Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Qualitative study of barriers and facilitators encountered by individuals with physical diseases in returning and continuing to work.

BACKGROUND: The number of employees with physical diseases is increasing, and there is a need for support to help them return and continue to work. To provide effective support, it is important to identify barriers and facilitators for individuals in returning and continuing to work. Previous studies have reported barriers and facilitators for specific diseases. However, few reports have dealt with these issues across various diseases. To identify a range of barriers and facilitators that may apply to different physical diseases, we conducted a qualitative analysis by interviewing patients with diverse characteristics being treated for diseases. METHODS: We conducted semi-structured interviews based on the criteria for qualitative research. We investigated three disease groups to obtain details of barriers and facilitators: impairments that were visible to other people (mainly stroke); impairments invisible to others (mainly heart disease); and impairments that changed over time (mainly cancer). Interview transcripts were analyzed and the results reported using systematic text condensation. RESULTS: We extracted 769 meaning units from 28 patient interviews. We categorized barriers and facilitators that were generalizable to various diseases into three themes (personal factors, workplace factors, and inter-sectoral collaboration and social resources) and 10 sub-themes (work ability, psychological impacts, health literacy, social status, family background, workplace structure, workplace system, workplace support, inter-sectoral collaboration, and social resources). CONCLUSIONS: This study identified 10 sub-themes that can be applied for workers with physical diseases; those sub-themes may be used as a basis for communicating with those individuals about returning and continuing to work. Our results suggest that various barriers and facilitators for workers with physical diseases should be understood and addressed at medical institutions, workplaces, and support sites.

The Effectiveness of a Deep Learning Model to Detect Left Ventricular Systolic Dysfunction from Electrocardiograms.

Deep learning models can be applied to electrocardiograms (ECGs) to detect left ventricular (LV) dysfunction. We hypothesized that applying a deep learning model may improve the diagnostic accuracy of cardiologists in predicting LV dysfunction from ECGs. We acquired 37,103 paired ECG and echocardiography data records of patients who underwent echocardiography between January 2015 and December 2019. We trained a convolutional neural network to identify the data records of patients with LV dysfunction (ejection fraction < 40%) using a dataset of 23,801 ECGs. When tested on an independent set of 7,196 ECGs, we found the area under the receiver operating characteristic curve was 0.945 (95% confidence interval: 0.936-0.954). When 7 cardiologists interpreted 50 randomly selected ECGs from the test dataset of 7,196 ECGs, their accuracy for predicting LV dysfunction was 78.0% ± 6.0%. By referring to the model's output, the cardiologist accuracy improved to 88.0% ± 3.7%, which indicates that model support significantly improved the cardiologist diagnostic accuracy (P = 0.02). A sensitivity map demonstrated that the model focused on the QRS complex when detecting LV dysfunction on ECGs. We developed a deep learning model that can detect LV dysfunction on ECGs with high accuracy. Furthermore, we demonstrated that support from a deep learning model can help cardiologists to identify LV dysfunction on ECGs.

[Achievements and Future Challenges in the Support of the Balance of Work and Medical Treatment at the Hospital of the University of Occupational and Environmental Health, Japan, in 2018-2020].

The Japanese government is making full-scale efforts to support working people who suffer from cancer and/or other diseases, as it seeks to support a balance of work and receiving medical treatment. The Hospital of the University of Occupational and Environmental Health, Japan, opened its Support Center of Treatment and Work Balance in 2018. This is a multi-disciplinary department for supporting the balance of work and medical treatment. It also opened its Department of Occupational Medicine, the first such department in Japan to provide medical diagnosis and treatment dedicated to supporting that same balance. Our team has supported 704 patients through our activities over the past 3 years. The number of patients supported has increased each year, while the number of departments providing support has also trended upward. There has also been an increase in opinions by attending physicians regarding employment, as well as the number of cases covered by public medical insurance. Here we suggest two factors in our hospital's growth in these activities: (1) many of the clinicians are qualified as occupational physicians, and (2) the organizational strength of our team, which has a vision for balancing support and subsequently promotes that vision. We hope that this report will lead to the balance of support activities in Japan and contribute to the model internationally.

Development of Gentle Slope Light Guide Structure in a 3.4 µm Pixel Pitch Global Shutter CMOS Image Sensor with Multiple Accumulation Shutter Technology.

