Since the first case of COVID-19 was reported in Wuhan, China, in December 2019, the SARS-CoV-2 epidemic has spread all over the world and has become a significant public health issue. The development of treatments for COVID-19 is currently in progress; however, their effects remain limited, and the development of more effective therapeutics is desired. Thus, sufficient understanding of the pathophysiology of COVID-19 is essential to develop effective therapeutics for this disease. Pathological analyses in particular play an important role to demonstrate the causal link between an infectious disease and the pathogen and elucidate the mechanism of pathogenesis. As per pathological analyses to date, respiratory organs are identified as the major affected organs in most COVID-19 cases; also, various lesions were noted in other organs. Further, there have been increasing reports that show that the immune responses of the host contribute to the deterioration of the pathological condition of COVID-19, and a novel concept of MIS-C/MIS-A is also being established. Thus, in this article, we have provided an overview of the pathology of COVID-19 from a histopathological and immunological perspective focusing on the mechanisms of COVID-19 pathogenesis.

The year 2020 opened with news of an epidemic of pneumonia caused by a new coronavirus similar to the SARS coronavirus in Wuhan, China, and subsequently caused a worldwide pandemic. In Japan, the first infected person was found in January, and later, more than 700 passengers and crew members of the Diamond Princess, a large cruise ship that called at Yokohama port, were found to be infected, and the ship was forced to respond to the outbreak. The causative virus was quickly identified as a beta coronavirus similar to the severe acute respiratory syndrome (SARS) coronavirus of 2003 and was named SARS coronavirus 2 (SARS-CoV-2). The disease was named COVID-19. SARS-CoV-2, like SARS-CoV and MERS-CoV, infects the epithelial cells of the lungs and causes viral pneumonia. As of March 7, 2021, more than 116 million people have been infected and more than 2.5 million people have died worldwide. As a result of the global pandemic, regional blockades have been imposed around the world, and the development of vaccines and therapeutic agents has become an urgent necessity in order to restore normal social activities. In this review, the experience of the development of SARS-CoV-2 vaccine is described.

Case management of COVID-19 is critically important to save lives and reduce the fear and anxiety evoked by this disease in communities. However, most healthcare systems have been overwhelmed in many parts of the world. It is also essential to screen patients to be able to identify those who are likely to suffer from severe disease, to ensure more effective use of medical resources. Disease severity can be determined based on simple vital signs; some laboratory markers are useful adjuncts.

Treatment for COVID-19 is largely supportive although a number of repurposed drugs have been evaluated for its efficacy in clinical trials. For example, dexamethasone has now been considered as a standard therapy for severe cases, while remdesivir and tocilizumab are promising agents in selected patient groups.

Introduction: Coronavirus disease 2019 (COVID-19) has caused unprecedented global morbidity and mortality. Japan has faced three epidemic "waves" of COVID-19 from early 2020 through early 2021. Here we narratively review the three waves in Japan, describe the key epidemiologic features of COVID-19, and discuss lessons learned.

Methods: We assessed publicly available surveillance data, routine surveillance reports, and other relevant sources-multiple indicators were monitored to improve interpretation of surveillance data. Weekly trends for each wave were described based on the number of case notifications; number of tests performed; proportion of those tests that were positive for the novel coronavirus; the prevalent number of COVID-19 hospitalizations (total hospitalizations and those categorized as severe); and number of COVID-19 deaths. For each indicator and wave, we recorded the first calendar week to show an increase over two consecutive previous weeks, along with the peak week.

Results: The spring wave was characterized by detection of cases imported from China, followed by notifications of sporadic cases without travel history, clusters, and mild/asymptomatic cases. The summer wave saw a large increase in notifications and a younger age distribution, but in the context of increased testing with lower test positivity. The winter wave brought considerable morbidity and mortality, surpassing the cumulative case counts and fatalities from the earlier waves, with high peak values. Overall, relative to the first wave, the burden of severe outcomes was lower in the second and higher in the third wave, but varied by prefecture. In all three waves, severe outcomes peaked after notification counts and test positivity peaked; severe outcomes were also consistently skewed toward the elderly.

Conclusions: Important lessons were learned from each wave and across waves-some aspects remained constant, while others changed over time. In order to rapidly detect an increase in incidence, continuous, timely, and sensitive surveillance-using multiple information sources with careful interpretations-will be key in COVID-19 control.

