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1.  Recurrent Kawasaki disease, United States and Japan 
Background
Descriptive epidemiologic studies of recurrent and non-recurrent Kawasaki disease (KD) may identify other potentially important differences between these illnesses.
Methods
Data from the United States and Japan, the Centers for Disease Control and Prevention (CDC) national KD surveillance (1984–2008) and the 17th Japanese nationwide survey (2001–2002), respectively, were analyzed to examine recurrent KD patients <18 years of age meeting the CDC KD case or atypical KD case definition. These patients were compared to non-recurrent KD patients.
Results
Of the 5557 US KD patients <18 years of age during 1984–2008, 97 (1.7%) were identified as having had recurrent KD. Among the US Asian/Pacific Islander KD patients, 3.5% had recurrent KD, which was similar to the percentage identified among KD patients (3.5%) in the Japanese survey. Compared to non-recurrent KD patients, KD patients experiencing a recurrent KD episode were more likely to be older, fulfill the atypical KD case definition, and have coronary artery abnormalities (CAA) despite IVIG treatment.
Conclusions
Differences in the age, race, and frequency of CAA exist between recurrent and non-recurrent KD patients. The increased association of CAA with recurrent KD suggests that more aggressive treatment strategies in conjunction with IVIG may be indicated for the second episode of KD.
doi:10.1111/ped.12733
PMCID: PMC4676732  PMID: 26096590
Epidemiology Kawasaki disease; Kawasaki syndrome; mucocutaneous lymph node syndrome; recurrence
2.  Association between mental disorders and subsequent adult onset asthma 
Background and objectives
Associations between asthma and anxiety and mood disorders are well established, but little is known about their temporal sequence. We examined associations between a wide range of DSM-IV mental disorders with adult onset of asthma and whether observed associations remain after mental comorbidity adjustments.
Methods
During face-to-face household surveys in community-dwelling adults (n = 52,095) of 19 countries, the WHO Composite International Diagnostic Interview retrospectively assessed lifetime prevalence and age at onset of 16 DSM-IV mental disorders. Asthma was assessed by self-report of physician’s diagnosis together with age of onset. Survival analyses estimated associations between first onset of mental disorders and subsequent adult onset asthma, without and with comorbidity adjustment.
Results
1,860 adult onset (21 years+) asthma cases were identified, representing a total of 2,096,486 person-years of follow up. After adjustment for comorbid mental disorders several mental disorders were associated with subsequent adult asthma onset: bipolar (OR=1.8; 95%CI 1.3–2.4), panic (OR=1.4; 95%CI 1.0–2.0), generalized anxiety (OR=1.3; 95%CI 1.1–1.7), specific phobia (OR=1.4; 95%CI 1.2–1.6); post-traumatic stress (OR=1.5; 95%CI 1.1–2.0); binge eating (OR=1.9; 95%CI 1.2–2.9) and alcohol abuse (OR=1.5; 95%CI 1.2–2.0). Mental comorbidity linearly increased the association with adult asthma. The association with subsequent asthma was stronger for mental disorders with an early onset (before age 21).
Conclusions
A wide range of temporally prior mental disorders are significantly associated with subsequent onset of asthma in adulthood. The extent to which asthma can be avoided or improved among those with early mental disorders deserves study.
doi:10.1016/j.jpsychires.2014.09.007
PMCID: PMC5120389  PMID: 25263276
Asthma; Mental Disorders; Population; Epidemiology; Chronic Disease; Comorbidity
3.  Carotid plaque is a new risk factor for peripheral vestibular disorder: a retrospective cohort study 
Medicine  2016;95(31):e4510.
Abstract
Many chronic diseases are associated with dizziness or vertigo, as is peripheral vestibular disorder (PVD). Although carotid plaque development is linked to atherosclerosis, it is unclear whether such plaques can lead to the development of PVD. We therefore conducted this study to investigate the presence of an association between carotid plaque and new PVD events.
In this retrospective study, we consecutively enrolled 393 patients ≥20 years old who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for ≥6 months at a primary care clinic (Oki Clinic, Japan) between November 2011 and March 2013. Carotid plaque presence was measured with high-resolution ultrasonography for all patients. During a 1-year follow-up period, an otorhinolaryngologist diagnosed and reported any new PVD events (the main end point). Hazard ratios (HRs) and 95% confidence intervals (CIs) for new PVD occurrence were estimated using the Cox proportional hazard regression model.
The mean age of the participants was 65.5 years; 33.8% were men, and 12.7%, 82.4%, and 93.1% had diabetes mellitus, hypertension, and dyslipidemia, respectively. There were 76 new PVD events; patients with carotid plaque had a greater risk of such events (crude HR: 3.25; 95% CI: 1.62–6.52) compared to those without carotid plaque. This risk was even higher after adjusting for traditional risk factors for atherosclerosis (adjusted HR: 4.41; 95% CI: 1.75–11.14).
