Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma recurrence.

The proto-oncogene MYCN expression marked a cancer stem-like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre- and post-surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non-cirrhotic or single-tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long-term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment.

Determination of a Serum 25-Hydroxyvitamin D Reference Ranges in Japanese Adults Using Fully Automated Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Despite an increasing interest in vitamin D status, a reference range of the nutrient has not been fully established. This is partly due to a paucity of standardized measuring systems with high throughput. In addition, the range may vary by populations and may change with modernization of lifestyles. OBJECTIVES: This study aims to calculate the current reference concentration of 25-hydroxyvitamin D (25(OH)D) among healthy people living in an urban area in Japan. METHODS: A newly developed fully automated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system was used to measure serum 25(OH)D concentrations. Reproducibility was assessed by measuring standardized samples. Accuracy was validated by comparing with commercially available immunoassays. Then, mass screening was conducted targeting participants who received medical checkups in Tokyo from April 2019 to March 2020, and the reference ranges were calculated. RESULTS: The coefficients of variations of interoperator and interday reproducibility were 4.1%-8.5% and 3.7%-8.0% for 25-hydroxyvitamin D2 (25(OH)D2) and 4.7%-7.0% and 4.0%-6.9% for 25-hydroxyvitamine D3, respectively. The measured total 25(OH)D concentrations correlated well with those measured by immunoassays. In total, 5518 participants were measured for 25(OH)D concentrations, among whom 98% showed inadequate concentrations (<30 ng/mL). The reference ranges of total 25(OH)D for female, male, and total participants were 7-30 ng/mL, 5-27 ng/mL, and 6-29 ng/mL, respectively. After excluding those with abnormal renal and liver function, the range was 6-30 ng/mL. CONCLUSIONS: The high prevalence of vitamin D insufficiency among seemingly healthy population may be attributed to lifestyle characteristics of people living in urban areas of Japan, including spending less time outdoors and lower intake of traditional foods. Longitudinal follow-up and mass screenings targeting different population will help elucidate reasons for discrepancies between official guidelines and the observed concentrations, to which the well-validated measurement system is essential.

Difficult-to-treat rheumatoid arthritis with respect to responsiveness to biologic/targeted synthetic DMARDs: a retrospective cohort study from the FIRST registry.

OBJECTIVES: Difficult-to-treat rheumatoid arthritis (dt-RA) is an emerging concept defined as persistency of signs and/or symptoms despite prior treatment. However, whether this refractoriness affects effectiveness and tolerance to next treatment is not fully understood. This study aimed to find cut-off values for a definition of dt-RA with respect to responsiveness to newly used biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). METHODS: A retrospective cohort study was conducted using the FIRST registry. An inadequate response to current b/tsDMARDs was defined as clinical disease activity index >10 at week 22 or termination of treatment within 22 weeks due to insufficient efficacy. Cut-off values were defined according to the number of past failures to DMARDs and current dose of glucocorticoid. Responsiveness to newly used b/tsDMARDs were compared with respect to above versus below cut-off values. RESULTS: Failures to ≥2 conventional synthetic DMARDs (csDMARDs) and ≥4 b/tsDMARDs as well as ≥3mg/day of glucocorticoid were independent cut-off values associated with poor responsiveness to newly used b/tsDMARD treatment. Concomitant use of glucocorticoid was significantly correlated with an increased hazard of infection. Failures to ≥2 csDMARDs was associated with less improvement in inflammatory symptoms, while that to ≥4 b/tsDMARDs was associated with less improvement in health assessment questionnaire and global health as well. CONCLUSIONS: We propose cut-off values of ≥2 failures to csDMARDs and/or ≥4 b/tsDMARDs as a definition of dt-RA with respect to responsiveness to use of b/tsDMARDs.

Association between COVID-19 vaccine hesitancy and generalized trust, depression, generalized anxiety, and fear of COVID-19.

