Modeling and predicting individual variation in COVID-19 vaccine-elicited antibody response in the general population.

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Primary care clinic visits in formerly evacuated areas due to radiation disaster following the Great East Japan Earthquake: A retrospective descriptive study.

Radiation disasters pose distinctive medical challenges, requiring diverse care approaches. Beyond radiation exposure assessment, addressing health impacts due to lifestyle changes, especially among vulnerable populations, is vital. Evacuation orders issued in radiation-affected areas introduce unique healthcare dynamics, with their duration significantly influencing the recovery process. Understanding evolving patient demographics and medical needs after lifting evacuation orders is crucial for post-disaster care planning. Minamisoma Municipal Odaka Hospital, located 13 to 20 km from Fukushima Daiichi Nuclear power plant in a post-evacuation zone, was greatly affected by the Great East Japan Earthquake and subsequent radiation disaster. Data were retrospectively collected from patient records, including age, gender, visit date, diagnoses, and addresses. Patient records from April 2014 to March 2020 were analyzed, comparing data before and after the July 2016 evacuation order lift. Data was categorized into pre and post-evacuation order lifting periods, using International Classification of Diseases, Tenth Edition codes, to identify the top diseases. Statistical analyses, including χ-square tests, assessed changes in disease distributions. Population data for Odaka Ward and Minamisoma City fluctuated after lifting evacuation orders. As of March 11, 2011, Odaka Ward had 12,842 residents (27.8% aged 65+ years), dropping to 8406 registered residents and 2732 actual residents by April 30, 2018 (49.7%). Minamisoma City also saw declines, with registered residents decreasing from 71,561 (25.9%) to 61,049 (34.1%). The study analyzed 11,100 patients, mostly older patients (75.1%), between 2014 and 2020. Post-lifting, monthly patient numbers surged from an average of 55.2 to 213.5, with female patients increasing from 33.8% to 51.7%. Disease patterns shifted, with musculoskeletal cases declining from 23.8% to 13.0%, psychiatric disorders increasing from 9.3% to 15.4%, and trauma-related cases decreasing from 14.3% to 3.9%. Hypertension (57.1%) and dyslipidemia (29.2%) prevailed post-lifting. Urgent cases decreased from 1.3% to 0.1%. This study emphasizes the importance of primary care in post-evacuation zones, addressing diverse medical needs, including trauma, noncommunicable diseases, and psychiatric disorders. Changing patient demographics require adaptable healthcare strategies and resource allocation to meet growing demands. Establishing a comprehensive health maintenance system tailored to these areas' unique challenges is crucial for future disaster recovery efforts.

Gingipain-carrying outer membrane vesicles from Porphyromonas gingivalis cause barrier dysfunction of Caco-2 cells by releasing gingipain into the cytosol.

Ingestion of Porphyromonas gingivalis, a periodontal pathogen, disrupts the intestinal barrier in mice. However, the involvement of outer membrane vesicles (OMVs) secreted from P. gingivalis in the destruction of the intestinal barrier remains unclear. In this study, we tested the hypothesis that OMVs carrying gingipains, the major cysteine proteases produced by P. gingivalis, affects the intestinal barrier function. OMVs increased the permeability of the Caco-2 cell monolayer, a human intestinal epithelial cell line, accompanied by degradation of the tight junction protein occludin. In contrast, OMVs prepared from mutant strains devoid of gingipains failed to induce intestinal barrier dysfunction or occludin degradation in Caco-2 cells. A close histological examination revealed the intracellular localization of gingipain-carrying OMVs. Gingipain activity was detected in the cytosolic fraction of Caco-2 cells after incubation with OMVs. These results suggest that gingipains were internalized into intestinal cells through OMVs and transported into the cytosol, where they then directly degraded occludin from the cytosolic side. Thus, P. gingivalis OMVs might destroy the intestinal barrier and induce systemic inflammation via OMV itself or intestinal substances leaked into blood vessels, causing various diseases.

Human ß-Defensin 3 Inhibition of P. gingivalis LPS-Induced IL-1ß Production by BV-2 Microglia through Suppression of Cathepsins B and L.

