Heart failure (HF) is a leading cause of death worldwide. In Japan, the number of HF patients has increased with its aging population, resulting in "HF pandemic." HF is the final stage of various cardiovascular diseases, including valvular heart disease, ischemic heart disease, atrial fibrillation, and hypertension.

Cardiac hypertrophy is a compensatory response to increased workload and maintains cardiac function. Pressure overload due to mechanical stress causes cardiac hypertrophy, whereas continuous cardiac stress reduces wall thickness and consequently causes HF. Understanding the molecular mechanisms underlying this process is crucial to elucidate HF pathophysiology.

We demonstrated that ischemia and DNA damage are important in the progression of hypertrophy to HF. Genetic mutations associated with cardiomyopathy and prognosis has been identified. To realize precision medicines for HF, the underlying molecular mechanisms need to be elucidated. In this review, we introduce new paradigms for understanding HF pathophysiology discovered through basic research.

One of the major complications of diabetes mellitus is diabetic cardiomyopathy. One of the mechanisms that initiates the irreversible deterioration of cardiac function in diabetic cardiomyopathy is mitochondrial dysfunction. Functionally impaired mitochondria result in greater levels of oxidative stress and lipotoxicity, both of which exacerbate mitochondrial damage. Mitochondrial health is constantly monitored by mitochondrial quality control mechanisms. Mitophagy selectively degrades damaged mitochondria, thereby maintaining the healthy pool of mitochondria and preserving myocardial function. Mitophagy in diabetic cardiomyopathy is mediated by multiple mechanisms in a time-dependent manner. Potential targets for the treatment of diabetic cardiomyopathy include increased oxidative stress, mitochondrial dynamics, and mitochondrial clearance. Thus, stimulation of mitophagy represents a promising strategy for the alleviation of diabetic cardiomyopathy.

Introduction: Adverse drug reactions (ADRs) are among the leading causes of morbidity and mortality worldwide. ADRs of anticancer drugs are ubiquitous. However, in Nepal, studies on chemotherapy-induced ADRs are scarce. Thus, this study aimed to assess the ADRs associated with the use of anticancer drugs and their management along with causality assessment and severity of ADRs.

Methods: A prospective cross-sectional observational and single-center study was conducted at Bhaktapur Cancer Hospital, Nepal, for 6 months. All the patients who fulfilled the study criteria were analyzed to identify ADRs occurring daily. In addition, all collected data were recorded and analyzed using descriptive statistics.

Results: A total of 861 ADRs were detected among 102 cancer patients. The mean ± S.D. age of the patients was 49.93 ± 14.27 years, and each enrolled patient experienced one or more ADRs with a mean ± S.D. of 8.44 ± 3.27. The common ADRs observed were fatigue, anorexia, alopecia, constipation, nausea, vomiting, and neuropathy. Cyclophosphamide, either alone or in combination with other chemotherapeutic agents, was responsible for most ADRs. According to Naranjo's causality assessment algorithm, most of the ADRs belonged to the probable (47.1%) category. Majority (54.9%) of the ADRs were moderate in their severity. Proton pump inhibitors, antiemetic, mouth gargle, protein powders, iron tablets, and multivitamin and mineral tablets were commonly used for ADR management.

Conclusions: The occurrence of chemotherapy-related ADRs in each enrolled patient is a crucial concern. The present study highlights the need for active monitoring of the patients to identify and manage ADRs promptly.

Introduction: This study explored the psychological and situational factors affecting dropout from regular visits to diabetes care using data obtained from the Japan Diabetes Outcome Intervention Trial 2 (J-DOIT2) Large-scale Trial (LT).

Methods: A total of 2,031 patients with type 2 diabetes who participated in the J-DOIT2-LT were included in the analysis. Responses to a baseline questionnaire with 17 items asking about the experience of dropout from regular visits in diabetes care and its reasons were analyzed using principal component analysis, and factors related to dropout were extracted. Using Cox regression analysis, the association of these factors with the incidence of dropout was investigated.