BACKGROUND: Although numerous studies have been published on the predictors of COVID-19 vaccine hesitancy, some possible predictors remain underexplored. In this study, we explored the associations of unwillingness and indecisiveness regarding COVID-19 vaccination with generalized trust, mental health conditions such as depression and generalized anxiety, and fear of COVID-19. METHODS: Data of wave 1 (from October 27 till November 6, 2020) and wave 3 (from April 23 till May 6, 2021) of a longitudinal online study conducted in Japan were used for the analyses. Unvaccinated participants were asked at wave 3 about their willingness to be vaccinated, with possible responses of willing, unwilling, or undecided. These three responses were used as the outcome variable, and multinomial logistic regression analyses were conducted with willingness to be vaccinated as the reference group. Explanatory variables included generalized trust, depression, generalized anxiety, and fear of COVID-19 both at wave 1 and 3, and sociodemographic and health-related variables. RESULTS: Of the 11,846 valid respondents, 209 (1.8%) answered that they had already been vaccinated against COVID-19, 7089 (59.8%) responded that they were willing to be vaccinated, 3498 (29.5%) responded that they were undecided, and 1053 (8.9%) responded that they were unwilling to be vaccinated. After adjusting for covariates, we found that: (1) participants with lower levels of generalized trust at wave 1 and 3 were more likely to be undecided or unwilling at wave 3; (2) respondents with moderately severe or severe depression at wave 1 and 3 were more likely to be undecided at wave 3; (3) participants with moderate or severe levels of generalized anxiety at wave 3 but not at wave 1 were more likely to be unwilling at wave 3; and (4) respondents with high levels of fear of COVID-19 at wave 1 and 3 were less likely to be undecided and unwilling at wave 3. CONCLUSIONS: Generalized trust, mental health conditions such as depression and generalized anxiety, and low level of fear of COVID-19 are associated with unwillingness or indecision regarding being vaccinated against COVID-19.

Establishment of a Rapid Detection System for ISG20-Dependent SARS-CoV-2 Subreplicon RNA Degradation Induced by Interferon-α.

Inhaled nebulized interferon (IFN)-α and IFN-ß have been shown to be effective in the management of coronavirus disease 2019 (COVID-19). We aimed to construct a virus-free rapid detection system for high-throughput screening of IFN-like compounds that induce viral RNA degradation and suppress the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We prepared a SARS-CoV-2 subreplicon RNA expression vector which contained the SARS-CoV-2 5'-UTR, the partial sequence of ORF1a, luciferase, nucleocapsid, ORF10, and 3'-UTR under the control of the cytomegalovirus promoter. The expression vector was transfected into Calu-3 cells and treated with IFN-α and the IFNAR2 agonist CDM-3008 (RO8191) for 3 days. SARS-CoV-2 subreplicon RNA degradation was subsequently evaluated based on luciferase levels. IFN-α and CDM-3008 suppressed SARS-CoV-2 subreplicon RNA in a dose-dependent manner, with IC50 values of 193 IU/mL and 2.54 µM, respectively. HeLa cells stably expressing SARS-CoV-2 subreplicon RNA were prepared and treated with the IFN-α and pan-JAK inhibitor Pyridone 6 or siRNA-targeting ISG20. IFN-α activity was canceled with Pyridone 6. The knockdown of ISG20 partially canceled IFN-α activity. Collectively, we constructed a virus-free rapid detection system to measure SARS-CoV-2 RNA suppression. Our data suggest that the SARS-CoV-2 subreplicon RNA was degraded by IFN-α-induced ISG20 exonuclease activity.

Breast cancer patient delay in Fukushima, Japan following the 2011 triple disaster: a long-term retrospective study.

