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Background: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high‐risk mature B‐cell non‐Hodgkin lymphoma (B‐NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. Methods: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single‐arm multicenter trial. Results: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B‐cell lymphoma, and aggressive mature B‐NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow‐up period was 47.5 months. Three‐year event‐free survival and overall survival were 97.7% (95% confidence interval, 84.9–99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B‐cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non‐hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre‐phase treatment, with a frequency of 54.5%. Conclusion: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high‐risk mature B‐NHL was observed in Japan. [ABSTRACT FROM AUTHOR]

We investigated the applicability of Ion Beam Induced Luminescence (IBIL) analysis for identifying biological components in sequentially collected airborne particulate matter (PM) samples obtained using the automated sampler. A series of micro-IBIL spectroscopies were performed on a PTFE (polytetrafluoroethylene) membrane tape filter from the Atmospheric Environmental Regional Observation System (AEROS) during a highly concentrated air pollution event on 26–27 March 2020, collected at Ota, Japan (36.290°n, 139.381°e) using an external 3 MeV proton microprobe. IBIL at typical wavelengths associated with organic compounds such as NADH and riboflavin were identified through the series of IBIL analyses, which is a key factor for identifying existence of organic pollutions, or bioaerosols. The decay times of the IBIL indicate that the peak measured is due to organic compounds rather than inorganic particles or ambient substances. These results suggest that micro-IBIL spectroscopy can be used to identify bioaerosols in hourly collected AEROS PTFE membrane tape filters taken from the atmosphere. [ABSTRACT FROM AUTHOR]

The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of the three major criteria listed for the diagnosis of polycythemia vera (PV) in the 2017 World Health Organization Classification. However, a nationwide study has not yet been conducted in Japan since the discovery of JAK2 mutations. Therefore, the Japanese Society of Hematology (JSH) retrospectively analyzed the clinical characteristics of 596 Japanese patients with PV diagnosed between April 2005 and March 2018. Among the 473 patients with complete data on JAK2 mutations available, 446 (94.3%) and 10 (2.1%) were positive for the JAK2 V617F and JAK2 exon 12 mutations, respectively. During a median follow-up of 46 months (range: 0-179 months), 47 (7.9%) deaths occurred. The major causes of death were secondary malignancies (23.4%), acute leukemia (12.8%), non-leukemic progressive disease (10.6%) and thrombotic (6.4%) and hemorrhagic complications (6.4%). Thrombotic and hemorrhagic events occurred during the clinical course in 4.0% (n = 24) and 3.5% (n = 21) of patients, respectively. These results show that the international PV prognostic score (age, venous thrombosis and leukocytosis) is applicable to Japanese patients with PV. [ABSTRACT FROM AUTHOR]

