Objective The onset of acute myocardial infarction (AMI) shows characteristic circadian variations involving a definite morning peak and a less-defined night-time peak. However, the factors ...influencing the circadian patterns of AMI onset and their influence on morning and night-time peaks have not been fully elucidated. Design, setting and participants An analysis of patients registered between 1998 and 2008 in the Osaka Acute Coronary Insufficiency Study, which is a prospective, multicentre observational study of patients with AMI in the Osaka region of Japan. The present study included 7755 consecutive patients with a known time of AMI onset. Main outcomes and measures A mixture of two von Mises distributions was used to examine whether a circadian pattern of AMI had uniform, unimodal or bimodal distribution, and the likelihood ratio test was then used to select the best circadian pattern among them. The hierarchical likelihood ratio test was used to identify factors affecting the circadian patterns of AMI onset. The Kaplan-Meier method was used to estimate survival curves of 1-year mortality according to AMI onset time. Results The overall population had a bimodal circadian pattern of AMI onset characterised by a high and sharp morning peak and a lower and less-defined night-time peak (bimodal p<0.001). Although several lifestyle-related factors had a statistically significant association with the circadian patterns of AMI onset, serum triglyceride levels had the most prominent association with the circadian patterns of AMI onset. Patients with triglyceride ≥150 mg/dL on admission had only one morning peak in the circadian pattern of AMI onset during weekdays, with no peaks detected on weekends, whereas all other subgroups had two peaks throughout the week. Conclusions The circadian pattern of AMI onset was characterised by bimodality. Notably, several lifestyle-related factors, particularly serum triglyceride levels, had a strong relation with the circadian pattern of AMI onset. Trial registration number UMIN000004575.
Mechanisms underpinning the dysfunctional immune response in SARS-CoV-2 infection are not yet fully understood. In addition, the functional roles of the genetic variants identified by COVID-19 ...genome-wide association study (GWAS) remain elusive, especially in non-European ancestry. We analyzed single-cell transcriptomes and T and B cell receptors of > 895,000 peripheral blood mononuclear cells from 73 COVID-19 patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19, suggesting that the dysfunction of ncMono might be closely involved in the immunopathology of COVID-19 severity. Clonal expansions of B cell receptors were evident in plasmablasts of patients. Putative disease genes identified by the GWAS of severe phenotypes showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had COVID-19-specific and monocyte-specific expression quantitative trait loci effects, indicating the enrichment of host genetic risk in innate immune cells. Our multimodal and integrative single-cell analyses highlight biological and host genetic involvement of innate immune cells in COVID-19 severity.
Mechanisms underpinning the dysfunctional immune response in SARS-CoV-2 infection are not yet fully understood. In addition, the functional roles of the genetic variants identified by COVID-19 ...genome-wide association study (GWAS) remain elusive, especially in non-European ancestry. We analyzed single-cell transcriptomes and T and B cell receptors of > 895,000 peripheral blood mononuclear cells from 73 COVID-19 patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19, suggesting that the dysfunction of ncMono might be closely involved in the immunopathology of COVID-19 severity. Clonal expansions of B cell receptors were evident in plasmablasts of patients. Putative disease genes identified by the GWAS of severe phenotypes showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had COVID-19-specific and monocyte-specific expression quantitative trait loci effects, indicating the enrichment of host genetic risk in innate immune cells. Our multimodal and integrative single-cell analyses highlight biological and host genetic involvement of innate immune cells in COVID-19 severity.
BACKGROUNDNivolumab is an anti-PD-1 blocking monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). However, some patients on immunotherapy may experience rapid ...progression and worsening clinical status, known as hyperprogressive disease. We retrospectively reviewed the clinical records of patients with NSCLC administered nivolumab therapy at Toneyama National Hospital, Japan, from January 2016 to January 2018. Of the 87 patients administered nivolumab therapy, five experienced rapid progression during one cycle of nivolumab therapy. Four patients were treated with corticosteroids to overcome their symptomatic events. Nivolumab exhibited efficacy after temporal progression, so-called "pseudoprogression", in three patients, and their symptoms and laboratory results improved. In the other patient, pleural and pericardial effusions increased after nivolumab therapy, and drainage was required, with no subsequent recurrence. The clinical courses of our case series indicate that alternative treatment, namely high-dose corticosteroids, antibiotics, and drainage, effectively treated the symptoms of rapid tumor progression. Of note, corticosteroids suppressed the temporary inflammatory reaction to nivolumab. Although hyperprogressive disease is thought to be associated with poor quality of life and survival, these treatment strategies may be useful in patients with expected responses to immunotherapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUNDBronchial thermoplasty (BT) is a bronchoscopic treatment that can ameliorate the symptoms of severe asthma. However, little is known about the mechanism by which BT improves exertional ...dyspnea without significantly changing the resting pulmonary function in asthmatics. To understand the mechanism, cardiopulmonary variables were investigated using cardiopulmonary exercise testing (CPET) in a patient with severe asthma before and after BT. CASE PRESENTATIONA 57-year-old Japanese man visited our hospital for consultation of the intractable asthma, which we managed with three treatment sessions of BT. Comparison of the findings pre-BT and at 1 year after BT demonstrated that (1) the resting tests for respiration showed no improvement in forced expiratory volume in 1 s, but the forced oscillation technique showed decreases in both inhalation and exhalation respiratory resistance values, and (2) the CPET results showed (i) improvement in exertional dyspnea, exercise endurance, and arterial oxygen saturation at the end of exercise; (ii) that the expiratory tidal volume exceeded the inspiratory tidal volume during exercise, which implied that a sufficient exhalation enabled longer inspiratory time and adequate oxygen absorption; and (iii) that an increase in respiratory frequency could be prevented throughout exercise. CONCLUSIONSThis case report described a novel mechanism of BT in improving exertional dyspnea and exercise duration, which was brought about by ventilatory improvements related to the breathing pattern of inspiration to expiration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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