BACKGROUND: Little information is available concerning how patient delay may be affected by mass disasters. The main objectives of the present study are to identify whether there was a post-disaster increase in the risk of experiencing patient delay among breast cancer patients in an area affected by the 2011 triple disaster in Fukushima, Japan, and to elucidate factors associated with post-disaster patient delay. Sociodemographic factors (age, employment status, cohabitant status and evacuation status), health characteristics, and health access- and disaster-related factors were specifically considered. METHODS: Records of symptomatic breast cancer patients diagnosed from 2005 to 2016 were retrospectively reviewed to calculate risk ratios (RRs) for patient delay in every year post-disaster compared with the pre-disaster baseline. Total and excessive patient delays were respectively defined as three months or more and twelve months or more from symptom recognition to first medical consultation. Logistic regression analysis was conducted for pre- and post-disaster patient delay in order to reveal any factors potentially associated with patient delay, and changes after the disaster. RESULTS: Two hundred nineteen breast cancer patients (122 pre-disaster and 97 post-disaster) were included. After adjustments for age, significant post-disaster increases in RRs of experiencing both total (RR: 1.66, 95% Confidence Interval (CI): 1.02-2.70, p < 0.05) and excessive patient delay (RR: 4.49, 95% CI: 1.73-11.65, p < 0.01) were observed. The RRs for total patient delay peaked in the fourth year post-disaster, and significant increases in the risk of excessive patient delay were observed in the second, fourth, and fifth years post-disaster, with more than five times the risk observed pre-disaster. A family history of any cancer was the only factor significantly associated with total patient delay post-disaster (odds ratio: 0.38, 95% CI: 0.15-0.95, p < 0.05), while there were no variables associated with delay pre-disaster. CONCLUSIONS: The triple disaster in Fukushima appears to have led to an increased risk of patient delay among breast cancer patients, and this trend has continued for five years following the disaster.

Pseudo-SLE by human immunodeficiency virus infection.

A 61-year-old woman was admitted for long-lasting fever and recurrent opportunistic infections during the treatment of SLE. She had been diagnosed as SLE and type-IV nephritis based on a renal biopsy and serological findings. A colonoscopy and liver biopsy revealed disseminated Mycobacterium avium complex infection. Human immunodeficiency virus (HIV) infection status was then examined and found to be positive. From the clinical course, the first symptoms were inferred to have been those of HIV infection.

The great East Japan earthquake disaster: distribution of hospital damage in Miyagi Prefecture.

INTRODUCTION: In catastrophic events, a key to reducing health risks is to maintain functioning of local health facilities. However, little research has been conducted on what types and levels of care are the most likely to be affected by catastrophic events. Problem The Great East Japan Earthquake Disaster (GEJED) was one of a few "mega disasters" that have occurred in an industrialized society. This research aimed to develop an analytical framework for the holistic understanding of hospital damage due to the disaster. METHODS: Hospital damage data in Miyagi Prefecture at the time of the GEJED were collected retrospectively. Due to the low response rate of questionnaire-based surveillance (7.7%), publications of the national and local governments, medical associations, other nonprofit organizations, and home web pages of hospitals were used, as well as literature and news sources. The data included information on building damage, electricity and water supply, and functional status after the earthquake. Geographical data for hospitals, coastline, local boundaries, and the in undated areas, as well as population size and seismic intensity were collected from public databases. Logistic regression was conducted to identify the risk factors for hospitals ceasing inpatient and outpatient services. The impact was displayed on maps to show the geographical distribution of damage. RESULTS: Data for 143 out of 147 hospitals in Miyagi Prefecture (97%) were obtained. Building damage was significantly associated with closure of both inpatient and outpatient wards. Hospitals offering tertiary care were more resistant to damage than those offering primary care, while those with a higher proportion of psychiatric care beds were more likely to cease functioning, even after controlling for hospital size, seismic intensity, and distance from the coastline. CONCLUSIONS: Implementation of building regulations is vital for all health care facilities, irrespective of function. Additionally, securing electricity and water supplies is vital for hospitals at risk for similar events in the future. Improved data sharing on hospital viability in a future event is essential for disaster preparedness.

Streamlining of medical relief to areas affected by the Great East Japan earthquake with the "area-based/line-linking support system".