Carotid plaques are associated with an increased risk of new PVD events.
doi:10.1097/MD.0000000000004510
PMCID: PMC4979859  PMID: 27495105
atherosclerosis; carotid plaque; intima–media thickness; peripheral vestibular disorder; primary health care; retrospective cohort study
4.  Quantifying penetrance in a dominant disease gene using large population control cohorts 
Science translational medicine  2016;8(322):322ra9.
More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance - the probability that a carrier of the purported disease-causing genotype will indeed develop the disease - is generally unknown. Here we assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30× more common in the population than expected based on genetic prion disease prevalence. While some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1% to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, supporting the safety of therapeutic suppression of prion protein expression.
doi:10.1126/scitranslmed.aad5169
PMCID: PMC4774245  PMID: 26791950
5.  Association between toothbrushing and risk factors for cardiovascular disease: a large-scale, cross-sectional Japanese study 
BMJ Open  2016;6(1):e009870.
Objectives
To clarify the association between toothbrushing and risk factors for cardiovascular disease—namely, hypertension (HT), diabetes mellitus (DM), dyslipidaemia (DL), hyperuricaemia (HUA) and chronic kidney disease (CKD).
Design
A large-scale, single-centre, cross-sectional study.
Setting
St Luke's International Hospital, Center for Preventive Medicine, Tokyo, Japan, between January 2004 and June 2010.
Participants
This study examined the toothbrushing practices of 85 866 individuals according to the 3-category frequency criterion: ‘after every meal’, ‘at least once a day’ and ‘less than once a day’. The ORs by frequency were calculated for the prevalences of HT, DM, DL, HUA and CKD according to binominal logistic regression analyses adjusted for age, gender, body mass index and lifestyle habits—smoking, drinking, walk time and sleep time.
Results
The prevalences of the risk factors were as follows: HT (‘after every meal’: 13.3%, ‘at least once a day’: 17.9% and ‘less than once a day’: 31.0%), DM (3.1%, 5.3% and 17.4%, respectively), DL (29.0%, 42.1% and 60.3%, respectively), HUA (8.6%, 17.5% and 27.2%, respectively) and CKD (3.8%, 3.1% and 8.3%, respectively). The prevalences were significantly higher in the ‘less than once a day’ group than in the ‘after every meal’ group for DM (OR=2.03; 95% CI 1.29 to 3.21) and DL (OR=1.50; 95% CI 1.06 to 2.14), but not for HT, HUA and CKD.
Conclusions
Even taking into account lifestyle habits, a lower frequency of toothbrushing was associated with high prevalences of DM and DL. Toothbrushing practices may be beneficial for oral health improvement and also for prevention of certain systemic diseases.
doi:10.1136/bmjopen-2015-009870
PMCID: PMC4735199  PMID: 26769787
Toothbrushing; Diabetes mellitus; Dyslipidemia
6.  Incidence of dizziness and vertigo in Japanese primary care clinic patients with lifestyle-related diseases: an observational study 
Objective
Dizziness and vertigo are highly prevalent symptoms among patients presenting at primary care clinics, and peripheral vestibular disorder (PVD) is their most frequent cause. However, the incidence of PVD has not been well documented. This study aimed to investigate the incidence of dizziness, vertigo, and PVD among patients presenting at a primary care clinic.
Design
This was an observational study.
Setting and participants
Between November 2011 and March 2013, we observed 393 patients, all at least 20 years old, who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for at least 6 months at a primary clinic (Oki Clinic) in Japan.
Outcome
The main outcome of interest was new incidence of dizziness, vertigo, and PVD events. During the 1-year follow-up period, the otorhinolaryngologist diagnosed and reported new PVD events.
Results
The mean age of the 393 participants at entry was 65.5 years. Of the study participants, 12.7%, 82.4%, and 92.6% had diabetes mellitus, hypertension, and dyslipidemia, respectively. We followed up all the participants (100%). During the 662.5 person-years of follow-up, 121 cases of dizziness or vertigo (dizziness/vertigo) and 76 cases of PVD were observed. The incidence of dizziness/vertigo and PVD was 194.7 (95% confidence interval: 161.6–232.6) per 1,000 person-years and 115.7 (95% confidence interval: 92.2–142.6) per 1,000 person-years, respectively. There were 61 cases of acute peripheral vestibulopathy, 12 of benign paroxysmal positional vertigo, and three of Meniere’s disease among the 76 PVD patients.
Conclusion
We reported the incidence of dizziness/vertigo among Japanese primary care clinic patients, which was higher than that usually observed in the general population. Furthermore, we described the incidence of PVD and found that it was a major cause of dizziness/vertigo.
doi:10.2147/IJGM.S82018
PMCID: PMC4404935  PMID: 25931828
dizziness; incidence; primary health care; observational study
7.  Comorbidity of common mental disorders with cancer and their treatment gap: Findings from the World Mental Health Surveys 
Psycho-oncology  2013;23(1):40-51.