To determine whether increasing thrombectomy-capable hospitals with moderate comprehensive stroke center (CSC) capabilities is a valid alternative to centralization of those with high CSC capabilities. This retrospective, nationwide, observational study used data from the J-ASPECT database linked to national emergency medical service (EMS) records, captured during 2013–2016. We compared the influence of mechanical thrombectomy (MT) use, the CSC score, and the total EMS response time on the modified Rankin Scale score at discharge among patients with acute ischemic stroke transported by ambulance, in phases I (2013–2014, 1461 patients) and II (2015–2016, 3259 patients). We used ordinal logistic regression analyses to analyze outcomes. From phase I to II, MTs increased from 2.7 to 5.5%, and full-time endovascular physicians per hospital decreased. The CSC score and EMS response time remained unchanged. In phase I, higher CSC scores were associated with better outcomes (1-point increase, odds ratio [95% confidence interval]: 0.951 [0.915–0.989]) and longer EMS response time was associated with worse outcomes (1-min increase, 1.007 [1.001–1.013]). In phase II, neither influenced the outcomes. During the transitional shortage of thrombectomy-capable hospitals, increasing hospitals with moderate CSC scores may increase nationwide access to MT, improving outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Gamification, the use of game design elements in nongame contexts, in combination with insights from behavioral economics, has been applied increasingly to behavior change interventions. However, little is known about the effectiveness or scalability of this approach, especially in the long term. We tested a large-scale smartphone-based intervention to encourage physical activity among Japanese baseball fans using gamification techniques that leveraged fandom and interteam competition inherent in sports. Methods : A quasi-experimental study was conducted among fans of the Japanese Pacific League. The app, Pa-League Walk, included gamification elements, such as competition between opposing teams' fans based on total daily step counts on game days (>60,000 free downloads since March 2016). We analyzed daily steps of 20,052 app users, supplemented by online survey data of 274 users and 613 matched controls. Difference-in-differences estimators evaluated change in daily steps before and after app installation in users versus matched controls. Results : Users' daily steps increased by 574 (95% confidence interval, 83-1064) steps 3 months after installation, compared with controls. The increase was maintained for up to 9 months (559 (99-1018) more steps per day vs baseline), attenuating over a longer follow-up. Positive effect modification was found by high-frequency of the app use (P < 0.001) but not by other covariables (P >= 0.14) such as education or income. Days with 10,000-step achievement increased from 24.4% to 27.5% after the additional introduction of incentives (digital player photographs; P < 0.001). Conclusions : Using existing fandom and solidarity, the gamification app increased physical activity at scale among baseball fans, including people with lower socioeconomic status underrepresented in traditional health programs. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) collected hourly by an automated sampling unit of the Atmospheric Environmental Regional Observation System (AEROS) was characterized by external micro-particle-induced X-ray emission (PIXE) analysis and imaging. Micro-PIXE analysis revealed the overall elemental composition and differences in the elemental composition ratios of PM 2.5 and PM 2.5-10 collected as individual spots on Teflon tape filters from the unit, and the blank Teflon tape showed a clean background. Moreover, micro-PIXE imaging visualized regions with different elemental compositions in PM 2.5 and PM 2.5-10. Accumulation of PM 2.5 particles was found frequently on tape filters which accounted approximately for 70% of particular elemental composition including heavy metals like iron, compared to that from whole area. The results suggest that PIXE effectively reveals elemental composition of hourly-collected PM by AEROS system for futuristic application for source apportionment of those over Japan. [ABSTRACT FROM AUTHOR]

Objective: We sought to examine whether the effect of treatment modality and drugs for cerebral vasospasm on clinical outcomes differs between elderly and non-elderly subarachnoid hemorrhage (SAH) patients in Japan. Methods: We analyzed the J-ASPECT Study Diagnosis Procedure Combination database (n = 17,343) that underwent clipping or coiling between 2010 and 2014 in 579 hospitals. We stratified patients into two groups according to their age (elderly [≥75 years old], n = 3,885; non-elderly, n = 13,458). We analyzed the effect of treatment modality and anti-vasospasm agents (fasudil hydrochloride, ozagrel sodium, cilostazol, statin, eicosapentaenoic acid [EPA], and edaravone) on in-hospital poor outcomes (mRS 3–6 at discharge) and mortality using multivariable analysis. Results: The elderly patients were more likely to be female, have impaired levels of consciousness and comorbidity, and less likely to be treated with clipping and anti-vasospasm agents, except for ozagrel sodium and statin. In-hospital mortality and poor outcomes were higher in the elderly (15.8% vs. 8.5%, 71.7% vs. 36.5%). Coiling was associated with higher mortality (odds ratio 1.43, 95% confidence interval 1.2–1.7) despite a lower proportion of poor outcomes (0.84, 0.75–0.94) in the non-elderly, in contrast to no effect on clinical outcomes in the elderly. A comparable effect of anti-vasospasm agents on mortality was observed between non-elderly and elderly for fasudil hydrochloride (non-elderly: 0.20, 0.17–0.24), statin (0.63, 0.50–0.79), ozagrel sodium (0.72, 0.60–0.86), and cilostazol (0.63, 0.51–0.77). Poor outcomes were inversely associated with fasudil hydrochloride (0.59, 0.51–0.68), statin (0.84, 0.75–0.94), and EPA (0.83, 0.72–0.94) use in the non-elderly. No effect of these agents on poor outcomes was observed in the elderly. Conclusions: In contrast to the non-elderly, no effect of treatment modality on clinical outcomes were observed in the elderly. A comparable effect of anti-vasospasm agents was observed on mortality, but not on functional outcomes, between the non-elderly and elderly. [ABSTRACT FROM AUTHOR]