INTRODUCTION: When disasters that affect a wide area occur, external medical relief teams play a critical role in the affected areas by helping to alleviate the burden caused by surging numbers of individuals requiring health care. Despite this, no system has been established for managing deployed medical relief teams during the subacute phase following a disaster. After the Great East Japan Earthquake and tsunami, the Ishinomaki Medical Zone was the most severely-affected area. Approximately 6,000 people died or were missing, and the immediate evacuation of approximately 120,000 people to roughly 320 shelters was required. As many as 59 medical teams came to participate in relief activities. Daily coordination of activities and deployment locations became a significant burden to headquarters. The Area-based/Line-linking Support System (Area-Line System) was thus devised to resolve these issues for medical relief and coordinating activities. METHODS: A retrospective analysis was performed to examine the effectiveness of the medical relief provided to evacuees using the Area-Line System with regards to the activities of the medical relief teams and the coordinating headquarters. The following were compared before and after establishment of the Area-Line System: (1) time required at the coordinating headquarters to collect and tabulate medical records from shelters visited; (2) time required at headquarters to determine deployment locations and activities of all medical relief teams; and (3) inter-area variation in number of patients per team. RESULTS: The time required to collect and tabulate medical records was reduced from approximately 300 to 70 minutes/day. The number of teams at headquarters required to sort through data was reduced from 60 to 14. The time required to determine deployment locations and activities of the medical relief teams was reduced from approximately 150 hours/month to approximately 40 hours/month. Immediately prior to establishment of the Area-Line System, the variation of the number of patients per team was highest. Variation among regions did not increase after establishment of the system. CONCLUSION: This descriptive analysis indicated that implementation of the Area-Line System, a systematic approach for long-term disaster medical relief across a wide area, can increase the efficiency of relief provision to disaster-stricken areas.

Reliability of telecommunications systems following a major disaster: survey of secondary and tertiary emergency institutions in Miyagi Prefecture during the acute phase of the 2011 Great East Japan Earthquake.

INTRODUCTION: Telecommunication systems are important for sharing information among health institutions to successfully provide medical response following disasters. HYPOTHESIS/PROBLEM: The aim of this study was to clarify the problems associated with telecommunication systems in the acute phase of the Great East Japan Earthquake (March 11, 2011). METHODS: All 72 of the secondary and tertiary emergency hospitals in Miyagi Prefecture were surveyed to evaluate the telecommunication systems in use during the 2011 Great Japan Earthquake, including satellite mobile phones, multi-channel access (MCA) wireless systems, mobile phones, Personal Handy-phone Systems (PHS), fixed-line phones, and the Internet. Hospitals were asked whether the telecommunication systems functioned correctly during the first four days after the earthquake, and, if not, to identify the cause of the malfunction. Each telecommunication system was considered to function correctly if the hospital staff could communicate at least once in every three calls. RESULTS: Valid responses were received from 53 hospitals (73.6%). Satellite mobile phones functioned correctly at the highest proportion of the equipped hospitals, 71.4%, even on Day 0. The MCA wireless system functioned correctly at the second highest proportion of the equipped hospitals. The systems functioned correctly at 72.0% on Day 0 and at 64.0% during Day 1 through Day 3. The main cause of malfunction of the MCA wireless systems was damage to the base station or communication lines (66.7%). Ordinary (personal or general communication systems) mobile phones did not function correctly at any hospital until Day 2, and PHS, fixed-line phones, and the Internet did not function correctly at any area hospitals that were severely damaged by the tsunami. Even in mildly damaged areas, these systems functioned correctly at <40% of the hospitals during the first three days. The main causes of malfunction were a lack of electricity (mobile phones, 25.6%; the Internet, 54.8%) and damage to the base stations or communication lines (the Internet, 38.1%; mobile phones, 56.4%). CONCLUSION: Results suggest that satellite mobile phones and MCA wireless systems are relatively reliable and ordinary systems are less reliable in the acute period of a major disaster. It is important to distribute reliable disaster communication equipment to hospitals and plan for situations in which hospital telecommunications systems do not function.

Predictors of functional improvement and pain reduction in rheumatoid arthritis patients who achieved low disease activity with disease-modifying antirheumatic drugs: a retrospective study of the FIRST Registry.