Objective
To study the comorbidity of common mental disorders (CMDs) and cancer, and the mental health treatment gap among community residents with active cancer, cancer survivors and cancer-free respondents in 13 high- and 11 low-middle income countries.
Methods
Data were derived from the World Mental Health Surveys (N=66,387; n=357 active cancer, n=1,373 cancer survivors, n=64,657 cancer free respondents). The WHO/Composite International Diagnostic Interview was used in all surveys to estimate CMDs prevalence rates. Respondents were also asked about mental health service utilization in the preceding 12 months. Cancer status was ascertained by self-report of physician’s diagnosis.
Results
Twelve month prevalence rates of CMDs were higher among active cancer (18.4% SE=2.1) than cancer free respondents (13.3%, SE=0.2) adjusted for socio-demographic confounders and other lifetime chronic conditions (Adjusted Odds Ratio (AOR)=1.44 95% CI 1.05–1.97). CMD rates among cancer survivors (14.6% SE=0.9) compared with cancer-free respondents did not differ significantly (AOR=0.95 95% CI 0.82–1.11). Similar patterns characterized high and low-middle income countries. Of respondents with active cancer who had CMD in the preceding 12 months 59% sought services for mental health problems (SE=5.3). The pattern of service utilization among people with CMDs by cancer status (highest among persons with active cancer, lower among survivors and lowest among cancer-free respondents) was similar in high- (64.0% SE=6.0, 41.2% SE=3.0, 35.6% SE=0.6) and low-middle income countries (46.4% SE=11.0, 22.5% SE=9.1, 17.4% SE=0.7).
Conclusions
Community respondents with active cancer have relatively higher CMD rates and relatively high treatment gap. Comprehensive cancer care should consider both factors.
doi:10.1002/pon.3372
PMCID: PMC3992888  PMID: 23983079
Cancer; Epidemiology; Mental health; Oncology; Treatment gap; World Mental Health Surveys
8.  Clinical features of genetic Creutzfeldt-Jakob disease with V180I mutation in the prion protein gene 
BMJ Open  2014;4(5):e004968.
Objectives
Genetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective.
Design
We analysed clinical symptoms, prion protein genetics, biomarkers in cerebrospinal fluid (CSF) and MRI of patients.
Participants
186 Japanese patients with the V180I mutation in PRNP.
Results
Our results indicate that the V180I mutation caused CJD at an older age, with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance compared with classical sporadic CJD with methionine homozygosity at codon 129 of PRNP. Cognitive impairment was the major symptom. Diffuse hyperintensity of the cerebral cortex in diffusion-weighted MRI might be helpful for diagnosis. Owing to the low positivity of PrPSc in the CSF, genetic analysis was often required for a differential diagnosis from slowly progressive dementia.
Conclusions
We conclude that the V180I mutation in PRNP produces a late-developing and slow-developing, less severe form of CJD, whose lesions are uniquely distributed compared with sporadic and other genetic forms of CJD.
doi:10.1136/bmjopen-2014-004968
PMCID: PMC4025468  PMID: 24838726
9.  Associations Between Diabetes, Leanness, and the Risk of Death in the Japanese General Population 
Diabetes Care  2013;36(5):1186-1192.
OBJECTIVE
To examine the BMI-stratified associations between diabetes and the risks of all-cause death, cardiovascular disease (CVD) death, and cancer death.
RESEARCH DESIGN AND METHODS
Using a prospective study with 12 rural Japanese general populations (n = 3,641, mean age, 53.7 years; 33.5% men), we examined the associations between diabetes and the risk of all-cause death, CVD death, and cancer death. We also examined the effects of BMI and age on such associations.
RESULTS
During an average duration of 10.2 years (37,278 person-years), 240 deaths occurred (54 deaths from CVD, 101 from cancer, and 85 from other causes). Cox regression analysis showed leanness (defined as the lowest quartile of entire BMI; mean, 19.5 kg/m2), but not obesity (BMI ≥25 kg/m2), and diabetes were independently associated with an increased risk of all-cause death (hazard ratio [HR] 1.70 and 1.65, respectively; both P < 0.01.). Stratification with cause-specific deaths showed that leanness and obesity were associated with CVD death (HR 3.77 and 2.94, respectively), whereas diabetes was associated with cancer death (HR 1.87; all P < 0.05). The increased risk of all-cause death in diabetes was substantially higher in lean subjects aged <65 years (HR 3.4) or those aged ≥65 years (HR 4.2), whereas the risk in obese diabetes patients was significant only in subjects aged <65 years (HR 2.32; all P < 0.05).
CONCLUSIONS
Among the Japanese general population, diabetes confers an increased risk of all-cause death. Particular attention must be paid to the pronounced high mortality in diabetes accompanied with leanness, regardless of age.
doi:10.2337/dc12-1736
PMCID: PMC3631853  PMID: 23250802
10.  INCIDENCE OF KAWASAKI DISEASE IN NORTHERN EUROPEAN COUNTRIES 
Background
We sought to compare the epidemiologic features of Kawasaki disease (KD) in three Northern European countries and Japan.