Background: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances.Methods: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis.Results: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs.Conclusions: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine the association between accessibility to cardiovascular emergency centers and cardiovascular mortality in Japan.Design: A semi-ecological study.Setting: Three databases were generated: accessibility to emergency cardiovascular centers, population records and death records.Main Outcome Measures: The standardized mortality ratio (SMR) for cardiovascular disease was adjusted by age and sex. Accessibility was represented by transfer time, number of cardiovascular emergency hospitals, and the proportion of habitable areas. Combinations of the three were divided into Categories 1-8 from the worst to the best, and the association with SMR was analyzed.Results: There were 1998 cardiovascular emergency hospitals. The median of crude mortality was 0.16%. The median SMR of the reference Category 8 (transfer time <30 min and habitable area ≥50% with cardiovascular emergency hospitals) was 0.96, but that of the low accessibility Category 1 (transfer time ≥30 min and habitable area <50% without cardiovascular emergency hospitals) was 1.10. The SMR of accessibility Category 1 : Category 8 was 1.18 (95% confidence interval: 1.14-1.21).Conclusions: Decreased accessibility to cardiovascular emergency hospitals was associated with increased SMR. Areas with less accessibility and higher cardiovascular mortality were characterized by geographical variability in Japan. [ABSTRACT FROM AUTHOR]

Objective: To assess sex-specific differences regarding use of conventional risks and coronary artery calcification (CAC) to detect coronary artery disease (CAD) using coronary CT angiography (CCTA).Methods: The Nationwide Gender-specific Atherosclerosis Determinants Estimation and Ischemic Cardiovascular Disease Prospective Cohort study is a prospective, multicentre, nationwide cohort study. Candidates with suspected CAD aged 50-74 years enrolled from 2008 to 2012. The outcome was obstructive CAD defined as any stenosis ≥50% by CCTA. We constructed logistic regression models for obstructive CAD adjusted for conventional risks (clinical model) and CAC score. Improvement in discrimination beyond risks was assessed by C-statistic; net reclassification index (NRI) for CAD probability of low (<30%), intermediate (30%-60%) and high (≥60%); and risk stratification capacity.Results: Among 991 patients (456 women, 535 men; 65.2 vs 64.4 years old), women had lower CAC scores (median, 4 vs 60) and lower CAD prevalence (21.7% vs 37.0%) than men. CAC significantly improved model discrimination compared with clinical model in both sexes (0.66-0.79 in women vs 0.61-0.83 in men). The NRI for women was 0.33, which was much lower than that for men (0.71). Adding CAC to clinical model had a larger benefit in terms of moving an additional 43.3% of men to the most determinant categories (high or low risk) compared with -1.4% of women.Conclusions: The addition of CAC to a prediction model based on conventional variables significantly improved the classification of risk in suspected patients with CAD, with sex differences influencing the predictive ability.Trial Registration Number: UMIN-CTR Clinical Trial: UMIN000001577. [ABSTRACT FROM AUTHOR]

