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Abstract Aim To evaluate the feasibility and safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. Methods This prospective, multicenter, single‐arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3‐4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)‐based long‐course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate. Results Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41–79] y), the long‐course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near‐complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%–41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment‐related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%). Conclusion ENSEMBLE‐2 demonstrated comparable pathologic complete response rates and well‐tolerated safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation. Patients with JMML demonstrate characteristic manifestations such as splenomegaly, monocytosis and the presence of myeloid or erythroid precursors in the peripheral blood. Here, we present the case of a male infant with ectodermal dysplasia, bacterial septicemia, Pneumocystis pneumonia, severe inflammation and transient manifestations mimicking JMML. Genetic analysis revealed a deep intronic germline variant of IKBKG. Full-length IKBKG cDNA and NEMO protein expression were almost inexistent. Peripheral mononuclear cells (PBMCs) from the patient showed increased RAS signaling activation with GM-CSF or Phorbol 12-myristate 13-acetate without the RAS-associated gene variant, although the increased RAS signaling activation in induced-pluripotent stem cell-derived myeloid lineage and bone marrow-derived mesenchymal cells was not evident. The patient with NEMO deficiency demonstrated JMML-like manifestation and severe inflammation. PBMCs of the patient demonstrated increased RAS signaling activation with unknown pathophysiology.

Abstract Cardiac rehabilitation is crucial for the secondary prevention of cardiovascular disease, the leading cause of death worldwide. In Japan, as hospitalization periods have been shortened due to advances in medical technology and government policies, outpatient rehabilitation focused on lifestyle and physical activity (PA) is becoming increasingly important as hospital stays shorten. This study was aimed to identify patient characteristics that define the different types of PA and sedentary behaviors, and patient factors in 92 Japanese outpatients by using accelerometers. The patients were found to spend considerable time being sedentary (663.7 ± 118.1 min/day) and very little time engaging in moderate-to-vigorous PA (MVPA, 25.6 (10.6–43.4) min/day). Regression analysis revealed that the daily duration of sedentary behavior was 64 min longer in men than in women (β = 64.2, 95% CI[12.9, 115], p = 0.015); furthermore, men engaged in 22% less light PA (β = -0.245, 95% CI[-0.388, -0.102], p = 0.001). Additionally, MVPA increased by 43% for every 1 metabolic equivalent (MET) task increase in the anaerobic threshold (AT) (β = 0.367, 95% CI[0.035, 0.698], p = 0.031) but decreased by 3% per year of age(β = -0.035, 95% CI[-0.056, -0.015], p

Abstract Background Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura. Findings Fifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex. Conclusions Female mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

Abstract Aims Sudden cardiac death (SCD) is a common mode of death in patients with congestive heart failure (CHF). Implantable cardioverter defibrillator (ICD) implantation is established treatment for SCD prevention, but current eligibility criteria based on left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class may be due for reconsideration given the increasing effectiveness of pharmacological therapy. We sought to reconsider the risk stratification of SCD in patients with symptomatic CHF. Methods In total, 1,676 consecutive patients (74 ± 13 years old; 56% male) with NYHA class II or III CHF between 2008 and 2015 were enrolled for this prospective study. The endpoint was SCD. Results During a median (interquartile range) follow‐up period of 25 (4–70) months, 198 (11.8%) patients suffered SCD. Of those events, 23% occurred within 3 months of discharge. In the adjusted analyses, estimated glomerular filtration rate (eGFR)

This study examines the impact of educational attainment on employment and earnings in Nepal. Using the Nepal Labour Force Survey 2017-2018 cycle, we employ an extended earnings function derived from the foundational Mincer equation to estimate returns to education. The results underscore the overall positive impact of education (1.76, 3.73, 7.68 and 11.00% increase in earnings by primary, secondary, bachelor's and master's degrees, respectively), which is lower than the average observed in other low- and middle- income countries, except in higher education. The results also indicate persisting disparities for females and disadvantaged groups. The study emphasizes the need for strategic interventions, improved educational infrastructure and inclusive policies to foster equitable opportunities.

Inequality and injustice in education have been viewed from the perspective of social justice. Since the emergence of John Rawls's "A Theory of Justice," social justice issues have attracted the attention of social and political philosophers. Theoretical consequences of social and political philosophy have been actively incorporated into the field of education. However, the issue of educational justice remains controversial and requires further philosophical consideration. To further philosophical consideration, this paper explores how the class or the classroom can generate space and time for democracy, by focusing on the educational specificity of the classroom community, which is called 'Gakkyu' in Japanese. Social justice in education is not only a policy issue, but also a practical issue which should be tackled in the classroom. Rethinking the ways of democracy to face conflicts arising due to differences and equality of children in the classroom is an important method of bridging social justice and education. In this paper, the following question will be explored: how classroom democracy can be nurtured and the classroom community transformed into a democratic place where children from various background and experiences gather and learn from each other.