Results: The mean age of the 2,031 patients was 56.4 ± 5.9 years and 742 (36.5%) were women. They were followed for a median of 392 days, and 125 patients dropped out from regular visits during the follow-up period. In the principal component analysis of the questionnaire, there were four latent factors with eigenvalues of >1.0, which were labeled as "negative perceptions for regular visits," "social pressure," "lack of perceived necessity," and "environmental obstacles" based on the retained items. The Cox regression analysis demonstrated that patients with high scores of "lack of perceived necessity" and "environmental obstacles" had a significantly increased risk of dropout from regular visits.

Conclusions: The present study revealed psychological and situational factors related to dropout, which may be useful for detecting patients at high risk of dropout. Effective measures focusing on such patients to prevent dropouts should be investigated in future studies (The trial registration number: UMIN000002186, registered at the University Hospital Medical Information Network-Clinical Trials Registry).

Introduction: In recent years, public hospitals have seen an increasing need for management reform in light of increasing social security costs due to the aging population. This study investigated the relationship between collaboration with neighboring medical institutions and management efficiency in public hospitals.

Methods: Data envelopment analysis was used to calculate the dependent variable. We used the referral rate for each public hospital as an independent variable to indicate active collaboration. Univariate and multivariate analyses examined the association between the two variables above. The adjustment variables in the multivariate analysis incorporated those variables that were considered significant in the univariate analysis when the significance level was 10% on a two-sided basis. The Tobit regression model was used in both univariate and multivariate analyses.

Results: Ultimately, the analysis included 402 public hospitals. Approximately 8% fell into the high-collaboration group. Even after adjusting for significant variables from the univariate analysis, the inefficiency value was significantly lower in the high-collaboration group than in the low-collaboration group; namely, the efficiency value in the high-collaboration group was significantly higher than in the low-collaboration group. Moreover, hospitals with a higher ratio of subsidies to revenue had significantly lower values for management efficiency.

Conclusions: The analysis of the relationship between efficiency value and the percentage of referred patients in Japan indicated that higher percentages of referred patients, that is, higher degrees of cooperation, were significantly associated with higher efficiency scores.

Introduction: Health literacy has been identified an essential factor in leading a healthy lifestyle. Because some cancer prevention and screening methods have been established, we believe that identifying disadvantaged populations with low literacy regarding cancer is crucial. Thus, in this study, we aim to create a self-administered cancer-specific health literacy scale to be administered to Japanese laypersons.

Methods: Using definitions from previous studies, we constructed a scale named the Japanese Cancer Intelligence Quotient (JCIQ) for both literacy (JCIQ-L) and knowledge (JCIQ-K) aspects. We generated potential items for both aspects, extracted appropriate ones using two-step online surveys, and compared the JCIQ and cancer-preventive behaviors and cancer-screening intentions, both of which we set as alternative indicators of the right attitude and practice toward cancer by performing a multiple regression analysis from another web survey.

Results: Between April and May 2020, we conducted three-step surveys online. After conducting the two-step surveys for thousands of people, we extracted 12 literacy questions and 22 knowledge questions using factor analysis and the correct answer ratio of every item. In the final investigation of 3,094 people, a multiple regression analysis found that the JCIQ-L and JCIQ-K were significant factors in terms of predicting both behaviors (JCIQ-L:β = 0.07, p < 0.001, JCIQ-K:β = 0.05, p < 0.01) and willingness (JCIQ-L:β = 0.04, p < 0.05, JCIQ-K:β = 0.17, p < 0.001) after adjusting for participant characteristics (e.g., gender, age, income level, employment status).

Conclusions: We developed the first reliable scale for measuring cancer literacy and knowledge of Japanese laypersons.

Introduction: The insufficient quantity and quality of clinical epidemiological evidence in the field of rare diseases have posed methodological challenges to develop clinical practice guidelines (CPGs). Guideline development groups struggle to provide patients and their families with beneficial guidance, such as that for medical care and in complex circumstances. Motivated by the challenges, we focused on information on resources for supporting the daily and social life to improve the CPGs for users. We aimed to assess the methodological quality of CPGs for rare diseases in Japan and to evaluate information on resources to support the daily and social life in the CPGs.