Abstract: Background: Long‐term follow up in adulthood after childhood cancer therapy is particularly important because of the risk of late effects, and information on the rate of continuing hospital visits by childhood cancer survivors (CCS) is also important for the planning of studies on the risk of late effects. Methods: The rate of continuing hospital visits (“long‐term follow up”) in 1,252 cases registered in the multicenter Japan Association of Childhood Leukemia Study on Acute Lymphoblastic Leukemia (JACLS ALL‐02) was investigated using data from its electronic data capture (EDC) system, including case number, date of diagnosis, date of therapy completion, date of birth, sex, survival or death, date of death, date of last outcome confirmation, and facility code. EDC entries of confirmed survival or death during the 2 years preceding the data lock represented continuing visitors, and the number of those cases, divided by the total number of cases (excluding cases of confirmation of death prior to those 2 years), was calculated as the proportion of continuing visitors (PCV). Results: The PCV for survivors of childhood acute lymphoblastic leukemia was found to decline over time from diagnosis. For subjects aged 21–29 years who were ≥9 years from diagnosis, PCV was approximately 30% overall, representing 23.5% for men and 41.8% for women, thus indicating a gender difference. Conclusions: Further studies may be necessary to assess whether CCS who stopped visiting childhood cancer treatment facilities, actually received therapeutic intervention or appropriate screening for late effects as adults. [ABSTRACT FROM AUTHOR]

Conclusion: It is important to suppress lymph node recurrence and distant metastasis to achieve better survival of advanced laryngeal cancer, especially supraglottic cancer. Objective: The therapeutic outcomes of 33 cases with advanced laryngeal cancer treated at Kyoto University Hospital between 2000 and 2008 were reviewed. Methods: Thirty-one males and two females were involved. Their ages ranged from 49 to 81 years (average 65.6 years). All tumors were squamous cell carcinoma, arising at the glottis in 21 cases and the supraglottis in 12 cases. Most glottic cancers (90.5%) and supraglottic cancers (83.3%) were classified as T3 or T4. Total laryngectomy with neck dissection was performed in the treatment of T3 or T4 cases. Two cases of T2 cancers were treated by radiotherapy (66-72 Gy) with neck dissection, and one case of T2 cancer was treated by radiotherapy (66 Gy). Partial laryngectomy with neck dissection was performed in one T3 case. Results: Five-year overall survival rates for stage III of glottic cancer, stage IV of glottic cancer, stage III of supraglottic cancer, and stage IV of supraglottic cancer were 100%, 40.9%, 100%, and 24.2%, respectively. Five-year disease-specific survival rates for stage III of glottic cancer, stage IV of glottic cancer, stage III of supraglottic cancer, and stage IV of supraglottic cancer were 100%, 56.3%, 100%, and 28.1%, respectively. No local recurrence occurred. Regional lymph node recurrence occurred in two cases- one patient with glottic cancer and one with supraglottic cancer. Both of them died of disease despite undergoing chemotherapy. One case initially had lung metastasis, and post-treatment distant metastasis occurred in the lung in four cases, in the skin in one, and in multiple organs in one case. [ABSTRACT FROM AUTHOR]

Conclusions: Once-daily radiotherapy for stage I glottic cancer and hyperfractionated radiotherapy for stage II glottic cancer achieved satisfactory results in terms of prognosis and laryngeal preservation. The treatment strategy for stage II glottal cancer with subglottal invasion needs to be reconsidered to further improve the outcome. Objectives: Although early glottic carcinomas are highly curable by radiation therapy, the laryngeal preservation rate is not always sufficient. We reviewed the stage I/II glottal cancer treated in our institute during a recent 15-year period to improve the outcome and prognosis. Methods: In all, 113 cases of stage I/II glottic cancer (81 stage I cases and 32 stage II cases) were treated in Kyoto University hospital from 1994 to 2008. In 81 cases with stage I glottic cancer, radiation was performed for 66 cases, transoral laser excision (TLE) was performed for 14 cases, and hyperfractionated radiotherapy was done for one case. Among 32 cases with stage II glottic cancer, 24 cases were treated with hyperfractionated radiotherapy, 6 cases were treated with radiation, and one case with partial laryngectomy. Total laryngectomy was performed for one patient who suffered mixed connective tissue disease. Kaplan-Meier estimates were used for the analysis of survival rate and laryngeal preservation rate. Results: The 5-year overall survival rates were 88.4% in stage I cases and 89.1% in stage II cases. The 5-year disease-specific survival rates were 100% in stage I cases and 93% in stage II cases. The 5-year laryngeal preservation rates were 99% in stage I cases and 90% in stage II cases. Two cases of stage II glottal cancer with subglottal invasion failed to be controlled and the patients died from local recurrence and mediastinum lymph node metastasis, respectively. [ABSTRACT FROM AUTHOR]