Cathepsin B (CatB) is thought to be essential for the induction of Porphyromonas gingivalis lipopolysaccharide (Pg LPS)-induced Alzheimer's disease-like pathologies in mice, including interleukin-1ß (IL-1ß) production and cognitive decline. However, little is known about the role of CatB in Pg virulence factor-induced IL-1ß production by microglia. We first subjected IL-1ß-luciferase reporter BV-2 microglia to inhibitors of Toll-like receptors (TLRs), IκB kinase, and the NLRP3 inflammasome following stimulation with Pg LPS and outer membrane vesicles (OMVs). To clarify the involvement of CatB, we used several known CatB inhibitors, including CA-074Me, ZRLR, and human ß-defensin 3 (hBD3). IL-1ß production in BV-2 microglia induced by Pg LPS and OMVs was significantly inhibited by the TLR2 inhibitor C29 and the IκB kinase inhibitor wedelolactonne, but not by the NLRPs inhibitor MCC950. Both hBD3 and CA-074Me significantly inhibited Pg LPS-induced IL-1ß production in BV-2 microglia. Although CA-074Me also suppressed OMV-induced IL-1ß production, hBD3 did not inhibit it. Furthermore, both hBD3 and CA-074Me significantly blocked Pg LPS-induced nuclear NF-κB p65 translocation and IκBα degradation. In contrast, hBD3 and CA-074Me did not block OMV-induced nuclear NF-κB p65 translocation or IκBα degradation. Furthermore, neither ZRLR, a specific CatB inhibitor, nor shRNA-mediated knockdown of CatB expression had any effect on Pg virulence factor-induced IL-1ß production. Interestingly, phagocytosis of OMVs by BV-2 microglia induced IL-1ß production. Finally, the structural models generated by AlphaFold indicated that hBD3 can bind to the substrate-binding pocket of CatB, and possibly CatL as well. These results suggest that Pg LPS induces CatB/CatL-dependent synthesis and processing of pro-IL-1ß without activation of the NLRP3 inflammasome. In contrast, OMVs promote the synthesis and processing of pro-IL-1ß through CatB/CatL-independent phagocytic mechanisms. Thus, hBD3 can improve the IL-1ß-associated vicious inflammatory cycle induced by microglia through inhibition of CatB/CatL.

Categorization of disaster-related deaths in Minamisoma city after the Fukushima nuclear disaster using clustering analysis.

The medical situation during disasters often differs from that at usual times. Disasters can lead to significant mortality that can be difficult to monitor. The types of disaster-related deaths are largely unknown. In this study, we conducted a survey to categorize the disaster-related deaths caused by a radiation disaster. A total of 520 people living in Minamisoma City, Fukushima Prefecture, at the time of the Fukushima Daiichi Nuclear Power Plant accident, who were certified to have died due to disaster-related causes were surveyed. We divided the participants into those who were at home at the time of the earthquake and those who were in hospitals or facilities when the disaster struck and conducted a hierarchical cluster analysis of the two groups. Disaster-related deaths could be divided into seven groups for those who were at home at the time of the disaster and five groups for those who were in hospitals or facilities at the time of the disaster. Each group showed different characteristics, such as "the group with disabilities," "the group receiving care," and "the group with depression," and it became evident that not only uniform post-disaster support, but support tailored to the characteristics of each group is necessary.

Insights and viewpoints from a small-scale survey on current nuclear disaster preparedness measures in Japan after the Fukushima Daiichi Nuclear Power Plant accident.

In nuclear disaster prevention, it is essential not only to make daily efforts to prevent accidents from occurring but also to properly apply lessons learnt from actual disasters. Although significant changes have been made to nuclear disaster preparedness in Japan since the Fukushima Daiichi Nuclear Power Plant accident, there is insufficient information on whether these changes have been evaluated as practical and appropriate for the needs of the Japanese public. In this survey, 20 officials of the Cabinet Office and Japan Atomic Energy Agency, in charge of planning nuclear disaster prevention policy, were asked to evaluate the current nuclear disaster prevention plan through a questionnaire, and compare it with that before the accident, and indicate what elements are lacking in the current plan. The survey results revealed that 30% of the participants (six respondents) had a positive view of the enhancement of resources, including physical and human assets. However, as many as 60% (12 respondents) expressed negative sentiments, primarily due to perceived deficiencies in organisational measures, particularly the coordination of these resources. Moreover, the participants expressed keen interest in obtaining health data during evacuation, along with information on the physical and mental effects on evacuees living in evacuation centres. These crucial insights can inform the formulation of effective future preparedness plans for evacuation and radiation protection.

Impact of lifting the mandatory evacuation order after the Fukushima Daiichi Nuclear Power Plant accident on the emergency medical system: a retrospective observational study at Minamisoma City with machine learning analysis.

