Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients.

OBJECTIVE: To investigate characteristics of multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients associated with drugs other than natalizumab since our experience in other disease-modifying drugs (DMD) is still limited. METHODS: This is a descriptive observational study within the FAERS database, registered between July 2015 and June 2017. RESULTS: The primary cohort for the analysis consisted of 100,921 MS patients (mean (standard deviation (sd)) age, 48.9 (12.8) years, 20.9% male). Among them 786 (0.78%) developed PML. The adjusted odds ratio of PML for each drug was as follows; natalizumab 115.72 (95% CI; 83.83, 159.74), fingolimod 4.98 (3.64, 6.81) followed by dimethyl fumarate 1.77 (1.2, 2.62) and rituximab 3.22 (1.07, 9.72). The median time from the start of suspected drugs to the onset of PML for natalizumab and other agents were 1463 and 178 days, respectively. The proportion of PML appeared higher in Japan (2.4%) compared to that in the United States (0.24%). CONCLUSION: The reporting proportion of PML was relatively higher in natalizumab followed by fingolimod, dimethyl fumarate and rituximab. Other characteristics of PML associated with DMDs, including the time to onset and differences in reporting among countries, are described.

GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Genome-wide association studies (GWAS) identified more than 50 CRC loci. However, most of the previous studies were conducted in European population, and host genetic factors among Japanese population are largely remained to be identified. To identify novel loci in the Japanese population, here, we performed a large-scale GWAS using 6692 cases and 27 178 controls followed by a replication analysis using more than 11 000 case-control samples. We found the significant association of 10 loci (P < 5 × 10-8), including 2 novel loci on 16q24.1 (IRF8-FOXF1, rs847208, P = 3.15 × 10-9 and odds ratio = 1.107 with 95% confidence interval (CI) of 1.071-1.145) and 20q13.12 (TOX2, rs6065668, P = 4.47 × 10-11 and odds ratio = 0.897 with 95% CI of 0.868-0.926). Moreover, 35 previously reported single nucleotide polymorphisms (SNPs) in 24 regions were validated in the Japanese population (P < 0.05) with the same risk allele as in the previous studies. SNP rs6065668 was significantly associated with TOX2 expression in the sigmoid colon. In addition, nucleotide substitutions in the regulatory region of TOX2 were predicted to alter the binding of several transcription factors, including KLF5. Our findings elucidate the important role of genetic variations in the development of CRC in the Japanese population.

Cross-sectional analysis of BioBank Japan clinical data: A large cohort of 200,000 patients with 47 common diseases.

BACKGROUND: To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012. METHODS: We analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development. RESULTS: Distribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset. CONCLUSIONS: Cross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine.

Overview of BioBank Japan follow-up data in 32 diseases.

BACKGROUND: We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data. METHODS: A total of 141,612 participants were included. The survival data were last updated in 2014. Kaplan-Meier survival analysis was performed after categorizing subjects according to sex, age group, and disease status. Relative survival rates were estimated using a survival-rate table of the Japanese general population. RESULTS: Of 141,612 subjects (56.48% male) with 1,087,434 person-years and a 97.0% follow-up rate, 35,482 patients died during follow-up. Mean age at enrollment was 64.24 years for male subjects and 63.98 years for female subjects. The 5-year and 10-year relative survival rates for all subjects were 0.944 and 0.911, respectively, with a median follow-up duration of 8.40 years. Patients with pancreatic cancer had the least favorable prognosis (10-year relative survival: 0.184) and patients with dyslipidemia had the most favorable prognosis (1.013). The most common cause of death was malignant neoplasms. A number of subjects died from diseases other than their registered disease(s). CONCLUSIONS: This is the first report to perform follow-up survival analysis across various common diseases. Further studies should use detailed clinical and genomic information to identify predictors of mortality in patients with common diseases, contributing to the implementation of personalized medicine.

Overview of the BioBank Japan Project: Study design and profile.

BACKGROUND: The BioBank Japan (BBJ) Project was launched in 2003 with the aim of providing evidence for the implementation of personalized medicine by constructing a large, patient-based biobank (BBJ). This report describes the study design and profile of BBJ participants who were registered during the first 5-year period of the project. METHODS: The BBJ is a registry of patients diagnosed with any of 47 target common diseases. Patients were enrolled at 12 cooperative medical institutes all over Japan from June 2003 to March 2008. Clinical information was collected annually via interviews and medical record reviews until 2013. We collected DNA from all participants at baseline and collected annual serum samples until 2013. In addition, we followed patients who reported a history of 32 of the 47 target diseases to collect survival data, including cause of death. RESULTS: During the 5-year period, 200,000 participants were registered in the study. The total number of cases was 291,274 at baseline. Baseline data for 199,982 participants (53.1% male) were available for analysis. The average age at entry was 62.7 years for men and 61.5 years for women. Follow-up surveys were performed for participants with any of 32 diseases, and survival time data for 141,612 participants were available for analysis. CONCLUSIONS: The BBJ Project has constructed the infrastructure for genomic research for various common diseases. This clinical information, coupled with genomic data, will provide important clues for the implementation of personalized medicine.

Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry.

We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4(+) cells from peripheral blood, CADM1(-) CD7(+) (P), CADM1(+) CD7(dim) (D) and CADM1(+) CD7(-) (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4(+) cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (>4 copies/100 cells) had a CADM1(+) (D + N) frequency of >10%. AC with 25% < CADM1(+) ≤ 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25% < CADM1(+) ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.

Effect of ABO blood group incompatibility on the outcome of single-unit cord blood transplantation after myeloablative conditioning.

ABO blood group incompatibility between donor and recipient has been associated with poor transplant outcomes in allogeneic hematopoietic stem cell transplantation. However, its effect on the outcome of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. Major mismatch showed a significantly lower incidence of platelet engraftment compared with ABO match as a reference (hazard ratio, .57; P = .01). Nevertheless, there was no increase in graft-versus-host disease, transplant-related mortality, and overall mortality after ABO-incompatible CBT. These data suggested that donor-recipient ABO incompatibility does not have a significant impact on outcome after myeloablative CBT for hematological malignancies.

Single-unit cord blood transplantation after granulocyte colony-stimulating factor-combined myeloablative conditioning for myeloid malignancies not in remission.

High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF-combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF-combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.

Development of a national agreement on human papillomavirus vaccination in Japan: an infodemiology study.

BACKGROUND: A national agreement on human papillomavirus (HPV) vaccination was achieved relatively quickly in Japan as compared to the United States and India. OBJECTIVE: The objective was to identify the role of print and online media references, including references to celebrities or other informants, as factors potentially responsible for the relatively rapid national acceptance of HPV vaccination in Japan. METHODS: A method of text mining was performed to select keywords, representing the context of the target documents, from articles relevant to the promotion of HPV vaccination appearing in major Japanese newspapers and Web pages between January 2009 and July 2010. The selected keywords were classified as positive, negative, or neutral, and the transition of the frequency of their appearance was analyzed. RESULTS: The number of positive and neutral keywords appearing in newspaper articles increased sharply in early 2010 while the number of negative keywords remained low. The numbers of positive, neutral, and negative keywords appearing in Web pages increased gradually and did not significantly differ by category. Neutral keywords, such as "vaccine" and "prevention," appeared more frequently in newspaper articles, whereas negative keywords, such as "infertility" and "side effect," appeared more frequently in Web pages. The extraction of the positive keyword "signature campaign" suggests that vaccine beneficiaries cooperated with providers in promoting HPV vaccination. CONCLUSIONS: The rapid development of a national agreement regarding HPV vaccination in Japan may be primarily attributed to the advocacy of vaccine beneficiaries, supported by advocacy by celebrities and positive reporting by print and online media.

Effect of renal impairment on the pharmacokinetics of memantine.

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.

Public Attitudes toward COVID-19 Vaccinations before Dawn in Japan: Ethics and Future Perspectives.

Improving public understanding and acceptance are critical for promoting coronavirus (COVID-19) vaccination. However, how to promote COVID-19 vaccine programs remains controversial due to various ethical issues. This study, thus, aimed to survey the acceptance of COVID-19 vaccines among Japanese citizens and discuss relevant ethical issues. A cross-sectional survey was conducted via an online platform. An anonymous, quantitative, self-administered online questionnaire was sent to 6965 registered Japanese residents (20-79 years of age), which included questions regarding the respondent's general knowledge, experience, and opinions of vaccines, vaccine development, COVID-19, and COVID-19 vaccines. Of the 1569 respondents, 730 (46.5%) and 839 (53.5%) were categorized into the younger and older groups, respectively. Most of the respondents possessed general knowledge of COVID-19 vaccines and their features. Of the respondents, 57.8% definitely agreed (10.5%) or somewhat agreed (47.3%) to receive COVID-19 vaccines. The older group showed significantly greater willingness to receive vaccines and higher literacy regarding vaccines in general. Possible reasons for the older group's greater willingness to receive COVID-19 vaccines are a high risk of severe COVID-19 infection and their past accumulated experience of receiving various vaccinations. Although active public intervention could increase vaccination rates, most of the respondents did not agree with mandatory vaccination. Furthermore, a gap between the participants in the COVID-19 vaccine trials and the prioritized population in real-world vaccination should be adjusted in future vaccine development. Supplementary Information: The online version contains supplementary material available at 10.1007/s41649-022-00207-4.