Autophagy is a major intracellular degradation system and plays important roles in various physiological processes such as metabolic adaptation and intracellular homeostasis. It degrades intracellular components both randomly and selectively. Autophagic activity is tightly regulated primarily by nutrient availability, but also by other extracellular and intracellular signals. Growing evidence suggests that there are multiple links between autophagy and the primary cilium. The primary cilium is an organelle present on the cell surface and is important for keeping cellular integrity by transducing extracellular stimuli inside the cell. Recent studies have revealed that autophagy selectively degrades the ciliogenesis inhibitory proteins OFD1 and MYH9, promoting ciliogenesis. Conversely, autophagy also inhibits ciliogenesis under growth conditions. The primary cilium can also regulate autophagic activity. These findings suggest that the relationship between autophagy and the primary cilia is bidirectional, and that both are important for maintaining the normal function of various organs.

Vasculitis is an autoimmune disease characterized by the infiltration of leukocytes in blood vessels.

An increasing number of studies on human and animal models have implicated various microorganisms in the pathogenesis of vasculitis. Previous studies have shown the presence of infectious agents, including viruses, bacteria, and fungi, in diseased vessels. However, despite continued research, the link between infection and vasculitis is not fully understood, possibly owing to the lack of appropriate animal models that mirror human disease and the technical limitations of pathogen detection in blood vessels. Among the pathogen-induced animal models, Candida albicans water-soluble fraction (CAWS) -induced coronary arteritis is currently considered one of the representative models of Kawasaki (KD) disease. Advances in metagenomic next-generation sequencing have enabled the detection of all nucleic acids in tissue, which can help identify candidate pathogens, including previously unidentified viruses. In this review, we discuss the findings from reports on pathogen-associated vasculitis in animal models and humans, with a specific focus on the investigation of the pathogenesis of vasculitis. Further studies on animal models and microbes in diseased vessels may provide important insights into the pathogenesis of vasculitis, which is often considered an idiopathic disease.

Lower extremity peripheral artery disease, or often simply called peripheral artery disease (PAD), is a common cardiovascular disease, as coronary artery disease is. Atherosclerotic disease of the arteries of the lower extremity, or arteriosclerosis obliterans, accounts for the vast majority of PAD today. Rest pain, nonhealing ulcers, and gangrenes associated with chronic ischemia (i.e., Fontaine stage III and IV or Rutherford category 4 to 6) are referred to as chronic limb-threatening ischemia (CLTI), formally called critical limb ischemia (CLI). This narrative review focuses on atherosclerotic PAD, especially CLTI, mainly highlighting its link with diabetes mellitus (DM). This article will first overview the clinical impact of DM in patients with symptomatic PAD and that of symptomatic PAD in patients with DM, followed by the clinical features of CLTI, which will be discussed from a viewpoint of its prognosis, patient profile, onset, and seasonality. DM poses a great clinical impact on CLTI, and vice versa. Patient profile appears different between DM patients complicated with CLTI and the general population with DM. Furthermore, although CLTI is pathologically rooted in atherosclerosis as is acute coronary syndrome (ACS), CLTI has considerably different clinical features compared with ACS. CLTI has an extremely poor prognosis even after revascularization, and there is ample room for improvement in terms of its prognosis. Some measures might be needed in healthcare and clinical settings before revascularization: e.g., DM control and regular ischemia risk evaluation before CLTI onset, proper diagnosis at CLTI onset, and prompt referral to a vascular specialist after CLTI onset, although its evidence is still scanty. Piling up evidence of patients with CLTI, by patients with CLTI, and for patients with CLTI is needed.

In 1995, we were the first to propose antisense oligonucleotide (ASO) -mediated exon-skipping therapy for the treatment of Duchenne muscular dystrophy (DMD), a noncurable, progressive muscle-wasting disease. DMD is caused by deletion mutations in one or more exons of the DMD gene that shift the translational reading frame and create a premature stop codon, thus prohibiting dystrophin production. The therapy aims to correct out-of-frame mRNAs to produce in-frame transcripts by removing an exon during splicing, with the resumption of dystrophin production. As this treatment is recognized as the most promising, many extensive studies have been performed to develop ASOs that induce the skipping of DMD exons. In 2016, an ASO designed to skip exon 51 was first approved by the Food and Drug Administration, which accelerated studies on the use of ASOs to treat other monogenic diseases. The ease of mRNA editing by ASO-mediated exon skipping has resulted in the further application of exon-skipping therapy to nonmonogenic diseases, such as diabetes mellites. Recently, this precision medicine strategy was drastically transformed for the emergent treatment of only one patient with one ASO, which represents a future aspect of ASO-mediated exon-skipping therapy for extremely rare diseases. Herein, the invention of ASO-mediated exon-skipping therapy for DMD and the current applications of ASO-mediated exon-skipping therapies are reviewed, and future perspectives on this therapeutic strategy are discussed. This overview will encourage studies on ASO-mediated exon-skipping therapy and will especially contribute to the development of treatments for noncurable diseases.