OBJECTIVES: This study aimed to identify factors that delayed emergency medical services (EMS) in evacuation order zones after the 2011 Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident and to investigate how the lifting of the evacuation affected these factors over time. DESIGN: This research was a retrospective observational study. The primary outcome measure was onsite EMS time. A gradient boosting model and a decision tree were used to find the boundary values for factors that reduce EMS. SETTING: The target area was Minamisoma City, Fukushima, Japan that was partly designated as an evacuation order zone after the 2011 Fukushima disaster, which was lifted due to decreased radiation. PARTICIPANTS: This study included patients transferred by EMS from 1 January 2013 through 31 October 2018. Patients who were not transported and those transported for community events, interhospital patient transfer and natural disasters were excluded. OUTCOME MEASURES: This study evaluated the total EMS time using on-site time which is the time from arrival at the scene to departure to the destination, and other independent factors. RESULTS: The total number of transports was 12 043. The decision tree revealed that the major factors that prolonged onsite time were time of day and latitude, except for differences by year. While latitude was a major factor in extending on-site time until 2016, the effect of latitude decreased and that of time of day became more significant since 2017. The boundary was located at N37.695° latitude. CONCLUSIONS: The onsite time delay in EMS in evacuation order zones is largely due to regional factors from north to south and the time of day. However, the north-south regional factor decreased with the lifting of evacuation orders.

Importance of continuing health care before emergency hospital evacuation: a fatal case of a hospitalized patient in a hospital within 5 km radius of Fukushima Daiichi Nuclear Power Plant: a case report.

BACKGROUND: After a disaster, it is essential to maintain the health care supply levels to minimize the health impact on vulnerable populations. During the 2011 Fukushima Daiichi Nuclear Power Plant accident, hospitals within a 20 km radius were forced to make an immediate evacuation, causing a wide range of short- and long-term health problems. However, there is limited information on how the disaster disrupted the continuity of health care for hospitalized patients in the acute phase of the disaster. CASE PRESENTATION: An 86-year-old Japanese man who needed central venous nutrition, oxygen administration, care to prevent pressure ulcers, skin and suctioning care of the trachea, and full assistance in the basic activities of daily living had been admitted to a hospital within 5 km radius of Fukushima Daiichi Nuclear Power Plant and experienced Fukushima Daiichi Nuclear Power Plant accident. After the accident, the hospital faced a manpower shortage associated with hospital evacuation, environmental changes caused by infrastructure and medical supply disruptions, and the difficulty of evacuating seriously ill patients. As a result, antibiotics and suction care for aspiration pneumonia could not be appropriately provided to the patient due to lack of caregivers and infrastructure shortages. The patient died before his evacuation was initiated, in the process of hospital evacuation. CONCLUSIONS: This case illustrates that decline in health care supply levels to hospitalized patients before evacuation during the acute phase of a radiation-released disaster may lead to patient fatalities. It is important to maintain the health care supply level even in such situations as the radiation-released disaster; otherwise, patients may experience negative health effects.

How to Deal With the Risk of Evacuation of Psychiatric Hospital in Nuclear Disaster: A Case Study.

OBJECTIVE: People with psychiatric disorders are one of the most vulnerable populations in disasters, and the 2011 Great East Japan Earthquake reported higher post-evacuation mortality rates among psychiatric inpatients. A psychiatric hospital evacuated after the nuclear accident was surveyed to gain valuable insights for future disaster preparedness. METHODS: The authors interviewed two Odaka Akasaka Hospital (a private psychiatric hospital) staff responsible for evacuation due to the nuclear accident. RESULTS: At the time of the earthquake, 104 patients had been admitted to the hospital. They were instructed to evacuate on the grounds that they existed within a 20 km radius of Fukushima Daiichi Nuclear Power Station. Although the evacuation process was extraordinarily demanding, the staff acted professionally, and no patient experienced a significant deterioration in health during the evacuation. CONCLUSION: It was reasonable to follow the evacuation order because of the difficulty of obtaining accurate information about radiation exposure and staff availability in high-risk situations. The staff's knowledgeable and attentive care of the patients was one of the factors that enabled them to successfully carry out this severe evacuation. However, this may be related to the high mortality rate after the evacuation of patients who were separated from such caregivers.

Disaster-related deaths with alcohol-related diseases after the Fukushima Daiichi nuclear power plant accident: case series.

Introduction: The health of patients with mental disorders, such as alcohol-related diseases, often deteriorates after disasters. However, the causes of death among those with alcohol-related diseases during and after radiation disasters remain unclear. Methods: To minimize and prevent alcohol-related deaths in future radiation disasters, we analyzed and summarized six cases of alcohol-related deaths in Minamisoma City, a municipality near the Fukushima Daiichi nuclear power plant. Results: Patients were generally treated for alcohol-related diseases. In one case, the patient was forced to evacuate because of hospital closure, and his condition worsened as he was repeatedly admitted and discharged from the hospital. In another case, the patient's depression worsened after he returned home because of increased medication and drinking for insomnia and loss of appetite. Discussion: The overall findings revealed that, in many cases, evacuation caused diseases to deteriorate in the chronic phase, which eventually resulted in death sometime after the disaster. To mitigate loss of life, alcohol-related diseases must be addressed during the chronic phases of future large-scale disasters, including nuclear disasters.