Background: Ultrasonography is not chosen as the common imaging modality to diagnose spinal cord diseases. The present report indicates good diagnostic efficacy of ultrasonography for identifying spinal cord compressed by subcutaneous mass when scanning through the defected vertebral laminae and spinous process. Case Description: A five-month-old female Holstein calf presented with progressive hindlimb paralysis following a surgical resection of back mass conducted at 21 days of age. The mass was subsequently histopathologically diagnosed as a pulmonary choristoma. Alongside hindlimb paralysis, the calf developed a swollen back at the lumbar region where the mass was removed. This suggested regrowth of the resected mass, causing injury to the underlying spinal cord. Ultrasonography identified the subcutaneous involvement of the capsular mass, which had three anechoic cavities separated by the echogenic septal structures. The spinal cord could be ultrasonographically demonstrated as adjacent to the mass through the defected vertebral laminae and spinous process in the second and third lumbar vertebras. Ultrasound-guided centesis allowed collection of purulent exudates in which Escherichia coli was isolated. Myelography and subsequent computed tomography revealed a partial blockage of the intradural flow of contrast media at the levels of the second and third lumbar vertebras, diagnosed as spina bifida on the computed tomographic images. When applying ultrasonography to the spinal cord within a saline pool soon after the subcutaneous abscess was successfully resected, the spinal cord was characterized by the interrupted and partly-extended hyperechogenic line of the central canal within the echogenic parenchyma. The echotexture of the spinal cord showed damage due to compression from the subcutaneous abscess. The animal had a sub-optimal postoperative outcome, including limited improvement of the neurological signs. Conclusion: In the present case, combining ultrasonography, radiography (myelography) and computed tomography was very effective for diagnosing spina bifida, with the subcutaneous abscess inducing spinal cord compression. Additionally, using intraoperative ultrasonographic scanning to evaluate the degree of spinal cord damage can contribute to predicting the postoperative outcome. [Open Vet J 2024; 14(8.000): 2097-2109]

Background: Different energy sources of balloon-based ablation for pulmonary vein isolation cause different kinds of endothelial damage and coagulation responses associated with thromboembolic risk. Objectives: The study sought to compare the impact of different balloon-based ablation, cryoballoon ablation (CBA) and laser balloon ablation (LBA), on coagulation/fibrinolysis biomarkers and silent cerebral events (SCEs) in paroxysmal atrial fibrillation. Methods: Paroxysmal atrial fibrillation patients who underwent pulmonary vein isolation using either CBA (n = 52) or LBA (n = 53) without radiofrequency touch-up ablation were eligible. Time course (day 0 [before ablation], day 1, day 2, and day 28) of myocardial enzymes and inflammatory and coagulation/fibrinolysis biomarkers was evaluated during the perioperative period. Brain magnetic resonance imaging was performed within 2 days after the procedure to evaluate SCEs. Results: There was no difference in patient characteristics between CBA and LBA.CBA had greater myocardial injury (troponin I and creatine kinase-MB) and lower inflammatory reaction (white blood cell count and neutrophil/lymphocyte ratio) than LBA. The coagulation biomarkers maximally increased by day 2 and then decreased in both groups. In day 28, the serum prothrombin fragment 1+2 and D-dimer levels in LBA were significantly higher than the values in CBA. The fibrinolysis biomarker (plasmin-α2 plasmin inhibitor complex) did not increase after the procedure in either group. The incidence of SCEs was comparable between CBA and LBA (11% vs 15%; P = .591). No thromboembolic event was observed. Conclusion: CBA and LBA had different effects on myocardial injury, inflammatory reaction, and coagulation activity but did not affect the incidence of thromboembolic events. LBA had significantly higher coagulation activity in day 28 and may require more careful postprocedural anticoagulation than CBA.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Abstract The prenatal diagnosis of fetal heart disease potentially influences parental decision-making regarding pregnancy termination. Existing literature indicates that the severity, whether in complexity or lethality, significantly influences parental decisions concerning abortion. However, questions remain as to how fetal heart disease severity impacts parental decisions, given recent advancements in postsurgical outcomes. Therefore, we investigated risk factors associated with parents’ decision-making regarding abortion following a prenatal diagnosis of fetal heart disease. Our analysis included 73 (terminated: n = 37; continued: n = 36) pregnancies with a fetal heart disease diagnosed before 22 weeks of gestation. Increased gestational age at diagnosis reduced the likelihood of parents’ decision on termination (Model 1: adjusted odds ratio, 0.94; 95% confidence interval 0.89–0.99; Model 2: 0.95 0.90–0.997). Critical disease (5.25; 1.09–25.19) and concurrent extracardiac or genetic abnormalities (Model 1: 4.19, 1.21–14.53; Model 2: 5.47, 1.50–19.96) increased the likelihood of choosing abortion. Notably, complex disease did not significantly influence parental decisions (0.56; 0.14–2.20). These results suggest that parental decision-making regarding abortion may be influenced by earlier gestational age at diagnosis, the lethality of heart disease, and extracardiac or genetic abnormalities, but not its complexity if prenatal diagnosis and parental counseling are provided at a cardiovascular-specialized facility.