CMOS image sensors (CISs) with global shutter (GS) function are strongly required in order to avoid image degradation. However, CISs with GS function have generally been inferior to the rolling shutter (RS) CIS in performance, because they have more components. This problem is remarkable in small pixel pitch. The newly developed 3.4 µm pitch GS CIS solves this problem by using multiple accumulation shutter technology and the gentle slope light guide structure. As a result, the developed GS pixel achieves 1.8 e- temporal noise and 16,200 e- full well capacity with charge domain memory in 120 fps operation. The sensitivity and parasitic light sensitivity are 28,000 e-/lx·s and -89 dB, respectively. Moreover, the incident light angle dependence of sensitivity and parasitic light sensitivity are improved by the gentle slope light guide structure.

Single plasma mirror providing 104 contrast enhancement and 70% reflectivity for intense femtosecond lasers: publisher's note.

This note points out a missed correction to the math on p. 5648 of [Appl. Opt.5, 5647 (2016)APOPAI0003-693510.1364/AO.55.005647].

Single plasma mirror providing 104 contrast enhancement and 70% reflectivity for intense femtosecond lasers.

To efficiently eliminate picosecond pre-pulses that accompany ultrashort pulses emitted from high-power chirped-pulse-amplification laser systems, we have developed a high-performance plasma mirror system. By reducing the reflectivity of the antireflection coating on the substrate for the plasma mirror to the limit of current technology (∼0.006%), we achieved the highest pre-pulse contrast enhancement reported to date for a single plasma mirror of 104 at 1 ps before the pulse peak. By optimizing the laser incidence to the plasma mirror and the laser fluence, the reflectivity of the plasma mirror has been improved to 70%. The contrast improvement indicates extensibility to 100 PW class lasers by doubling this plasma mirror system. Contrast enhancement of 108 should be possible without a serious reduction in energy (no more than 50%).

Relationship Between Firm Size and Perceived Organizational Support and the Moderating Role of Supervisor Support: A Nationwide Cross-sectional Study.

OBJECTIVE: The study aims to explore the relationship between firm size and perceived organizational support (POS) and to investigate how supervisor support might moderate this relationship. METHODS: The study involved a cross-sectional questionnaire survey in Japan with 25,648 participants. Assessing POS through eight-question. Firm size was categorized into small (2-49 employees), medium (50-999), and large (1000 or more). Coefficients were estimated using multiple regression analyses. RESULTS: The analysis revealed that medium and large firms had lower POS compared to small firms, with the difference being more pronounced in medium firms. A positive interaction between firm size and supervisor support was observed for POS. CONCLUSIONS: This study found that although POS is more likely to be lower in medium and large firms than in small firms, the effect of supervisor support on improving POS is stronger.

Sampling targets to assess occupational health in occupational health and safety management system audits: a mixed-methods research in Japan.

BACKGROUND: Occupational health and safety management systems (OHSMS) are the foundation of occupational health and safety activities within an organization. An important element of these systems is audits. However, OHSMS auditors often lack confidence in conducting occupational health audits compared with their proficiency in conducting occupational safety audits. For occupational health to be effectively managed by OHSMS, the sampling competence of auditors engaged in third-party audits should be improved. Therefore, we conducted this study to identify appropriate sampling targets for occupational health related to International Organization for Standardization (ISO) 45001. METHODS: We adopted a mixed methods approach to identify appropriate sampling targets. This involved conducting focus group discussions with experts in occupational health and performing systematic text condensation analysis. The validity of our findings was further reinforced through confirmation by external auditors who specialize in ISO 45001. RESULTS: In the qualitative phase, 6 occupational health sampling targets were identified, and of these, 5 were subsequently validated in the quantitative phase: (1) Health issues, legal requirements, and occupational health goals identified by the organization; (2) Occupational health risk assessment and control processes; (3) Processes related to occupational health and documented information showing the results of efforts; (4) Organizational roles and functions of occupational health professionals and opportunities for their professional development; and (5) Processes to ensure commitment to occupational health issues and objectives. CONCLUSION: To ensure effective and comprehensive occupational health audits, auditors should review these targets. This study will enhance the competence of auditors by identifying appropriate occupational health sampling targets.

Determinants of job continuity among older workers: a mixed-methods research in Japan.