Human ß-Defensin 3 Inhibits Porphyromonas Gingivalis Lipopolysaccharide-Induced Oxidative and Inflammatory Responses of Microglia by Suppression of Cathepsins B and L.

Recently, the effects of antibacterial peptides are suggested to have therapeutic potential in Alzheimer's disease. Furthermore, systemic treatment of Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) induced Alzheimer's disease-like neuropathological changes in middle-aged mice. Then, we examined whether human ß-defensins (hBDs), antimicrobial peptides produced by the oral mucosa and salivary glands, can suppress Pg LPS-induced oxidative and inflammatory responses by microglia. hBD3 (1 µM) significantly suppressed Pg LPS-induced production of nitric oxide and interleukin-6 (IL-6) by MG6 cells, a mouse microglial cell line. hBD3 (1 µM) also significantly inhibited Pg LPS-induced expression of IL-6 by HMC3 cells, a human microglial cell line. In contrast, neither hBD1, hBD2 nor hBD4 failed to inhibit their productions. Furthermore, hBD3 suppressed Pg LPS-induced p65 nuclear translocation through the IκBα degradation. Pg LPS-induced expression of IL-6 was significantly suppressed by E64d, a cysteine protease inhibitor, and CA-074Me, a known specific inhibitor for cathepsin B, but not by pepstatin A, an aspartic protease inhibitor. Interestingly, hBD3 significantly inhibited enzymatic activities of recombinant human cathepsins B and L, lysosomal cysteine proteases, and their intracellular activities in MG6 cells. Therefore, hBD3 suppressed oxidative and inflammatory responses of microglia through the inhibition of cathepsins B and L, which enzymatic activities are necessary for the NF-κB activation.

ATP13A2 modifies mitochondrial localization of overexpressed TOM20 to autolysosomal pathway.

Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson's Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies highlight its unique mechanics, how PD pathology is linked to ATP13A2 function remains unclear. Here we report that localization of overexpressed TOM20, a mitochondrial outer-membrane protein, is significantly altered upon ATP13A2 expression to partially merge with lysosome. Using Halo-fused version of ATP13A2, ATP13A2 was identified in lysosome and autophagosome. Upon ATP13A2 co-expression, overexpressed TOM20 was found not only in mitochondria but also within ATP13A2-containing autolysosome. This modification of TOM20 localization was inhibited by adding 1-methyl-4-phenylpyridinium (MPP+) and not accompanied with mitophagy induction. We suggest that ATP13A2 may participate in the control of overexpressed proteins targeted to mitochondrial outer-membrane.

Work-related stress and coping methods of internists and primary care physicians during the COVID-19 pandemic in Japan: A mixed-method study.

Background: The COVID-19 pandemic has affected the mental health of health care workers. This study aimed to investigate the stress factors that cause burnout in Japanese physicians and their coping methods during the COVID-19 pandemic. Methods: We conducted a sequential explanatory mixed-method study to investigate the psychological responses of physicians in the early stages of the pandemic. A cross-sectional, web-based, anonymous survey was conducted among members of the American College of Physicians Japan Chapter to quantitatively investigate the stress factors and prevalence of burnout. An open-ended questionnaire with questions about stress factors and coping methods was additionally administered. The qualitative data were analyzed using qualitative content analysis. Results: Among the 1173 physicians surveyed, 214 (18.2%) responded. Among the participants, 107 (50.0%) responded "yes" to the question "I feel or have felt very stressed at work during the COVID-19 pandemic," and 68 (31.8%) reported burnout symptoms. Those who reported feeling stress (117 respondents) were asked to select 12 items of the stress factors related to COVID-19. The most significant stress factor related to COVID-19 was "Perceived risk of spreading COVID-19 to family members" (n = 47). Content analysis identified 12 categories for the stress factors and 7 for stress-coping methods corresponding to COVID-19 (Cohen's kappa = 0.84 and 0.95, respectively). Conclusion: Several distinct stressors existed during the COVID-19 pandemic, which might be related to burnout among physicians. Practicing stress-coping strategies, as identified in the present study, may help reduce work-related stress and prevent burnout.

Symposium on disaster-related deaths after the Fukushima Daiichi Nuclear Power Plant accident.