Hepatic resection or liver transplantation for hepatocellular carcinoma (HCC) represents the only chance for achieving a cure. For the past several decades in Japan, aggressive hepatic resection has been performed for advanced HCC, with consequent good outcomes. According to the 21st Nationwide Follow-Up Survey of Primary Liver Cancer in Japan, 38.3% of patients were treated with hepatic resection or liver transplantation as the initial treatment. The median overall survival of patients who underwent surgery was 57.0 months, and the 5- and 10-year survival rates were 48.4% and 25.2%, respectively. Since 1964, a total of 10,038 liver transplants (595 deceased-donor and 9,443 living-donor transplants) have been performed in Japan. Neoplastic disease, including HCC, was reported to be the third-most common cause of liver transplantation, and the cumulative 1-, 3-, 5-, and 10-year survival rates of living-donor liver transplants for HCC were 85.0%, 76.2%, 70.9%, and 63.1%, respectively. However, molecular-targeted agents, including sorafenib and lenvatinib, have recently been developed. Furthermore, a significantly longer survival with atezolizumab, which is an immune checkpoint inhibitor, plus bevacizumab was observed compared with sorafenib for unresectable HCC patients. Herein, we review the current status of hepatic resection and liver transplantation for HCC in Japan and discuss the role of hepatic resection in the era of molecular-targeted agents and immune checkpoint inhibitors, as well as the need for a definition of borderline resectable-HCC.

Introduction: To clarify the causes, types, and mechanisms of injuries in children, we collected injury cases and analyzed their causes.

Methods: During the 3-year period from 2013, we collected injury cases from three sources: nursery schools and kindergartens (A), emergency clinics of hospitals (B), and schools and a clinic for the developmentally disabled (C), using a format designed by Safe Kids Japan.

Results: In all, 383 cases were collected during the 3-year period. The causes of the injuries in group A were crashes, falls, and so on. The types of injuries were cuts, bruises, fractures, injuries of teeth, etc. Dislocations and abrasions were prominent in nursery school children (aged less than 3 years) and bone fractures were prominent in kindergarten children aged more than 3 years.

Group B consisted of 144 cases. The most common causes of injuries were falls, traffic accidents, and so on, and the types of injuries were fractures, abrasions, sprains, etc. The incidence of fractures was particularly high and 50% of the accidents were bicycle accidents.

Group C consisted of 41 cases. Although the age distribution was similar to that of group B, the types of accidents and injuries were similar to those of group A.

The Bodygraphic Injury Surveillance System (BISS) analysis showed that groups A and C were similar, that is, injuries occurred mainly to the head, whereas in group B, the extremities were mainly affected.

Conclusions: We analyzed the causes, types, and mechanisms of childhood injuries. The BISS may help to clarify the mechanisms of injuries in childhood.

Introduction: The objectives of the present study were to clarify the frequency and content of family issues for patients in Japanese clinics, and the concordance between physicians' and patients' views of family issues.

Methods: In this study, we used a cross-sectional design with a questionnaire survey. Participants were outpatients and their physicians in charge (four family physicians) at four Japanese clinics. The main body of research was conducted between April 5 and May 15, 2004. After obtaining oral informed consent, the physician in charge distributed questionnaires to participating patients to complete at home. The questionnaire comprised three items: 1) Do you have any worries about your family? 2) Are you comfortable consulting a physician regarding your family issue?, and 3) If possible, could you tell us why you feel like that?

Participants provided written informed consent and answered the questionnaire before sealing it in an envelope and posting it back to the research center. Physicians in charge completed their version of the questionnaire and independently sent the data to the center.

Results: Of the 272 participating patients, 118 (45.6%) had family issues. "Health problems with family members" (28%) and "family life cycle issues" (19.5%) were the main content of these issues. Physicians indicated that 45.7% of patients had family issues. The rate of concordance between physicians' and patients' perspectives regarding family issues was 46.6%.

Conclusions: Family issues can therefore be regarded as a common health problem due to the frequency. There was some inconsistency between physicians' and patients' views, but much of this discrepancy may be resolved by developing the specialty of family practice.

Introduction: This longitudinal study aimed to investigate the distribution and retention of obstetricians and gynecologists in Japan.

Methods: I used descriptive statistics and multivariate logistic regression to analyze data from National Census surveys administered during 1996-2016.