This study aims to determine the factors that encourage older workers to continue working. This study had an exploratory sequential design using a mixed-methods approach, including interviews and questionnaire surveys. In the interview survey, we targeted 30 workers aged between 60-65 across three manufacturing companies. After using the results of the content analysis in the interviews, we conducted an online questionnaire survey with 1,500 workers aged between 60-89 across the country. We analyzed whether the 15 factors were related to intention to continue working using logistic regression analysis. We identified factors affecting job continuity from three perspectives: individual, company, and life. We determined several factors: health condition, job performance, self-esteem, conservatism, employment system, workload, medical insurance and welfare programs, monetary and non-monetary rewards, relationships, attachment to the organization, distance between living and work, social support, economic situation, and employment policy. In the questionnaire survey, some factors had no relationship with job continuity, including conservatism, employment systems, monetary rewards, and the distance between living and work. Employers and policymakers can use the findings to consider appropriate ways of supporting older workers.

The individual and work-related factors associated with the occupational future time perspective: a cross-sectional study of older workers in Japan.

OBJECTIVES: Occupational future time perspective (OFTP) is important concept for a successful career in older workers. The purpose of this study was to examine the associations between individual and work-related factors and OFTP. METHODS: We conducted a cross-sectional study via an online questionnaire survey. Respondents were stratified sampled according to the distribution of workers across Japan. To assess OFTP, we used the Japanese version of the OFTP scale. We included factors such as sex, age, education, marital status, subjective health status, personal income, length of employment, industry, size of company, employment status, working days per week, and night shift. Multiple regression analysis was employed to calculate the regression coefficients for each factor, with OFTP serving as the dependent variable. RESULTS: In total we included 1484 respondents. Our findings indicated that higher OFTP was associated with higher education, better subjective health status, higher personal income, and smaller size of company. Compared with manufacturing, certain industries such as agriculture and forestry, transportation and postal services, and health care showed lower OFTP. In contrast to permanent workers, contract and part-time workers demonstrated lower OFTP, whereas owners of non-family businesses exhibited higher OFTP. Furthermore, individuals working 1-4 d/wk showed lower OFTP compared with those working 5 d/wk. CONCLUSIONS: Older workers facing limitations in resources, such as educational background, personal income, precarious employment, and health status, tend to have lower OFTP. Such individuals should be given priority for support and assistance.

Research topics in occupational medicine, 1990-2022: A text-mining-applied bibliometric study.

OBJECTIVE: Occupational health has been influenced by societal and industrial changes. This study aimed to clarify topic trends in occupational health research in 1990-2022. METHODS: We conducted a text-mining-adjusted bibliometric study using research titles in occupational health. Data on research titles and the years of publication were collected from 26 peer-reviewed journals on PubMed. Using morphological and correspondence analyses in text mining, we structured research topics into multiple categories and visualized the relationship between all categories and publication years. Statistical analyses were conducted using the text mining software - KH Coder 3.0. RESULTS: We obtained 48 645 articles containing 714 890 words in their titles. The research topics were classified into 4 categories and 17 subcategories, of which those of occupations; countries; non-intervention; psychosocial factors; lifestyle factors; safety; symptoms; therapy and care; and productivity have recently shown an increasing trend. In contrast, the subcategories of risk, chemical factors, disease, and organ damage showed decreasing trends. Chemical factors, which were the main topics in the 1990s, included risk, organ damage, and disease. Productivity, the main topic in the 2020s, co-occurred with lifestyle factors, symptoms, and intervention. CONCLUSIONS: Focal areas in occupational-health research shift according to societal trends. Occupational-health research has primarily analyzed issues in developed countries with capitalist values and may not have sufficiently covered issues in developing countries. It is imperative for policymakers and public funding bodies to determine priorities for investigation in the field.

Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases.

BACKGROUND: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure. OBJECTIVES: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure. METHODS: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation. RESULTS: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001). CONCLUSIONS: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.

Association of Multiple Nonhypertrophic Cardiomyopathy-Related Genetic Variants and Outcomes in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. OBJECTIVES: In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. METHODS: The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants." RESULTS: Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). CONCLUSIONS: Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

Divergence-free transport of laser-produced fast electrons along a meter-long wire target.

We demonstrate that, from a 10-µm metal wire irradiated by a 10(19) W/cm2 laser pulse, fast electrons form a nearly perfect circular beam around the wire and propagate along it. The total charge and diameter of the electron beam are maintained over a propagation distance of 1 m. Moreover, the electron beam can be guided along a slightly bent wire. Numerical simulations suggest that a relatively weak steady electric field, which does not decay for several nanoseconds, is generated around the wire and plays a key role in the long-distance guidance.