BACKGROUND: Rheumatoid arthritis (RA) patients sometimes exhibit different levels of improvement in health assessment questionnaire-disability index (HAQ-DI) and subjective pain visual analogue score (VAS) even after achieving low disease activities (LDA). This study aimed to identify factors associated with improvement in HAQ-DI and pain VAS among those who achieved LDA. METHODS: Data of the FIRST registry, a multi-institutional cohort of RA patients treated with biological and targeted-synthetic DMARDs (b/tsDMARDs) were analyzed. Patients who were enrolled from August 2013 to February 2023 and who achieved clinical LDA [clinical disease activity index (CDAI) ≤ 10.0] at 6 months after starting treatment were included. Multiple logistic regression analyses were conducted to identify the factors that associated with achieving HAQ-DI normalization (< 0.5), HAQ-DI improvement (by > 0.22), or pain VAS reduction (≤ 40 mm). RESULTS: Among 1424 patients who achieved LDA at 6 months, 732 patients achieved HAQ-DI normalization and 454 achieved pain VAS reduction. The seropositivity and the use of JAK inhibitor compared with TNF inhibitor were associated with both HAQ-DI < 0.5 and pain VAS reduction at 6 months. On the other hand, older age, past failure in ≥ 2 classes of b/tsDMARDs, higher HAQ-DI at baseline, and use of glucocorticoid were associated with the lower likelihood of HAQ-DI normalization and pain VAS reduction. Longer disease duration, being female, and higher disease activity at baseline was negatively associated HAQ-DI normalization alone. Comorbidities were not associated with the outcomes. CONCLUSIONS: These results suggest some preferable treatment may exist for improvement of HAQ-DI and pain VAS reduction in the early stage of the treatment, which is a clue to prevention of a criteria of difficult-to-treat RA.

Investigating the causal effects of COVID-19 vaccination on the adoption of protective behaviors in Japan: Insights from a fuzzy regression discontinuity design.

BACKGROUND: During the COVID-19 pandemic, concerns emerged that vaccinated individuals might engage less in infection-preventive behaviors, potentially contributing to virus transmission. This study evaluates the causal effects of COVID-19 vaccination on such behaviors within Japan, highlighting the significance of understanding behavioral dynamics in public health strategies. METHODS: Utilizing Japan's age-based vaccination priority for those born before April 1, 1957, this research employs a regression discontinuity design (RDD) to assess the vaccination's impact. Data from the fourth round of a longitudinal online survey, conducted from July 20 to 27, 2021, served as the basis for analyzing 14 infection-protective behaviors, including mask usage, handwashing, and avoiding crowds. RESULTS: A total of 12067 participants completed the survey. The analyzed sample size varied by outcome variable, ranging from 1499 to 5233. The analysis revealed no significant differences in the 14 behaviors examined among fully vaccinated, partially vaccinated, and unvaccinated individuals. This consistency across groups suggests that vaccination status did not significantly alter engagement in protective behaviors during the observation period. CONCLUSIONS: Empirical findings highlight the complexity of behavioral responses following vaccination, indicating that such responses may be influenced by various factors, rather than by vaccination status alone. Additionally, this result underscores the importance of crafting public health policies that account for the intricate interplay between vaccination and behavior. This study contributes to the broader discourse on managing responses to the pandemic and tailoring interventions to sustain or enhance protective health behaviors amid vaccination rollouts.

A report from Fukushima: an assessment of bone health in an area affected by the Fukushima nuclear plant incident.

Bone health was assessed for inhabitants of an area affected by the Fukushima nuclear plant incident. Osteoporotic patients, who had been treated with active vitamin D3 and/or bisphosphonate at Soma Central Hospital before the Fukushima incident, were enrolled. Changes in bone turnover markers and bone mineral density were retrospectively analyzed. Serum levels of a bone resorption marker, serum type I collagen cross-linked N-telopeptide were decreased in all the treated groups, whereas those of a bone formation marker, bone-specific alkaline phosphatase, were increased. Accordingly, bone mineral density, estimated by dual-energy X-ray absorptiometry, was increased in the lumbar spine of all groups, but bone mass increase in the proximal femur was detected only in the group treated with the two agents in combination. From the degree of these parameter changes, the antiosteoporotic treatments looked effective and were equivalent to the expected potency of past observations. At this stage, the present study implies that the Fukushima nuclear incident did not bring an acute risk to bone health in the affected areas.