Methods
Data were obtained from discharge databases for hospitals in Finland, Norway, and Sweden from 1999–2009 and from nationwide epidemiologic surveys in Japan from 1998–2008. Annual incidence for each country was calculated using regional census data.
Results
During the 11-year period, 1,390 KD patients were recorded in the registries of the three Northern European countries. Average annual incidence rates per 100,000 children less than 5 years were: Finland 11.4, Norway 5.4, and Sweden 7.4. Overall, 86.4% of Japanese KD patients were less than 5 years compared to only 67.8% in the four Northern European countries (p<0.001).
Conclusions
The incidence of KD in Northern Europe was constant over the study period and much lower than in Japan. There was a significant age difference between Northern European and Japanese KD patients that remains unexplained.
doi:10.1111/j.1442-200X.2012.03692.x
PMCID: PMC3467350  PMID: 22726311
coronary artery aneurysm; epidemiology; Kawasaki disease; vasculitis
11.  Graft-related disease progression in dura mater graft-associated Creutzfeldt-Jakob disease: a cross-sectional study 
BMJ Open  2013;3(8):e003400.
Objectives
Details of abnormal prion protein (PrPSc) propagation in the human central nervous system (CNS) are unclear. To assess the spread of PrPSc through the human CNS, we evaluated dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) cases focusing on sites of grafting and dCJD pathological subtypes.
Design
A cross-sectional study.
Setting
nationwide surveillance data of human prion diseases in Japan over the past 12 years were applied for the study.
Participants
Clinical data were obtained from 84 dCJD patients.
Outcome measures
The clinical courses in cases of dCJD were analysed according to the grafting sites (supratentorial and infratentorial groups) and the pathological subtypes (non-plaque and plaque types).
Results
Of the 84 cases of dCJD in this study, 36 (43%) were included in the supratentorial group and 39 (46%) were included in the infratentorial group. As initial manifestations, vertigo (p=0.007) and diplopia (p=0.041) were significantly more frequent in the infratentorial group than in the supratentorial group. During their clinical course, cerebellar signs appeared more frequently in the infratentorial group than in the supratentorial group (p=0.024). In the non-plaque type cases (n=53), the infratentorial group developed vertigo more frequently than the supratentorial group (p=0.017); moreover, cerebellar signs appeared more frequently in the infratentorial group (p=0.014). However, there was no significant difference between groups in the plaque type (n=18).
Conclusions
The high frequency of clinical manifestations related to brain stem and cerebellar dysfunction in the non-plaque type dCJD with infratentorial grafting suggests that PrPSc commonly shows direct propagation into the CNS from contaminated dura mater grafts.
doi:10.1136/bmjopen-2013-003400
PMCID: PMC3753481  PMID: 23975105
Infectious Diseases
12.  Early-life mental disorders and adult household income in the World Mental Health Surveys 
Biological Psychiatry  2012;72(3):228-237.
Background
Better information on the human capital costs of early-onset mental disorders could increase sensitivity of policy-makers to the value of expanding initiatives for early detection-treatment. Data are presented on one important aspect of these costs: the associations of early-onset mental disorders with adult household income.
Methods
Data come from the WHO World Mental Health (WMH) Surveys in eleven high income, five upper-middle income, and six low/lower-middle income countries. Information about 15 lifetime DSM-IV mental disorders as of age of completing education, retrospectively assessed with the WHO Composite International Diagnostic Interview, was used to predict current household income among respondents ages 18-64 (n = 37,741) controlling for level of education. Gross associations were decomposed to evaluate mediating effects through major components of household income.
Results
Early-onset mental disorders are associated with significantly reduced household income in high and upper-middle income countries but not low/lower-middle income countries, with associations consistently stronger among women than men. Total associations are largely due to low personal earnings (increased unemployment, decreased earnings among the employed) and spouse earnings (decreased probabilities of marriage and, if married, spouse employment and low earnings of employed spouses). Individual-level effect sizes are equivalent to 16-33% of median within-country household income, while population-level effect sizes are in the range 1.0-1.4% of Gross Household Income.
Conclusions
Early mental disorders are associated with substantial decrements in income net of education at both individual and societal levels. Policy-makers should take these associations into consideration in making healthcare research and treatment resource allocation decisions.
doi:10.1016/j.biopsych.2012.03.009
PMCID: PMC3402018  PMID: 22521149
epidemiology; mental disorders; early-onset; income; cross-national; WHO World Mental Health (WMH)
13.  Relationships between Clinicopathological Features and Cerebrospinal Fluid Biomarkers in Japanese Patients with Genetic Prion Diseases 
PLoS ONE  2013;8(3):e60003.