Abstract This study aimed to investigate the rate of sedentary behaviour and differences in physical outcomes and activities of daily living (ADL) based on sedentary behaviour time of hospitalized older cardiovascular disease patients undergoing phase I cardiac rehabilitation. Older cardiovascular disease patients were enrolled from October 2020 to September 2023 and were divided into the high sedentary behaviour group (≥ 480 min/day) and low sedentary behaviour group (

Abstract Background Minimally invasive posterior fixation surgery for pyogenic spondylitis is known to reduce invasiveness and complication rates; however, the outcomes of concomitant insertion of pedicle screws (PS) into the infected vertebrae via the posterior approach are undetermined. This study aimed to assess the safety and efficacy of PS insertion into infected vertebrae in minimally invasive posterior fixation for thoracolumbar pyogenic spondylitis. Methods This multicenter retrospective cohort study included 70 patients undergoing minimally invasive posterior fixation for thoracolumbar pyogenic spondylitis across nine institutions. Patients were categorized into insertion and skip groups based on PS insertion into infected vertebrae, and surgical data and postoperative outcomes, particularly unplanned reoperations due to complications, were compared. Results The mean age of the 70 patients was 72.8 years. The insertion group (n = 36) had shorter operative times (146 versus 195 min, p = 0.032) and a reduced range of fixation (5.4 versus 6.9 vertebrae, p = 0.0009) compared to the skip group (n = 34). Unplanned reoperations occurred in 24% (n = 17) due to surgical site infections (SSI) or implant failure; the incidence was comparable between the groups. Poor infection control necessitating additional anterior surgery was reported in four patients in the skip group. Conclusions PS insertion into infected vertebrae during minimally invasive posterior fixation reduces the operative time and range of fixation without increasing the occurrence of unplanned reoperations due to SSI or implant failure. Judicious PS insertion in patients with minimal bone destruction in thoracolumbar pyogenic spondylitis can minimize surgical invasiveness.

Fluoroquinolones, which are widely used antibiotics, have been linked to aortic disease, which prompted an FDA warning in 2018. Recent reports have challenged the perception that fluoroquinolones pose a significant risk for vascular diseases. This study aimed to investigate whether fluoroquinolones increase the risk of aortic diseases by focusing on the onset of aortic dissection. Levofloxacin (LVFX), a fluoroquinolone, was studied in vitro using cultured vascular cells and in vivo using a mouse model prone to aortic dissection. Risk of adverse drug events was analyzed using VigiBase, a global safety database, and a retrospective cohort analysis was conducted using the JMDC Claims database. LVFX resulted in endothelial cell injury and increased matrix metalloproteinases in vitro. However, in vivo studies showed no significant effect on elastin degradation or aortic dissection incidence. The effect of LVFX on endothelial injury was altered during the onset of dissection, exacerbating injury before onset but inhibiting it afterward. Safety database analysis showed no significant risk signals for aortic dissection associated with fluoroquinolones, which was supported by findings in the receipt database. Inconsistencies were observed in the in vitro and in vivo actions of fluoroquinolones and differences in their effects on aortic dissection and aneurysms. Despite cytotoxicity, the risk of aortic dissection was not significantly increased in clinical scenarios. Based on our findings, concerns regarding aortic diseases do not justify discontinuation of fluoroquinolone use. Further studies are needed to elucidate the conflicting actions of fluoroquinolones, taking into account background pathophysiology such as infection and inflammation.