventricular fibrillation (VT/VF) in patients with CS, the generalizability of the AHA/ACC/HRS guidelines for Japanese patients with CS remains unclear., Methods: This study examined 188 consecutive patients with CS in 2 tertiary hospitals between 1979 and 2020. Patients were followed for a primary outcome of VT/VF or SCD., Results: During a median follow-up of 5.68 years, the primary outcome occurred in 44 patients (23%). Patients with a Class I recommendation for ICD implantation showed the highest incidence of the primary outcome among patients in whom the guideline recommendations for ICD implantation were used (log-rank test; p = 0.03). However, compared with patients with left ventricular ejection fractions (LVEFs) ≤35%, there was no significant difference in the incidence of the primary outcome among patients with LVEFs >35% and those who required a permanent pacemaker (p = 0.31); similar results were observed in those with LVEFs >35% and late gadolinium enhancement during cardiovascular magnetic resonance imaging (p = 0.22)., Conclusions: The American guideline recommendations for ICD implantation might be applicable to Japanese patients with CS. Implantation of an ICD may need to be considered in these patients if they require a permanent pacemaker or have late gadolinium enhancement, regardless of LVEF., Competing Interests: Funding Support and Author Disclosures Dr. Nagai was supported by a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (15K19402) and by a grant from the Japan Heart Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

High-power UV-LED irradiation (365 nm) effectively accelerated the decatungstate-anion-catalyzed oxidation of benzyl alcohol 1 to benzoic acid 3 via benzaldehyde 2 . As the power of the UV-LED light increased, both the selectivity and yield of benzoic acid also increased. The reaction was finished within 1 h to give 3 in a 93% yield using 2 mol% of decatungstate anion catalyst. The combination of a flow photoreactor and high-power irradiation accelerated the oxidation reaction to an interval of only a few minutes.

Background: Although the time difference between peak of left ventricular (LV) and aortic systolic pressures (T LV-Ao ), which is considered to in part reflect pulsus tardus, is reported to be associated with clinical outcome in aortic stenosis (AS), its physiological determinants remain to be elucidated. We hypothesized that not only AS severity but also LV systolic dysfunction could be associated with occurrence of pulsus tardus., Methods: T LV-Ao was measured by simultaneous LV and aortic pressure tracing in 74 AS patients and prolonged T LV-Ao was defined as ≥66 ms according to the previous report. Mean transaortic valvular pressure gradient (mPG) and effective orifice area index (EOAI) were estimated by Doppler echocardiography and severe AS was defined as EOAI ≤0.60 cm 2 /m 2 . Global longitudinal strain (GLS) was measured by using speckle-tracking method., Results: Although a weak correlation was observed between EOAI and T LV-Ao , there was substantial population showing discordance between the parameters: severe AS despite normal T LV-Ao (10 of 47 patients) and moderate AS despite prolonged T LV-Ao (9 of 17 patients). In severe AS, mPG was significantly higher in patients showing prolonged T LV-Ao (57±20 vs 36±10 mmHg, p<0.0001) whereas GLS was comparable between the groups (-15.2±3.5% vs -14.8±3.2%). In contrast, in moderate AS, GLS was significantly smaller in patients showing prolonged T LV-Ao (-12.6±4.7% vs -17.4±3.4%, p=0.0271) while mPG was comparable (34±7 mmHg vs 35±8 mmHg). Multivariable analysis revealed that not only mPG but also GLS was an independent determinant of T LV-Ao ., Conclusions: The occurrence of pulsus tardus could be associated with not only AS severity but also LV systolic dysfunction in AS patients., Competing Interests: Declaration of Competing Interest There is no conflict of interest to disclose relating to the present study., (Copyright © 2021. Published by Elsevier Ltd.)

Bacteriophages are viruses that specifically infect bacteria and are classified as either virulent phages or temperate phages. Despite virulent phages being promising antimicrobial agents due to their bactericidal effects, the implementation of phage therapy depends on the availability of virulent phages against target bacteria. Notably, virulent phages of Streptococcus gordonii , which resides in the oral cavity and is an opportunistic pathogen that can cause periodontitis and endocarditis have previously never been found. We thus attempted to isolate virulent phages against S. gordonii . In the present study, we report for the first time a virulent bacteriophage against S. gordonii , ΦSG005, discovered from drainage water. ΦSG005 is composed of a short, non-contractile tail and a long head, revealing Podoviridae characteristics via electron microscopic analysis. In turbidity reduction assays, ΦSG005 showed efficient bactericidal effects on S. gordonii. Whole-genome sequencing showed that the virus has a DNA genome of 16,127 bp with 21 coding sequences. We identified no prophage-related elements such as integrase in the ΦSG005 genome, demonstrating that the virus is a virulent phage. Phylogenetic analysis indicated that ΦSG005 forms a distinct clade among the streptococcus viruses and is positioned next to streptococcus virus C1. Molecular characterization revealed the presence of an anti-CRISPR (Acr) IIA5-like protein in the ΦSG005 genome. These findings facilitate our understanding of streptococcus viruses and advance the development of phage therapy against S. gordonii infection.

To assess myocardial fibrosis associated with muscular dystrophy, T 1 -mapping and extracellular volume fraction (ECV) quantification was prospectively performed using cardiovascular MR (CMR) imaging in 6 male patients with muscular dystrophy and 5 female putative carriers of Duchenne or Becker muscular dystrophy. Five patients and all putative carriers had an elevated ECV (>29.5% for men and >35.2% for women), suggesting that ECV has a potential to detect diffuse fibrotic changes in patients and putative carriers of muscular dystrophy.

Acute myocardial infarction (AMI) caused by severe stenosis of left main coronary artery (LMCA) presenting with cardiogenic shock and pulmonary edema during noncardiac surgery is uncommon, but a catastrophic event. A 77-year-old male with cholangiocarcinoma underwent hepatectomy. During the surgery, he presented with cardiogenic shock, which did not respond to infusion administration or vasopressor. A transesophageal echocardiogram revealed anterior, septal, and lateral severe hypokinesia and impaired left ventricular function. Emergent coronary angiogram showed severe stenosis of LMCA. The patient underwent primary percutaneous coronary intervention (PCI) under the support of intra-aortic balloon pump, followed by extracorporeal membrane oxygenation. The chest roentgenogram showed pulmonary edema. Two days after PCI, he successfully underwent hepatectomy and bile duct resection. Early identification of the cause of hemodynamic instability during noncardiac surgery and invasive strategy are important for minimizing the myocardial injury and improving clinical outcomes in AMI of LMCA., Competing Interests: The authors have no competing interests to disclose., (Copyright © 2021 Sakae Takenaka et al.)