A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrPSc) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrPSc was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrPSc in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrPSc in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrPSc. The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.
doi:10.1371/journal.pone.0060003
PMCID: PMC3610658  PMID: 23555862
14.  Cost-effectiveness of a tailored intervention designed to increase breast cancer screening among a non-adherent population: a randomized controlled trial 
BMC Public Health  2012;12:760.
Background
Although the percentage of women who initiate breast cancer screening is rising, the rate of continued adherence is poor. The purpose of this study was to examine the effectiveness and cost-effectiveness of a tailored print intervention compared with a non-tailored print intervention for increasing the breast cancer screening rate among a non-adherent population.
Methods
In total, 1859 participants aged 51–59 years (except those aged 55 years) were recruited from a Japanese urban community setting. Participants were randomly assigned to receive either a tailored print reminder (tailored intervention group) or non-tailored print reminder (non-tailored intervention group). The primary outcome was improvement in the breast cancer screening rate. The screening rates and cost-effectiveness were examined for each treatment group (tailored vs. non-tailored) and each intervention subgroup during a follow-up period of five months. All analyses followed the intention-to-treat principle.
Results
The number of women who underwent a screening mammogram following the reminder was 277 (19.9%) in the tailored reminder group and 27 (5.8%) in the non-tailored reminder group. A logistic regression model revealed that the odds of a woman who received a tailored print reminder undergoing mammography was 4.02 times those of a women who had received a non-tailored print reminder (95% confidence interval, 2.67–6.06). The cost of one mammography screening increase was 2,544 JPY or 30 USD in the tailored intervention group and 4,366 JPY or 52 USD in the non-tailored intervention group.
Conclusions
Providing a tailored print reminder was an effective and cost-effective strategy for improving breast cancer screening rates among non-adherent women.
doi:10.1186/1471-2458-12-760
PMCID: PMC3495210  PMID: 22962858
Mammography; Tailored intervention; Cancer worry; Cost-effectiveness; Non-adherent population
15.  Diagnostic Criteria, Clinical Features, and Incidence of Thyroid Storm Based on Nationwide Surveys 
Thyroid  2012;22(7):661-679.
Background
Thyroid storm (TS) is life threatening. Its incidence is poorly defined, few series are available, and population-based diagnostic criteria have not been established. We surveyed TS in Japan, defined its characteristics, and formulated diagnostic criteria, FINAL-CRITERIA1 and FINAL-CRITERIA2, for two grades of TS, TS1, and TS2 respectively.
Methods
We first developed diagnostic criteria based on 99 patients in the literature and 7 of our patients (LIT-CRITERIA1 for TS1 and LIT-CRITERIA2 for TS2). Thyrotoxicosis was a prerequisite for TS1 and TS2 as well as for combinations of the central nervous system manifestations, fever, tachycardia, congestive heart failure (CHF), and gastrointestinal (GI)/hepatic disturbances. We then conducted initial and follow-up surveys from 2004 through 2008, targeting all hospitals in Japan, with an eight-layered random extraction selection process to obtain and verify information on patients who met LIT-CRITERIA1 and LIT-CRITERIA2.
Results
We identified 282 patients with TS1 and 74 patients with TS2. Based on these data and information from the Ministry of Health, Labor, and Welfare of Japan, we estimated the incidence of TS in hospitalized patients in Japan to be 0.20 per 100,000 per year. Serum-free thyroxine and free triiodothyroine concentrations were similar among patients with TS in the literature, Japanese patients with TS1 or TS2, and a group of patients with thyrotoxicosis without TS (Tox-NoTS). The mortality rate was 11.0% in TS1, 9.5% in TS2, and 0% in Tox-NoTS patients. Multiple organ failure was the most common cause of death in TS1 and TS2, followed by CHF, respiratory failure, arrhythmia, disseminated intravascular coagulation, GI perforation, hypoxic brain syndrome, and sepsis. Glasgow Coma Scale results and blood urea nitrogen (BUN) were associated with irreversible damages in 22 survivors. The only change in our final diagnostic criteria for TS as compared with our initial criteria related to serum bilirubin concentration >3 mg/dL.
Conclusions
TS is still a life-threatening disorder with more than 10% mortality in Japan. We present newly formulated diagnostic criteria for TS and clarify its clinical features, prognosis, and incidence based on nationwide surveys in Japan. This information will help diagnose TS and in understanding the factors contributing to mortality and irreversible complications.
doi:10.1089/thy.2011.0334
PMCID: PMC3387770  PMID: 22690898
16.  Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment 
Emerging Infectious Diseases  2012;18(6):901-907.
