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Background: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT., Methods: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated., Results: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity., Conclusion: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The prevalence of respiratory sarcopenia and its effect on respiratory muscle strength (RMS) in patients with cardiovascular disease (CVD), who are transferred to a convalescent rehabilitation hospital after acute care and require continuous cardiac rehabilitation (CR), is currently unclear. This study aimed to assess changes in RMS, physical function, and activities of daily living (ADL) before and after CR performed in a rehabilitation hospital., Methods: Of 50 consecutive patients transferred to a rehabilitation hospital for ongoing CR, 30 fulfilled the inclusion criteria. Maximal inspiratory and expiratory pressures (MIP and MEP, respectively) were measured at transfer, and patients with decreased RMS were diagnosed with respiratory sarcopenia. RMS, physical function, exercise tolerance, ADL ability, and health-related quality of life (HR-QoL) were measured and compared at transfer and discharge., Results: The prevalence of respiratory sarcopenia at the time of transfer to the rehabilitation hospital was 93.3%. RMS assessments at transfer and discharge demonstrated significant improvements in %MIP (from 46.3±26.1% to 63.6±33.7%) and %MEP (from 44.8±17.3% to 56.6±21.8%). Short physical performance battery, gait speed, handgrip strength, and knee extension muscle strength significantly improved, along with significant prolongation of 6-min walking distance as a measure of exercise tolerance. ADL assessment using the functional independence measure revealed significant improvement, as did HR-QoL assessed according to the five-dimension, five-level, EuroQoL instrument, following CR., Conclusions: Although respiratory sarcopenia was highly prevalent among patients with CVD who required transfer to a rehabilitation hospital after acute care, continuous CR significantly improved RMS, ADL, physical function, and exercise tolerance. These findings support the continued expansion of CR, particularly in dedicated rehabilitation hospitals., Competing Interests: The authors declare no conflict of interest with this manuscript., (Copyright 2024, Matsuo et al.)

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences., (© 2023. The Author(s).)

Understanding the principles of cell migration necessitates measurements of the forces generated by cells. In traction force microscopy (TFM), fluorescent beads are placed on a substrate's surface and the substrate strain caused by the cell traction force is observed as displacement of the beads. Mathematical analysis can estimate traction force from bead displacement. However, most algorithms estimate substrate stresses independently of cell boundary, which results in poor estimation accuracy in low-density bead environments. To achieve accurate force estimation at low density, we proposed a Bayesian traction force estimation (BTFE) algorithm that incorporates cell-boundary-dependent force as a prior. We evaluated the performance of the proposed algorithm using synthetic data generated with mathematical models of cells and TFM substrates. BTFE outperformed other methods, especially in low-density bead conditions. In addition, the BTFE algorithm provided a reasonable force estimation using TFM images from the experiment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Phase 2 in-patient cardiac rehabilitation (CR) at a rehabilitation hospital is now added the medical service fees in Japan and in light of the recent reimbursement for CR, a study needed to be performed to determine exertional exercise on its effectiveness and benefits to patients. We examined the effects of daily aerobic exercise duration on health-related quality of life (HR-QoL) at 6 months after discharge from phase 2 CR., Methods: Of the 54 consecutive cardiovascular disease patients admitted to a rehabilitation hospital after acute care, 43 were considered acceptable candidates for enrollment according to predetermined inclusion and exclusion criteria. Of these, 40 patients completed study requirements, including return of a questionnaire on HR-QoL survey 6 months after discharge. The primary outcome was HR-QoL as evaluated using the EuroQol five-dimension five-level (EQ-5D-5L). Two multiple regression models were constructed to assess the influences of daily aerobic exercise duration (content of rehabilitation) and other clinicodemographic variables assessed during acute care (model 1) or at transfer from acute care to a rehabilitation hospital (model 2)., Results: Both model 1, which included age, Barthel index of daily function before hospitalization, and daily aerobic exercise duration in the rehabilitation hospital (R 2 = 0.553, P < 0.001), and model 2, which included New York Heart Association functional classification at transfer, Charlson comorbidity index at transfer, and daily aerobic exercise duration (R 2 = 0.336, P = 0.002) identified aerobic exercise duration as a significant independent factor influencing HR-QoL at 6 months post-discharge (model 1: P = 0.041; model 2: P = 0.010)., Conclusions: Enhanced daily aerobic exercise content during phase 2 in-hospital CR can significantly improve longer-term HR-QoL among cardiovascular disease patients independently of other clinicodemographic factors, including age, activities of daily living before treatment, and baseline condition at rehabilitation onset. These findings, that in the small sample size, support the continued expansion of phase 2 CR at a rehabilitation hospital in Japan., Competing Interests: The authors declare that there is no conflict of interest., (Copyright 2023, Matsuo et al.)