Methods: We conducted a systematic search using PubMed, three electronic Japanese databases, and two hand-searched sources in Japan. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument with six domains was used to assess the methodological quality of the CPGs. A content analysis of the CPG text was conducted using five keywords as information on non-medical resources, e.g., "Intractable Disease Consultation Support Center," "Japan Intractable Disease Information Center," and "Patient Association."

Results: A total of 55 CPGs met the inclusion criteria. Among four domains of AGREE II with low scores (Stakeholder Involvement, Rigor of Development, Applicability, and Editorial Independence), Rigor of Development had the lowest median score. As for information on non-medical resources, 41 CPGs included at least 1 of the 5 keywords, while 14 CPGs included none.

Conclusions: At the Rigor of Development domain, methodological challenges may have resulted in an insufficient description of items regarding the translation evidence to recommendations. As the sufficiency of five keywords as information on non-medical resources could be improved, the information will be advocative as clues to provide pragmatic guidance, particularly for rare diseases with limited medical evidence.

Introduction: Efforts are being made to reduce doctors' working hours and implement reforms in the way doctors work. This study aims to determine the associations between depressive symptoms and work environment/lifestyle among <40-year-old male orthopedic physicians in Japan.

Methods: Participants were 1,343 male orthopedic physicians selected from a survey (N = 25,139) of all regular members conducted in 2019 by the Japanese Orthopaedic Association. Participants completed the Quick Inventory of Depressive Symptomatology and provided information about total working hours, number of on-call/night duties, number of patient complaints received, smoking habits, exercise habits, and sleep time.

Results: Of the participants, 6.6% had depressive symptoms. Factors associated with depressive symptoms were total working hours of ≥80 h per week (80-99 h: adjusted odds ratio [AOR] = 2.06; 95% confidence interval [CI], 1.02-4.18; ≥100 h: AOR = 3.89; 95% CI, 1.92-7.88), one or more unreasonable patient demands/complaints in the previous 6 months (AOR = 1.61; 95% CI, 1.00-2.60), current smoking (AOR = 2.98), no sweat-inducing exercise sessions of ≥30 min per week in the previous month (AOR = 2.50), and an average of <6 h of sleep per night in the previous month (AOR = 2.15).

Conclusions: Work factors at the main medical institution (i.e., total working hours of ≥80 h per week) were associated with depressive symptoms. In addition, associations between depressive symptoms and unhealthy living conditions, such as smoking habits, lack of exercise, and <6 h of sleep per night, were observed.

Introduction: PM_2.5 exposure is a suspected risk factor for diabetes. It is hypothesized that maternal PM_2.5 exposure contributes to the development of gestational diabetes mellitus (GDM). The association between PM_2.5 exposure and GDM is controversial and limited evidence is available for the exposure to PM_2.5 chemical components. We investigated the association between maternal exposure to total PM_2.5 mass and its components, particularly over the first trimester (early placentation period), and GDM.

Methods: Data were obtained from the Japan Perinatal Registry Network database, which includes all live births and stillbirths after 22 weeks of gestation at 39 cooperating hospitals in 23 Tokyo wards (2013-2015). At one fixed monitoring site, we performed daily filter sampling of fine particles and measured daily concentrations of carbon and ion components. The average concentrations of total PM_2.5 and its components over the 3 months before pregnancy and the first (0-13 gestational weeks) and second (14-27 gestational weeks) trimesters were calculated and assigned to each woman. We estimated the odds ratios (ORs) of GDM in a multilevel logistic regression model.

Results: Among 82,773 women (mean age at delivery = 33.7 years) who delivered singleton births, 3,953 (4.8%) had GDM. In the multiexposure period model, an association between total PM_2.5 exposure and GDM was observed for exposure over the first trimester (OR per interquartile range (IQR = 3.63 μg/m³) increase = 1.09; 95% confidence interval (CI) = 1.02-1.16), but not for the 3 months before pregnancy or the second trimester. For PM_2.5 components, only organic carbon exposure over the first trimester was positively associated with GDM (OR per IQR (0.51 μg/m³) increase = 1.10; 1.00-1.21).