The book on iatrogenic Creutzfeldt-Jakob disease (CJD) in humans is almost closed. This form of CJD transmission via medical misadventures was first detected in 1974. Today, only occasional CJD cases with exceptionally long incubation periods still appear. The main sources of the largest outbreaks were tissues from human cadavers with unsuspected CJD that were used for dura mater grafts and growth hormone extracts. A few additional cases resulted from neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infections from blood transfusions. Although the final solution to the problem of iatrogenic CJD is still not available (a laboratory test to identify potential donors who harbor the infectious agent), certain other measures have worked well: applying special sterilization of penetrating surgical instruments, reducing the infectious potential of donor blood and tissue, and excluding donors known to have higher than normal risk for CJD.
doi:10.3201/eid1806.120116
PMCID: PMC3358170  PMID: 22607808
Creutzfeldt-Jakob disease; dura mater; human growth hormone; iatrogenic disease; PRNP codon 129; variant Creutzfeldt-Jakob disease; prions and related diseases
17.  Epidemiologic Features of Kawasaki Disease in Japan: Results of the 2009–2010 Nationwide Survey 
Journal of Epidemiology  2012;22(3):216-221.
Background
Although the number of patients and incidence rate of Kawasaki disease (KD) are increasing in Japan, the most recent epidemiologic features of KD are not known.
Methods
The 21st nationwide survey of KD was conducted in 2011 and included patients treated for the disease in 2009 and 2010. Hospitals specializing in pediatrics, and hospitals with a total of 100 or more beds and a pediatric department, were asked to report all patients with KD during the 2 survey years.
Results
A total of 1445 departments and hospitals reported 23 730 KD patients (10 975 in 2009 and 12 755 in 2010): 13 515 boys and 10 215 girls. The annual incidence rates were 206.2 and 239.6 per 100 000 children aged 0 to 4 years in 2009 and 2010, respectively; the 2010 rate was the highest ever reported in Japan. Monthly number of patients peaked during winter to spring months; lower peaks were noted during summer months. However, the seasonal patterns in 2009 and 2010 differed from those of previous years. The age-specific incidence rate had a monomodal distribution, with a peak during the latter half of the year of birth. The prevalences of cardiac lesions during acute KD and cardiac sequelae were higher among infants and older age groups. Despite a decrease in prevalence, the proportion of patients with giant coronary aneurysms—the most severe sequela of KD—did not substantially decrease.
Conclusions
The incidence rate and number of patients with KD continue to increase in Japan.
doi:10.2188/jea.JE20110126
PMCID: PMC3798622  PMID: 22447211
mucocutaneous lymph node syndrome; incidence; cardiovascular diseases; immunoglobulin, intravenous; epidemiology
18.  Duration of Prion Disease is Longer in Japan Than in Other Countries 
Journal of Epidemiology  2011;21(4):255-262.
Background
Prion diseases are untreatable, progressive, and fatal brain disorders that occur worldwide, and the annual incidence rate is approximately 1 case per 1 million people. The duration of these diseases in Japan is unclear.
Methods
Based on data from 1 April 1999 through 4 September 2008 provided by the Japanese Creutzfeldt-Jakob disease (CJD) surveillance program, we analyzed disease duration and its relationship with clinical features. Duration was assumed to be the time from disease onset to death.
Results
Evaluation by the surveillance committee indicated that during the observed period 1128 individuals received a diagnosis of prion disease and were registered in the surveillance program. Mean disease duration in the 855 patients who died was 17.4 months. Overall, 46.0% of patients died within 1 year and 77.2% died in less than 2 years. Among those with sporadic Creutzfeldt-Jakob disease, which represented 77.0% of cases, mean disease duration was 15.7 months, while that of patients surveyed by the European Creutzfeldt Jakob Disease Surveillance Network (EUROCJD) was only 5 months.
Conclusions
Disease duration among Japanese with prion diseases was much longer than that of patients in Western countries conducting surveillance of prion diseases. This finding suggests that the characteristics of the system for providing life-sustaining treatment for patients with fatal, progressive diseases in Japan are related to the longer duration of these illnesses.
doi:10.2188/jea.JE20100085
PMCID: PMC3899417  PMID: 21628843
prion disease; Creutzfeldt-Jakob Syndrome; epidemiology; disease duration; Japan
19.  Kawasaki Disease in Mongolia: Results From 2 Nationwide Retrospective Surveys, 1996–2008 
Journal of Epidemiology  2011;21(4):293-298.
Background
Kawasaki disease (KD) has been reported in many countries. However, the incidence of KD in Mongolia is not known. This is the first report of incident cases of KD in Mongolia, which were identified using data from 2 nationwide surveys.
Methods
Two nationwide retrospective surveys were conducted: medical histories were collected from patients aged 0 to 16 years who were hospitalized countrywide between 1996 and 2008. Hospital records for these patients were also reviewed. Nationwide training seminars on KD were conducted before each survey.
Results
For the nationwide surveys, the participation rates among all hospitals with pediatric wards were 97% and 94%. Inpatient medical histories from 1996 through 2008 were reviewed, and, among children younger than 16 years, 9 patients with KD were investigated. The age of KD patients ranged from 1.4 to 14 years; 7 of 9 patients were male. Six (67%) patients fulfilled all 6 clinical diagnostic criteria; the other 3 (33%) were defined as having KD based on the presence of 5 such criteria. Fever persisting 5 or more days, bilateral conjunctival congestion, and changes of the lips and oral cavity were the most common symptoms, and cervical lymphadenopathy was the least common symptom. Cardiac sequelae developed in 5 of the patients, 4 of whom were older than 10 years.