Motivation: Human diseases are characterized by multiple features such as their pathophysiological, molecular and genetic changes. The rapid expansion of such multi-modal disease-omics space provides an opportunity to re-classify diverse human diseases and to uncover their latent molecular similarities, which could be exploited to repurpose a therapeutic-target for one disease to another., Results: Herein, we probe this underexplored space by soft-clustering 6955 human diseases by multi-modal generative topic modeling. Focusing on chronic kidney disease and myocardial infarction, two most life-threatening diseases, unveiled are their previously underrecognized molecular similarities to neoplasia and mental/neurological-disorders, and 69 repurposable therapeutic-targets for these diseases. Using an edit-distance-based pathway-classifier, we also find molecular pathways by which these targets could elicit their clinical effects. Importantly, for the 17 targets, the evidence for their therapeutic usefulness is retrospectively found in the pre-clinical and clinical space, illustrating the effectiveness of the method, and suggesting its broader applications across diverse human diseases., Availability and Implementation: The code reported in this article is available at: https://github.com/skozawa170301ktx/MultiModalDiseaseModeling., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: To investigate the changes in the proportion of antimicrobial prophylaxis (AP) during the urodynamic study (UDS) and the frequency of posttest genito-urinary tract infections (GUTI) before and after coronavirus disease 2019 (COVID-19) pandemic, and evaluate this associations., Patients and Methods: Patients who underwent UDS between 2015 and 2021 were targeted, and they were allocated to pre-2020 as before the appearance of COVID-19 and post-2020 as after that, and propensity score matching was performed. The impact on AP was assessed by the administration rate, and that on the development of febrile GUTI after UDS was assessed for an equivalence by the GUTI-free rate at 7 days after testing., Results: After matching, 384 cases of 192 cases each were included. The frequency of AP was 58.3% in pre-2020 and 77.1% in post-2020, an increase of about 19%, and the rate increased significantly in post-2020 (p < 0.001). However, the incidence of GUTI after UDS was 4.2% and 4.7%, respectively, with no significant difference. The ratio of GUTI-free rates was within the equivalence margin, confirming an equivalence before and after the appearance of COVID-19., Conclusions: Under the influence of COVID-19 pandemic, even though AP rate during UDS was increased by 19% from that brought by following the guideline-based administration methods, the frequency of GUTI after UDS was similar, so it is thought to be important to use AP during UDS appropriately for high-risk cases as recommended in the guidelines., (© 2022 Wiley Periodicals LLC.)

In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD., (© 2022. The Author(s).)