Conclusions: It is suggested that radiotherapy might be the first choice for stage I/II hypopharyngeal cancer, and that adjuvant treatment might be necessary for stage II patients to prevent distant metastasis. Objectives: To update the therapeutic outcome of early hypopharyngeal cancer. Methods: Twenty-eight patients with stage I/II hypopharyngeal cancer (8 in stage I, 20 in stage II) were treated at Kyoto University Hospital between 1995 and 2007. Of 8 cases in stage I, radiotherapy was applied for 4 cases, and surgical treatment for another 4, while 13 of 20 cases in stage II underwent radiotherapy and the remaining 7 cases underwent surgery. Results: The 5-year cumulative disease-specific survival and larynx preservation rates were 74.6% and 73.2%, respectively. Recurrent tumors were found in two cases in stage I treated by surgery and in five cases in stage II treated with radiotherapy. Two of five recurrent cases in stage II were rescued by salvage surgery. Distant metastasis to the lung appeared in two cases in stage II after initial treatment. [ABSTRACT FROM AUTHOR]

Conclusions: The prognosis of patients was related to the initial stage at diagnosis. These results suggest that early diagnosis and treatment are the most important factors to improve the prognosis in oral cancer patients. Adjuvant treatment is also warranted to improve locoregional control of advanced cases. Objectives: To update the therapeutic outcome of oral cancer. Methods: In all, 129 cases with oral cancer were treated at Kyoto University Hospital during 2000-2008. Surgery with/without irradiation was performed for 34 cases in stage I, 27 in stage II, 15 in stage III, 42 in stage IVa, and 1 case in stage IVb. Brachytherapy was performed for three cases in stage II. Definitive radiotherapy was performed for three cases in stage III and five cases in stage IV. The follow-up period varied from 12 to 96 months (mean 30 months). Results: The 5-year cumulative overall and disease-specific survival (DSS) rates were 74.5% and 75.3%. DSS was 86.2% in stage I, 91.6% in stage II, 70.7% in stage III, 60.2% in stage IVa, and 0% in stage IVb. DSS shows worse prognosis with advanced nodal status. Locoregional recurrence occurred in 32 of 129 cases, including local recurrence in 8 cases, nodal recurrence in 18, retropharyngeal node metastasis in 1, and local and nodal recurrence in 5 cases. Salvage operation with/without postoperative radiotherapy was performed for 22 cases with locoregional recurrence and 7 of them have survived. [ABSTRACT FROM AUTHOR]

Conclusion: Treatment of advanced hypopharyngeal cancer has become more conservative and more multidisciplinary, and the prognosis has been improved. Induction chemotherapy has the potential to extend organ preservation therapy even in cases with locally advanced primary lesion. It is also important to develop a strategy to reduce distant metastasis and to keep track of second primary cancers. Objectives: To update the therapeutic outcome of advanced hypopharyngeal cancer. Methods: A total of 72 cases with stage III/IV hypopharyngeal cancer were treated at Kyoto University Hospital during 2000-2008. Surgery was performed in 56 cases; total pharyngolaryngoesophagectomy (TPLE) in 39 cases and partial pharyngectomy (PPX) preserving the larynx in 17 cases. Radiotherapy (RT) with or without concurrent chemotherapy was applied in 16 cases. Induction chemotherapy (ICT) has been applied for 14 cases since 2006 to achieve organ preservation and reduction of distant metastasis. The follow-up period varied from 12 months to 96 months (mean 32 months). Therapeutic outcomes were chart reviewed. Results: Five years cumulative overall and disease-specific survival (DSS) rates were 52.1% and 63.8%, respectively. DSS rates in cases treated with surgery and those with RT were 65.1% and 56.1%, respectively. N2c status showed the worst prognosis according to nodal disease classification. Local control rates for cases treated with TPLE, PPX, and RT were 97.3%, 100%, and 80.4%, respectively. The effective rate of ICT was 79%, and laryngeal preservation was achieved in 79% of the cases with ICT. Recurrence occurred in 20 cases. Approximately half of the recurrence was distant disease. In the end, 17 cases died of the primary disease, while 10 cases died of other causes, mainly second primary cancers. [ABSTRACT FROM AUTHOR]