Conclusions
The results of these nationwide surveys reveal that KD cases do exist in Mongolia. However, knowledge of KD among Mongolian pediatricians is likely to be poor. Thus, there is a need to augment their understanding to improve management of KD patients. Further studies are crucial to clarify the epidemiologic characteristics of KD in Mongolia.
doi:10.2188/jea.JE20100144
PMCID: PMC3899422  PMID: 21691035
mucocutaneous lymph node syndrome; nationwide survey; Mongolia; children
20.  Frequency of Citrus Fruit Intake Is Associated With the Incidence of Cardiovascular Disease: The Jichi Medical School Cohort Study 
Journal of Epidemiology  2011;21(3):169-175.
Background
It has been reported that fruit intake protects against cardiovascular disease (CVD). However, most of the relevant studies were conducted in Western countries, and only a few investigated Japanese populations. The present cohort study assessed the effect of citrus fruit intake on the incidence of CVD and its subtypes in a Japanese population.
Methods
A baseline examination consisting of physical and blood examinations and a self-administered questionnaire was conducted during the period from April 1992 through July 1995. Dietary habits were assessed using a food frequency questionnaire that was divided into 5 categories. Citrus fruit was examined separately due to its frequent consumption by the general Japanese population. Using the Cox proportional hazards model, data from 10 623 participants (4147 men, 6476 women) who had no history of CVD or carcinoma were analyzed to assess the association between frequency of citrus fruit intake and CVD incidence.
Results
Frequent intake of citrus fruit was associated with a lower incidence of CVD: the hazard ratio for almost daily intake versus infrequent intake of citrus fruit was 0.57 (95% confidence interval: 0.33–1.01, P for trend = 0.04) in men and 0.51 (0.29–0.88, P for trend = 0.02) in women. Frequent intake of citrus fruit was also associated with lower incidences of both all stroke and cerebral infarction, but not hemorrhagic stroke or myocardial infarction.
Conclusions
Frequent intake of citrus fruit may reduce the incidence of CVD, especially cerebral infarction, in men and women.
doi:10.2188/jea.JE20100084
PMCID: PMC3899405  PMID: 21389640
citrus fruit; cardiovascular disease; cerebral infarction; cohort studies; Japan
21.  Distribution of Birth Weight for Gestational Age in Japanese Infants Delivered by Cesarean Section 
Journal of Epidemiology  2011;21(3):217-222.
Background
Neonatal anthropometric charts of the distribution of measurements, mainly birth weight, taken at different gestational ages are widely used by obstetricians and pediatricians. However, the relationship between delivery mode and neonatal anthropometric data has not been investigated in Japan or other countries.
Methods
The subjects were selected from the registration database of the Japan Society of Obstetrics and Gynecology (2003–2005). Tenth centile, median, and 90th centile of birth weight by sex, birth order, and delivery mode were observed by gestational age from 22 to 42 weeks among eligible singleton births.
Results
After excluding 248 outliers and 5243 births that did not satisfy the inclusion criteria, 144 980 births were included in the analysis. The distribution of 10th centile curves was skewed toward lower birth weights during the preterm period among both first live births and second and later live births delivered by cesarean section. More than 40% of both male and female live births were delivered by cesarean section at 37 weeks or earlier.
Conclusions
The large proportion of cesarean sections influenced the skewness of the birth weight distribution in the preterm period.
doi:10.2188/jea.JE20100123
PMCID: PMC3899412  PMID: 21478642
birth weight; distribution; gestational age; cesarean section; preterm
22.  Evaluating the drug use “gateway” theory using cross-national data: Consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys* 
Drug and alcohol dependence  2010;108(1-2):84-97.
Background
It is unclear whether the normative sequence of drug use initiation, beginning with tobacco and alcohol, progressing to cannabis and then other illicit drugs, is due to causal effects of specific earlier drug use promoting progression, or to influences of other variables such as drug availability and attitudes. One way to investigate this is to see whether risk of later drug use in the sequence, conditional on use of drugs earlier in the sequence, changes according to time-space variation in use prevalence. We compared patterns and order of initiation of alcohol, tobacco, cannabis, and other illicit drug use across 17 countries with a wide range of drug use prevalence.
Method
Analyses used data from World Health Organization (WHO) World Mental Health (WMH) Surveys, a series of parallel community epidemiological surveys using the same instruments and field procedures carried out in 17 countries throughout the world.
Results
Initiation of “gateway” substances (i.e. alcohol, tobacco and cannabis) was differentially associated with subsequent onset of other illicit drug use based on background prevalence of gateway substance use. Cross-country differences in substance use prevalence also corresponded to differences in the likelihood of individuals reporting a non- normative sequence of substance initiation.