Impact of the COVID-19 pandemic on exercise habits and overweight status in Japan: A nation-wide panel survey.

A catastrophic disaster may cause distant health impacts like immobility and obesity. The aim of this research was to analyse the association of the COVID-19 pandemic and lifestyle factors -exercise habit and overweight status in the Japanese population. Nation-wide online questionnaires were conducted five times from October 2020 to October 2021. The changes in exercise habit, body mass index (BMI) and overweight status (BMI >25kg/m2) were compared between the first questionnaire and a questionnaire conducted a year later. Risk factors for losing exercise habit or becoming overweight were analysed using multiple regression. Data were obtained from 16,642 participants. In the early phase of the pandemic, people with high income and elderly females showed a higher risk for decreased exercise days. The proportion of overweight status increased from 22.2% to 26.6% in males and from 9.3% to 10.8% in females. Middle-aged males, elderly females, and males who experienced SARS-CoV-2 infection were at higher risk of becoming overweight. Our findings suggest that risks for immobility and overweight are homogeneous. Continuous intervention for elderly females and long-term intervention for males infected with SARS-CoV-2 might be especially needed. As most disasters can cause similar social transformation, research and evaluation of immobility and obesity should address future disaster preparation/mitigation plans.

Correction: Impact of the COVID-19 pandemic on exercise habits and overweight status in Japan: a nation-wide panel survey.

[This corrects the article DOI: 10.1371/journal.pgph.0001732.].

Preferable outcome of Janus kinase inhibitors for a group of difficult-to-treat rheumatoid arthritis patients: from the FIRST Registry.

BACKGROUNDS: Treatment of difficult-to-treat rheumatoid arthritis (D2T RA) is one of the greatest unmet needs in rheumatology. This study aims to find out preferable treatment options for a group of D2T RA patients who are refractory to multiple biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). METHODS: Data were obtained from patients enrolled in the FIRST Registry who started either TNF inhibitor (TNFi), interleukin-6 receptor inhibitor, cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin, or Janus-kinase inhibitor (JAKi) in the period of August 2013 to December 2020. Those who failed to ≥ 2 and ≥ 3 b/tsDMARDs were categorised as D2T RA and very D2T RA (vD2T RA), respectively. Change in Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index were compared among the groups using propensity-based inverse probability treatment weighted (IPTW) method. RESULTS: Of 2128 cases included, 353 were categorised as D2T RA. Among the D2T RA, 106 were identified as vD2T RA. JAKi showed a significant improvement in CDAI in the patients with D2T RA and vD2T RA, compared to IPTW-adjusted patients treated with the other 3 regimens. Latent class analysis of the trajectories of treatment response revealed that the proportion of a group of patients who showed poor response was lower among the JAKi subgroup than among those with other subgroups. This superiority of JAKi was more apparent among methotrexate- and glucocorticoid-free individuals. The hazard ratio of severe adverse events was comparable among the four treatment subgroups in both the D2T RA and b/tsDMARD-naïve groups. CONCLUSIONS: This study compared responsiveness to different classes of b/tsDMARDs among D2T RA and vD2T RA patients who were refractory to multiple b/tsDMARDs. The results suggest JAKi is a preferable treatment choice for this type of D2T RA.

Autoamplification of NFATc1 expression determines its essential role in bone homeostasis.

NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1(-/-) hematopoietic stem cells to osteoclast-deficient Fos(-/-) mice, and by Fos(-/-) blastocyst complementation, thus avoiding the embryonic lethality of NFATc1(-/-) mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.

'Life communication' after the 2011 Fukushima nuclear disaster: what experts need to learn from residential non-scientific rationality.