Conclusions: This is the first evidence that exposure to total PM_2.5 and one of its components, organic carbon, over the first trimester increases GDM occurrence in Japan.

Introduction: Enzalutamide is approved for the treatment of patients with metastatic castration-resistant prostate cancer. Adverse effects (e.g., fatigue and anorexia) are often observed and cause difficulty with continuous therapy; however, no clinical data describing which patients are more likely to suffer adverse effects were observed. Therefore, this study hypothesized that body composition, comprising body fat distribution and psoas muscle volume, may affect the occurrence of subjective symptoms (e.g., fatigue and anorexia) in prostate cancer patients treated with enzalutamide.

Methods: Adverse effects, especially fatigue, anorexia, insomnia, and pain, were retrospectively evaluated by CTCAE v4.0 criteria. Sixty-seven prostate cancer patients treated with enzalutamide were enrolled, and body fat, visceral fat percentage, and psoas muscle ratio (psoas muscle, in cubic centimeter/height, in meters) were calculated using computed tomography images evaluated before enzalutamide, with SYNAPSE VINCENT software. Univariate analysis was performed to identify the factors associated with adverse effects.

Results: Univariate analysis showed that high psoas muscle ratio was significantly associated with fatigue (grade ≥ 2; odds ratio, 3.875; 95% confidence interval, 1.016-17.134; P = 0.047), but inversely related to anorexia (grade ≥ 2; odds ratio, 0.093; 95% confidence interval, 0.011-0.784; P = 0.029).

Conclusions: Psoas muscle ratio is a predictive marker of fatigue and anorexia in patients treated with enzalutamide.

Introduction: Based on the possible relation of atherosclerotic cardiovascular disease to the development of cancer, we examined whether polyvascular disease, as a surrogate marker of the severity of atherosclerosis, is associated with the incidence of cancer in patients with coronary artery disease (CAD).

Methods: A total of 8,856 patients with CAD between January 2009 and July 2014 were eligible for this observational study. Two cohorts were established based on the presence or absence of polyvascular disease (i.e., polyvascular disease and CAD only) and tracked for the incidence of cancer and all causes of death. Polyvascular disease was defined when accompanied by diagnosed aortic and/or peripheral arterial disease or other arterial diseases at enrollment.

Results: With a median follow-up of 1,095 d, the incidence of cancer was markedly higher in the cohort of 716 patients with polyvascular disease than in the cohort of 8,140 patients with CAD only (8.8% vs. 4.9%, P = 0.0001). A large difference in the incidence of cancer was also found in accordance with a number of the coexisting vascular disease with CAD. With the adjustment of shared common risks, polyvascular disease was an independent contributor to the incidence of cancer (hazard ratio, 1.362; 95% confidence interval [CI], 1.029-1.774). In a total of 548 patients (6.2% of participants) died during follow-up, and all-cause, cardiovascular, and cancer mortalities were all higher in the cohort with polyvascular disease than in the cohort with CAD only.

Conclusion: The presence of polyvascular disease may be associated with the incidence of cancer in patients with CAD, implying a pivotal role of the severity of atherosclerosis in cancer development (ClinicalTrials.gov. number: NCT04198896).

Introduction: The usefulness of various prognostic factors for advanced pancreatic cancer (APC) has been reported, but the number of elderly patients in these studies is disproportionately fewer than those in general practice. This study aimed to examine the prognostic factors for elderly patients with APC receiving gemcitabine plus nab-paclitaxel (GnP) considering the G8 geriatric assessment tool.

Methods: We retrospectively analyzed 77 elderly (≥65 years old) patients with APC who received GnP as first-line chemotherapy at our hospital. We used the receiver operating characteristic curve to set the optimal cutoff value for G8. Univariate and multivariate Cox regression models were applied to study independent prognostic factors.