The full-iterative model reconstruction generates ultra-high-resolution computed tomography (U-HRCT) images comprising a 1024 × 1024 matrix and 0.25 mm thickness while suppressing image noises, allowing evaluating small airways 1-2 mm in diameter. However, this technique imposes huge computational burdens and requires a long reconstruction time. This study evaluated whether a recently-established deep learning-based reconstruction, Advanced intelligent Clear-IQ Engine (AiCE), allows quantitative morphological analyses of smaller airways with equal or better quality than the full-iterative model reconstruction while shortening the reconstruction time. In phantom tubes mimicking small airways, the measurement error of 0.5-mm-thickness wall was smaller on the AiCE-based than the full-iterative model-based U-HRCT. Moreover, in five patients with chronic obstructive pulmonary disease, the AiCE-based U-HRCT decreased the reconstruction time approximately by 90% with a modest improvement in image noise, contrast, and sharpness compared to the full-iterative model-based U-HRCT. Therefore, the AiCE-based U-HRCT can be readily used clinically for morphologically evaluating peripheral small airways., Competing Interests: Conflict of Interest Yuji Nakamoto and Ryo Sakamoto received a research grant from Canon Medical Systems Corporation. The other authors have no conflicts of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Asthma onset before the age of 40 years is associated with distinct clinical manifestations in chronic obstructive pulmonary disease (COPD) patients, but its morphologic features remain unestablished. This study aimed to explore airway morphology in COPD patients with asthma onset before 40 years of age using ultra-high-resolution computed tomography (U-HRCT), which allows a more accurate quantitation of the lumen and the wall in smaller airways than using conventional CT., Materials and Methods: Clinical data of 500 consecutive patients undergoing full inspiratory U-HRCT (1024×1024 matrix and 0.25 mm slice thickness) were retrospectively analyzed. COPD patients without asthma, COPD patients with asthma onset at age below or 40 years and above, and non-COPD smoker controls (N=137, 29, 34, and 22, respectively) were enrolled. The length, lumen area (LA), wall thickness and area (WA), and wall area percent (WA%) of the segmental (third-generation) to sub-subsegmental (fifth-generation) bronchus and the low attenuation volume percent (LAV%) were measured., Results: LA and WA were smaller in the fourth and fifth generation in COPD patients than in non-COPD controls, regardless of the age of asthma onset. LA was smaller and WA% was larger in the fourth-generation and fifth-generation airways in COPD with asthma onset before 40 years than COPD without asthma, whereas WA did not differ between them. In multivariate analyses, asthma onset before 40 years was associated with smaller LA in COPD patients independent of demographics, use of inhaled corticosteroids and long-acting bronchodilators, airflow limitation, and LAV%., Conclusions: Asthma onset before 40 years of age could be associated with greater lumen narrowing of the airways in COPD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Dopamine type 1 receptor (D1R) signaling activates protein kinase A (PKA), which then activates mitogen-activated protein kinase (MAPK) through Rap1, in striatal medium spiny neurons (MSNs). MAPK plays a pivotal role in reward-related behavior through the activation of certain transcription factors. How D1R signaling regulates behavior through transcription factors remains largely unknown. CREB-binding protein (CBP) promotes transcription through hundreds of different transcription factors and is also important for reward-related behavior. To identify transcription factors regulated by dopamine signaling in MSNs, we performed a phosphoproteomic analysis using affinity beads coated with CBP. We obtained approximately 40 novel candidate proteins in the striatum of the C57BL/6 mouse brain after cocaine administration. Among them, the megakaryoblastic leukemia-2 (MKL2) protein, a transcriptional coactivator of serum response factor (SRF), was our focus. We found that the interaction between CBP and MKL2 was increased by cocaine administration. Additionally, MKL2, CBP and SRF formed a ternary complex in vivo. The C-terminal domain of MKL2 interacted with CBP-KIX and was phosphorylated by MAPK in COS7 cells. The activation of PKA-MAPK signaling induced the nuclear localization of MKL2 and increased SRF-dependent transcriptional activity in neurons. These results demonstrate that dopamine signaling regulates the interaction of MKL2 with CBP in a phosphorylation-dependent manner and thereby controls SRF-dependent gene expression. Cover Image for this issue: https://doi.org/10.1111/jnc.15067., (© 2021 International Society for Neurochemistry.)

Purpose: Dry eye syndrome is known to develop from several systemic inflammatory diseases. Although dry eye may develop due to extraintestinal complications of ulcerative colitis (UC), the pathogenesis is not well-known. This study aimed to investigate whether there was decrease in the tear secretion volume in a mice model with UC; the difference between the control and dextran sodium sulphate (DSS)-treated group was also determined., Materials and Methods: This study included a mice model with UC induced by the oral administration of 5.0% DSS for 7 days. Following the DSS treatment, the tear volume was measured using the Schirmer's test. The colon and ocular tissues, including the lacrimal gland, were evaluated using histological and protein analyses. Additionally, tumour necrosis factor (TNF)-α and interleukin (IL)-6 in the plasma were determined. Differences between groups (DSS-treated versus control mice) were determined using Student's t -test., Results: The tear volume in DSS-treated mice was decreased compared to that in the control mice. Plasma levels of TNF-α and IL-6 in DSS-treated mice was higher than that of control. Morphological change was observed with the invasion of the inflammatory cell in the lacrimal gland of DSS-treated mice. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL)-positive cells were increased in the lacrimal glands of DSS-treated mice compared with control group. The distribution of aquaporin-5 expressed in the lacrimal gland of DSS-treated mice was decreased compared to that in the control group., Conclusions: These findings suggest that a decrease in the tear volume in UC was associated with a functional decline in the inflamed lacrimal gland. This result therefore provides useful information that could contribute to the development of treatment approaches for dry eye associated with UC.