After chemical, biological, radiological, nuclear or explosive (CBRNE) disasters, trepidation and infodemics about invisible hazards may cause indirect casualties in the affected society. Effective communication regarding technical issues between disaster experts and the residents is key to averting such secondary impacts. However, misconceptions about scientific issues and mistrust in experts frequently occur even with intensive and sincere communications. This miscommunication is usually attributed to residents' conflicts with illiteracy, emotion, value depositions and ideologies. However, considering that communication is an interactive process, there are likely to be additional factors attributable to experts. This article aims to summarize the gaps in rationality between experts and residents observed after the 2011 Fukushima nuclear disaster to describe how residents perceived experts. There were discrepancies in the perception of 'facts', the perception of probability, the interpretation of risk comparison, what were included as risk trade-offs, the view of the disaster, whose behavior would be changed by the communication and whether risk should be considered a science. These findings suggest that there was a non-scientific rationality among residents, which often exercised a potent influence on everyday decision-making. It might not be residents but experts who need to change their behavior. The discrepancies described in this article are likely to apply to communications following any CBRNE disasters that affect people's lives, such as the current COVID-19 pandemic. Therefore, our experiences in Fukushima may provide clues to averting mutual mistrust between experts and achieving better public health outcomes during and after a crisis.

Prevention and Control of COVID-19 in Imperfect Condition: Practical Guidelines for Nursing Homes by Japan Environment and Health Safety Organization (JEHSO).

Infection control at nursing homes is a top priority to address the COVID-19 pandemic because people who are the most vulnerable to the pathogen live in close contact. Currently, control measures specifically for nursing homes often ignore under-resourced condition of the facilities. To make guidelines assuming realistic conditions, an expert meeting with 16 members established the key challenges in nursing homes, the basics of infection control, and the major transmission routes. A list of existing guidance was compiled and each item in the list was peer-reviewed by eight experts considering three aspects: significance, scientific validity, and feasibility. Factors related to the nursing home environment, the nature of SARS-CoV-2 transmission, and patient characteristics were identified as the causes of difficulties in infection control at nursing homes. To develop realistic prevention measures in under-resourced condition such as nursing homes, we may need to accept there are no perfect control measures that can achieve zero risk. Instead, the guidelines are based on the concept of deep defense, and practical checklists with 75 items were established. The evaluation of nursing homes by independent organizations using the checklists would be helpful to achieve sustainable infection control.

Similarity of Response to Biologics Between Elderly-onset Rheumatoid Arthritis (EORA) and Non-EORA Elderly Patients: From the FIRST Registry.

OBJECTIVE: Increasing numbers of patients are developing rheumatoid arthritis (RA) at an older age, and optimal treatment of patients with elderly-onset RA (EORA) is attracting greater attention. This study aimed to analyze the efficacy and safety of biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in EORA and non-EORA elderly patients. METHODS: A cohort of patients with RA treated with b/tsDMARDs were retrospectively analyzed. Only patients aged ≥ 60 years were included. Among them, patients who developed RA aged ≥ 60 years were categorized as EORA, whereas those aged < 60 years were categorized as non-EORA elderly. Disease activity was compared between the EORA and non-EORA elderly groups. RESULTS: In total, 1040 patients were categorized as EORA and 710 as non-EORA elderly. There were no significant differences in characteristics at baseline between the 2 groups. The proportion of patients with low and high disease activity was comparable at Weeks 2, 22, and 54 between the EORA and the non-EORA elderly group. There were no significant differences in the reasons for the discontinuation of b/tsDMARDs between the 2 groups. Elderly RA onset did not affect changes in Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index, nor did it affect the reasons for b/tsDMARD discontinuation between the 2 groups. The trajectory analysis on CDAI responses to b/tsDMARDs for 54 weeks identified 3 response patterns. The proportion of patients categorized into each group and CDAI response trajectories to b/tsDMARDs were very similar between EORA and non-EORA elderly patients. CONCLUSION: CDAI response patterns to b/tsDMARDs and HR of adverse events were similar between EORA and non-EORA elderly patients.