Effect of early nutritional initiation on post-cerebral infarction discharge destination: A propensity-matched analysis using machine learning.

AIM: Malnutrition is associated with poor outcomes in cerebral infarction patients, with research indicating that early nutritional initiation may improve the short-term prognosis of patients. However, evidence supported by big data is lacking. Here, to determine the effect of nutritional initiation during the first 3 days after hospital admission on home discharge rates, propensity score matching was conducted in patients with acute cerebral infarction. METHODS: This retrospective observational study, using the Diagnosis Procedure Combination anonymised database in Japan, included 41 477 ischaemic cerebral infarction patients hospitalised between 2016 and 2019. The patients were divided into two groups: those who received oral or enteral nutrition during the first 3 days of hospital admission (early nutrition group, n = 37 318) and those who did not (control group, n = 4159). One-to-one pair-matching was performed using propensity scores calculated via extreme gradient boosting to limit the confounding variables of the two groups. RESULTS: After propensity score matching, 3541 pairs of patients were selected. The dependence of home discharge rates on early nutrition was significant (p < 0.05), and the effectiveness of early nutrition for home discharge showed an odds ratio of 1.79 (95% confidence interval of 1.59-2.03 in Fisher's exact test). CONCLUSIONS: Our findings revealed that early nutritional initiation during the first 3 days of admission resulted in higher home discharge rates.

Age, gender, will, and use of home-visit nursing care are critical factors in home care for malignant diseases; a retrospective study involving 346 patients in Japan.

BACKGROUND: We aimed to clarify the factors affecting outcomes of home care for patients with malignant diseases. METHODS: Of 607 patients who were treated in 10 clinics specialized in home care between January and December 2007 at Chiba, Fukuoka, Iwate, Kagoshima, Tochigi and Tokyo prefectures across Japan, 346 (57%; 145 men and 201 women) had malignant diseases. We collected information on medical and social backgrounds, details of home care, and its outcomes based on their medical records. RESULTS: Median age of the patients was 77 years (range, 11-102), and 335 patients were economically self-sufficient. Their general condition was poor; advanced cancer (n = 308), performance status of 3-4 (n = 261), and dementia (n = 121). At the beginning of home care, 143 patients and 174 family members expressed their wish to die at home. All the patients received supportive treatments including fluid replacement and oxygenation. Median duration of home care was 47 days (range, 0-2,712). 224 patients died at home. For the remaining 122, home care was terminated due to complications (n = 109), change of attending physicians (n = 8), and others (n = 5). The factors which inhibited the continuity of home care were the non-use of home-visit nursing care (hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.05-3.00, p = 0.03), the fact that the patients themselves do not wish to die at home (HR = 1.83, CI: 1.09-3.07, p = 0.02), women (HR = 1.81, CI: 1.11-2.94, p = 0.02), and age (HR = 0.98, CI: 0.97-1.00, p = 0.02). CONCLUSIONS: Continuation of home care is influenced by patients' age, gender, will, and use of home-visit nursing.

Internet-based survey on medical manga in Japan.

The more manga (Japanese graphic novels) communicate medical information, the more people are likely to be influenced by manga. We investigated through an Internet search using Google the characteristics of medical manga published in Japan, defined as those in which the main character is a medical professional and that occur in a medical setting. As of December 2008, 173 medical manga had been published. For a period of time after the first medical manga by Osamu Tezuka in 1970, the number of publications maintained a steady level, but increased rapidly in the mid 1980s. The professions of the protagonist were 134 doctors, 19 nurses, 3 dentists, 3 medical students, and 1 nursing student. Although the main character was mostly a doctor, manga featuring paramedical professionals have increased since 1990s. Medical manga may be a powerful tool for increasing the awareness of the public regarding medicine.

Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan.

We have little information on chronic graft-versus-host disease (GVHD) after cord blood transplantation (CBT). We investigated its clinical features in 1072 Japanese patients with hematologic malignancies who received a transplant through the Japan Cord Blood Bank Network. The primary end point was to investigate the incidence of any chronic GVHD. Median age of the patients was 33 years (range, 0-79 years). The cumulative incidence of chronic GVHD 2 years after transplantation was 28%. Chronic GVHD was fatal in 29 patients. Multivariate analysis demonstrated that development of chronic GVHD was favorably associated with both overall survival and event-free survival. Multivariate analysis identified risk factors of chronic GVHD: higher patient body weight, higher number of mismatched antigens for GVHD direction, myeloablative preparative regimen, use of mycophenolate mofetil in GVHD prophylaxis, and development of grades II to IV acute GVHD. Although chronic GVHD is a significant problem after CBT, it is associated with improved survival, perhaps due to graft-versus-malignancy effects.