Results: Between 1996 and 2016, the number of obstetricians and gynecologists increased by 6% and urban physicians by 15%, whereas the number of rural physicians decreased by 25%. The annual retention rate, which was calculated using the square root of the biannual rates [the number of physicians still working as obstetricians and gynecologists at the time of the subsequent survey (e.g., in 1998) divided by the number of obstetricians and gynecologists in the original survey (e.g., in 1996) ], was >90%. Obstetricians and gynecologists were less likely to continue to work as obstetricians and gynecologists after 30-44 years of experience (1996-2006 cohort: OR = 0.20, 95% CI = 0.17-0.25; 2006-2016 cohort: OR = 0.32, 95% CI = 0.25-0.41) and >45 years of experience (1996-2006 cohort: OR = 0.14, 95% CI = 0.11-0.17; 2006-2016 cohort: OR = 0.11, 95% CI = 0.08-0.15). The odds were lower for rural obstetricians and gynecologists (1996-2006 cohort: OR = 0.65, 95% CI = 0.51-0.82; 2006-2016 cohort: OR = 0.59, 95% CI = 0.43-0.80). As the number of female physicians increased, the number of practicing obstetricians and gynecologists also increased. In 2004, the mandatory postgraduate clinical training that was newly implemented caused a drop in the number of young doctors; however, this reversed in 2006. Rural to urban migration was steady, and the working hours were consistently long. To stabilize high retention rates, the working environments need to be improved.

Conclusions: The present study clearly indicated the trend of the distribution of obstetricians and gynecologists in Japan. The result may be especially important for the health policy making in Japan.

Introduction: Routine preoperative testing for low-risk surgeries without a clinical indication should be avoided; however, such tests are still frequently performed in Japan. This study was performed to assess the impact of routine preoperative tests in low-risk surgery in a Japanese medical setting.

Methods: We performed a retrospective chart review to examine the utility of routine tests with respect to anesthetic management and postoperative complications in all patients aged ≥ 18 years whom ophthalmologists consulted with anesthesiologists before ophthalmologic surgery under general anesthesia.

Results: During the 10-year study period, 1,234 anesthetic consultations and 1,211 routine preoperative tests (laboratory tests, chest X-rays, and electrocardiograms) were performed in Toyama University Hospital. In total, 59 patients (4.8% of the study population) canceled surgery after a battery of preoperative evaluation. Among them, 10 patients had incidental abnormalities that necessitated additional tests, and only three patients (0.2%) canceled surgery. In-hospital postoperative complications developed in nine patients (0.7%) whose routine test results made it difficult to predict development of these adverse events. No severe life-threatening events were noted in this survey.

Conclusions: Routine tests prior to eye surgery for adults were of low value for perioperative management and prediction of development of in-hospital complications in this Japanese medical setting. Anesthesiologists and ophthalmologists should selectively order preoperative tests based on the medical interview and physical examination.

Low- and middle-income countries urgently need to improve emergency medical services (EMSs) as a component of their healthcare systems. Here, we detailed EMS resources and their provision in Hanoi, Vietnam, and discussed necessary policies to upgrade EMSs. Between 2013 and 2018, EMS resources, measured as provider-to-population and ambulance-to-population ratios, decreased, whereas service provision, measured as the number of patients transported by ambulance per population, increased. EMS resources and their provision in Hanoi are far below the standards of high-income countries or figures in neighboring Asian countries. Therefore, it is imperative to upgrade health policies for the appropriate allocation of healthcare resources to EMSs and hospital services.

Psychological distress among medical professionals due to the novel coronavirus disease 2019 (COVID-19) pandemic is of great concern as it may lead to mental health problems and, furthermore, work leaves. Studies suggest that immediate psychological interventions are needed to protect medical staff during this chaotic situation.

However, the importance of mental healthcare for the "future" medical staff, such as medical students, remains underestimated compared with that of current medical professionals. Medical students also face potential mental health stressors during their degrees and clinical clerkships, further increasing the risk of their psychological disorders. Hence, they should also be protected from burnout by various measures at governmental, organizational, and individual levels.

To maintain a sustainable, robust healthcare system, medical professionals, students, and society should unite and collaboratively overcome the hardships of the COVID-19 pandemic.

A 30 year-old man with a high fever (37.5°C-40°C), vomiting, slurred speech, and mild cognitive impairment was admitted to our Emergency Department. He had traveled from Spain to the UK on business at the end of February 2020. A nasopharyngeal swab was positive by RT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but a cerebrospinal fluid (CSF) sample was negative. His neurological abnormalities recovered completely on saline infusion to normalize his low serum sodium level. Although neurological abnormalities in patients with COVID-19 are rare, it is important to distinguish the etiologies including encephalitis, meningitis, or merely electrolyte abnormalities.

A 74-year-old woman with a history of pure red cell aplasia and hypogammaglobulinemia developed pneumonia. A urine antigen test and sputum subculture on buffered charcoal yeast extract (BCYE) α agar were positive for Legionella pneumophila. Serological testing identified L. pneumophila serogroup 2. An aerobic blood culture also became positive on day 5; its subculture on BCYEα agar revealed the same pathogen, but that on blood agar revealed Helicobacter cinaedi. We thus diagnosed her with bacteremia caused by both pathogens. Hence, in cases of H. cinaedi bacteremia along with pneumonia, the screening of other pathogens including L. pneumophila is needed.