Disaster deaths can be classified into direct and indirect deaths. Direct deaths are those caused by the direct physical effects of disasters, such as earthquakes, tsunamis, and radiation exposure. Indirect deaths are those caused by secondary health effects such as emergency evacuation, relocation, evacuation environment, disruption of health care delivery services, and psychosocial effects. In addition, in Japan, the term disaster-related deaths refers to indirect deaths in accordance with the disaster condolence payments system, which provides relief for bereaved families. On 11 March 2011, the Great East Japan Earthquake exposed several issues related to disaster-related deaths in Japan. Therefore, on 1 February 2022, a symposium on disaster-related deaths hosted by this study was held on the website. The symposium discussed the issues and challenges associated with disaster-related deaths for future disaster preparedness. The authors introduced the concept of 'shaking' at the symposium by defining 'shaking' as 'the repeated changes in the social and living environment that worsen health conditions, regardless of the disaster'. It was also pointed out that vulnerable populations are more likely to experience more pronounced health effects. This generalised concept of 'shaking' associated with disaster-related deaths suggests that it is important to anticipate disasters before they occur to take specific preventive measures, targeted at vulnerable populations. This study found that disaster-related deaths in Japan create several problems in terms of future radiation disaster preparedness and medical countermeasures. In the future, there will be a need to examine the relevance of the issues of disaster-related deaths identified as a result of this symposium for future radiation disaster preparedness.

Comparison of mortality patterns after the Fukushima Daiichi Nuclear Power Plant radiation disaster and during the COVID-19 pandemic.

The initial health impact caused by radiation disasters can be broadly classified into direct and indirect effects. Though no direct health hazards caused by radiation, such as acute radiation injury, were observed following the Fukushima Daiichi nuclear power plant accident, indirect deaths have been reported, including those caused by initial emergency evacuation and relocation, medical disruption, and psychological and social health effects. However, these indirect health effects have not been prioritised for addressal. We evaluated the radiation disaster experience with that of the coronavirus disease (COVID-19) pandemic that emerged while facing the challenges from the radiation disaster. Most of the health effects of COVID-19 are directly associated with infection, but indirect health effects of various scales and entities have been reported. The two disasters have similarities in terms of the strain on community healthcare and the large number of deaths. Adapting the measures implemented in the acute to subacute phases of the COVID-19 disaster to radiation disasters may help improve management following future radiation disasters. Based on the experience and findings during the COVID-19 pandemic, the pattern of deaths in radiation disasters can be divided into five major groups: direct deaths, and four indirect patterns of deaths due to a deteriorating supply-demand balance (a hospital-level problem), collapse of the healthcare system (a community-level problem), death due to neglect alongside underlying disease, and diseases other than direct invasion. From the similarities between the two disasters, three main issues should be prioritised as initial emergency evacuation measures in a radiation disaster: emergency exposure medicine, the establishment of a medical system, and protection of death with dignity. The validity of these priority issues needs to be verified in future research.

Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins.

Despite a clear correlation between the infiltration of periodontal pathogens in the brain and cognitive decline in Alzheimer's disease (AD), the precise mechanism underlying bacteria crossing the blood-brain barrier (BBB) remains unclear. The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteases termed gingipains. Gingipains appear to be key virulence factors that exacerbate sporadic AD. We herein report that gingipains are involved in increasing permeability of hCMEC/D3 cell monolayer, human cerebral microvascular endothelial cell lines, through degradation of tight junction proteins including Zonula occludens-1 (ZO-1) and occludin. There was a significant decrease in the mean protein levels of ZO-1 and occludin after infection of hCMEC/D3 cells with wild-type (WT) P. gingivalis. However, infection of these cells with a gingipain-deficient P. gingivalis strain showed significantly lower reduction of the mean protein levels of either ZO-1 and occludin, compared to the WT strain. Similar results were obtained after treatment with culture supernatant from WT and gingipain-deficient P. gingivalis strains. In vitro digestion of human recombinant ZO-1 and occludin by WT P. gingivalis culture supernatant in the absence or presence of gingipain inhibitors indicated that gingipains directly degraded these tight junction proteins. A close immunohistochemical examination using anti-gingipain antibody further revealed that gingipains localized in the cytosol and nuclei of hCMEC/D3 cells after infection with WT P. gingivalis and treatment with its culture supernatant. Furthermore, intracellular localization of outer membrane vesicles (OMVs) bound gingipains from WT P. gingivalis and OMV-induced degradation of ZO-1 and occludin were also observed in hCMEC/D3 cells. Thus, the delivery of gingipains into the cerebral microvascular endothelial cells, probably through OMV, may be responsible for the BBB damage through intracellular degradation of ZO-1 and occludin.