Results: The progression-free survival was 5.5 months, and the overall survival (OS) was 12.0 months in all patients. The most optimal cutoff of G8 was 10.5. OS of G8 ≥10.5 patients was superior to that of G8 <10.5 patients (18.5 versus 8.0 months). Multivariate analysis showed that Eastern Cooperative Oncology Group performance status 1 (hazard ratio [HR] 3.00, p = 0.02), neutrophil-lymphocyte ratio ≥3.9 (HR 2.73, p = 0.03), and G8 geriatric assessment <10.5 (HR 5.38, p < 0.001) were independent negative prognostic factors.

Conclusions: G8 is useful for predicting prognoses in elderly patients with APC receiving GnP.

Introduction: This study assessed changes in patients transported to an emergency and critical care center before and after the coronavirus disease 2019 (COVID-19) pandemic in Japan and examined problems that should be addressed in emergency medical care.

Methods: This single-center retrospective observational study was conducted at a university hospital. The subjects were patients who were transported to a "tertiary emergency department" receiving advanced medical care. With January 16, 2020, as the cutoff date, 4,197 patients who were transported to the hospital from January 16, 2019, to January 15, 2021, were recruited. The patients were classified into nine disease groups using the International Classification of Diseases, Tenth Revision. The emergency department (ED) visit count in 2020 was compared with that in 2019 using Poisson regression.

Results: The number of patients transported to the tertiary ED in 2020 decreased by 7.8% compared with that in 2019. The number of patients transported to the tertiary ED decreased compared with that in the previous year during the period when the number of confirmed COVID-19 cases in Japan increased and showed the opposite trend when the number of confirmed cases decreased. As per diagnostic classification, it decreased for all diagnoses except External causes, and significant decreases were observed in Infectious (47.5%), Non-COVID-19 respiratory (28.4%), and Trauma (25.2%). In External causes, the rate of change for suicide cases alone increased to 43.2%.

Conclusions: While the number of confirmed cases increased, the number of tertiary ED patients associated with COVID-19 decreased temporarily. It is necessary to fully consider the burden on medical institutions 1-2 months after the number of infected people peaks. It is also necessary to closely monitor suicides associated with COVID-19 as a factor that will cause changes in emergency medical care in the future.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly.

We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable.

The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented.

In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content.

We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions.

We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

On July 8, 2022, Shinzo Abe, the former Prime Minister of Japan, passed away. This tragedy may turn out to have a deep impact on public health throughout the world, not limited to Japan.

According to the most recent Japanese government reports, Mr. Abe was murdered with a firearm. This could spark a new debate in the current global debate over gun control, with far-reaching consequences for public health around the world. Furthermore, extensive media coverage may harm the mental health of Japanese civilians, and such issues should be addressed in a fair manner.

The Japanese have been strong against previous disasters and tragedies. It is hoped that Japan can build back a safe and resilient society for all.

The coronavirus disease 2019 (COVID-19) pandemic resulted in discrimination against patients and healthcare workers in the beginning. As more information about COVID-19 prevention became available, discrimination toward the patients and healthcare workers gradually reduced. Instead, people wearing masks in the general public were heavily discriminated when mask-wearing was recommended only for healthcare workers. After the universal use of masks was recommended, discrimination against those who were wearing masks decreased and increased among those who do not wear masks. However, due to the introduction of vaccine passports, the target for discrimination has shifted to people who have not received COVID-19 vaccines. Narrowing vaccine disparity could prevent discrimination toward unvaccinated people. However, some people are hesitating vaccination or cannot be vaccinated because of their health status. These people will remain targets for discrimination even if vaccines were equally distributed. To prevent discrimination during the COVID-19 pandemic, improving health literacy of the population could be effective in two ways. First, health literacy could reduce vaccine hesitancy by enabling people to critically evaluate vaccine information. Second, health literacy enables people to respect decisions of others to avoid vaccination. Therefore, interventions improving health literacy have the potential to contribute to cutting the chain of discrimination during the COVID-19 pandemic.