Conclusion
These results suggest the “gateway” pattern at least partially reflects unmeasured common causes rather than causal effects of specific drugs on subsequent use of others. This implies that successful efforts to prevent use of specific “gateway” drugs may not in themselves lead to major reductions in the use of later drugs.
doi:10.1016/j.drugalcdep.2009.12.001
PMCID: PMC2835832  PMID: 20060657
tobacco; alcohol; illicit drugs; gateway; WHO World Mental Health Surveys
23.  Characteristics and Validity of a Web-Based Kawasaki Disease Surveillance System in Japan 
Journal of Epidemiology  2010;20(6):429-432.
Background
Although regular nationwide surveys of Kawasaki disease (KD) are conducted in Japan, there is no system for detecting the real-time epidemic status of this disease.
Methods
A web-based surveillance system for KD was developed. After consideration of the number of patients reported by prefecture to the 19th nationwide survey, 355 pediatric departments were asked to participate in the surveillance, and 225 agreed. Since January 2008, pediatricians in these 225 hospitals have reported KD patient data immediately after diagnosis. The daily numbers of patients are available to the public via the internet at http://www.kawasaki-disease.net/kawasakidata/. The validity of the data in 2008 was evaluated using the Japanese 20th nationwide survey of KD as the gold standard.
Results
A total of 3376 patients were reported to the web-based surveillance system from the 1st week through 52nd week of 2008. The number of patients reported to the nationwide survey during the same period was 11 680: a total of 4950 patients from the hospitals participating in the web-based surveillance and 6730 from other hospitals. The epidemic curves were similar, and the correlation coefficient between the web-based surveillance and the total numbers in the nationwide survey was 0.806 (P < 0.01).
Conclusions
The web-based surveillance system for Kawasaki disease in Japan demonstrated good validity.
doi:10.2188/jea.JE20100006
PMCID: PMC3900818  PMID: 20814164
mucocutaneous lymph node syndrome; incidence; epidemiology; sentinel surveillance; internet
24.  Relationship between the Cumulative Incidence of Kawasaki Disease and the Prevalence of Electrocardiographic Abnormalities in Birth-Year Cohorts 
Journal of Epidemiology  2010;20(6):453-459.
Background
Kawasaki disease (KD) causes systemic vasculitis and coronary aneurysms. It frequently results in electrocardiographic (ECG) abnormalities of short duration. Cardiac sequelae persist beyond the acute stage in a few patients. There are many areas to be investigated concerning the effects on the vascular system of patients suffering from KD and its sequelae.
Methods
The cumulative incidences of KD and its cardiac sequelae were calculated in birth-year cohorts, using data obtained from KD nationwide surveys. The results were compared with the prevalence of ECG abnormalities detected in cardiac examinations conducted at primary and secondary schools for each birth-year cohort. This comparison allowed observation of relationships in these trends for each birth-year cohort.
Results
The cumulative incidence of late-stage cardiac sequelae gradually declined. However, there were increases in the cumulative incidence of ECG abnormalities and in the cumulative incidences of KD and acute-stage cardiac disorders related to KD.
Conclusions
The results suggest that even among children without late cardiac sequelae, KD can have a persistent effect on the cardiovascular system. It thus appears necessary to extend clinical observation of children with a history of KD, even if they developed only acute-stage cardiac lesions.
doi:10.2188/jea.JE20090159
PMCID: PMC3900822  PMID: 20827035
Kawasaki disease; mucocutaneous lymph node syndrome; cumulative incidence; birth-year cohort; prevalence of electrocardiographic abnormalities
25.  Epidemiologic Features of Kawasaki Disease in Japan: Results of the 2007–2008 Nationwide Survey 
Journal of Epidemiology  2010;20(4):302-307.
Background
The most recent epidemiologic features of Kawasaki disease (KD) are unknown.
Methods
The 20th nationwide survey of KD was conducted in 2009, and included patients treated for the disease in 2007 and 2008. Hospitals specializing in pediatrics, and hospitals with pediatric departments and 100 or more beds, were asked to report all patients with KD during the 2 survey years.
Results
From a total of 1540 departments and hospitals, 23 337 patients (11 581 in 2007 and 11 756 in 2008) were reported: 13 523 boys and 9814 girls. The annual incidence rates were 215.3 and 218.6 per 100 000 children aged 0–4 years in 2007 and 2008, respectively. These were the highest annual KD incidence rates ever recorded in Japan. The monthly number of patients peaked during the winter months; smaller increases were noted in the summer months. The age-specific incidence rate showed a monomodal distribution with a peak at age 9–11 months. The prevalences of both cardiac lesions during the acute phase of the disease and cardiac sequelae were higher among infants and older age groups.
Conclusions
The incidence rate and number of patients with KD in Japan continue to increase.
doi:10.2188/jea.JE20090180
PMCID: PMC3900790  PMID: 20530917
mucocutaneous lymph node syndrome; incidence; cardiovascular diseases; immunoglobulin, intravenous; epidemiology

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