In this paper I examine river governance or river policy in Japan through the process of modernization over one century and analyze three hidden paradigms, “modern technicism”, “nature conservationism” and “life environmentalism”, with the theory of environmental value. Japanese rivers were governed traditionally by local people (life environmentalism) but the river management was put under the control of administration and the specialist (modern technicism) in the tide of modernization, and in order to confront this situation a new paradigm of “nature conservationism” was born. In the analysis of the stages of river policy development, the development of economic and political power will be traced according to an environmental sociology point of view. This means analyzing people's initiatives resulting from their recognition and value in the political and economical arena. Structuring of river governance through the interactive process of “government and self-government” is also analyzed by putting an emphasis on local residents as a political body and second, I will describe the theoretical direction of environmental sociology. Lake Biwa and The Yodo River Basin system, which have historical importance in Japanese river policy, will be taken as an example. From the position of environmental sociology, river governance as an interactive process of “government and self-governance” based on independence of people, is one practical model that can give us important keys for the new river governance, transcending difference of social conditions. Consider learning the spirit of traditional communal structure as a process of practice for building a new communalism, life environmentalism model, which fits today's society. [ABSTRACT FROM AUTHOR]

Examines the historical aspects of a local cluster of individuals with lysinuric protein intolerance in a sample of patients and in a mass-screened populations in a northern area of Iwate, Japan. Estimation of the mutation age and analysis of haplotype diversity of the chromosome carrying the R410X mutation.

We investigated element composition ratios in two sets of sequentially collected airborne particulate matter (PM) samples obtained through the automatic sampler of the Atmospheric Environmental Regional Observation System (AEROS). A series of micro-PIXE analyses and imaging were performed on a PTFE (Polytetrafluoroethylene) membrane tape filter corresponding to two hourly time slots through a high-concentration air pollution event from 26th to 27th March 2020 sampled at Ota, Japan (36.290° N, 139.381° E) by utilizing an external 3 MeV proton microprobe. Latent variables of sequentially collected PM samples were analyzed by the non-linear least square method and classified by those clustering driven by house-made data analysis software. Micro-PIXE imaging effectively confirmed the presence of large elemental agglomerations on the PTFE membrane tape filter of AEROS that often appeared as outliners in data analysis. [ABSTRACT FROM AUTHOR]

Objective To investigate the prevalence of and the perinatal risk factors related to reading difficulty in school-aged very low birth weight infants (VLBWI) with normal intelligence. Methods Subjects were 79 Japanese children in the second to fourth grade of elementary school who had been born at very low birth weight and who regularly visited a follow-up clinic at one of four hospitals. All members had a full-scale IQ score of 80 or higher. Perinatal information was obtained retrospectively from medical records. Each subject underwent four reading tasks, testing monomoratic syllable reading, word reading, non-word reading and short sentence reading. Subjects with an SD reading time score greater than 2.0 in two or more tasks were considered to have reading difficulty (RD). Furthermore we investigated the relations between RD and perinatal factors using logistic regression analysis adjusted for potential confounding factors. Results Twenty-five (31.6%) out of 79 subjects had RD. We discovered that treated retinopathy of prematurity (tRoP) was a significant risk factor (adjusted OR = 5.80, 95% confidence interval = 1.51–22.33). Conclusion The rate of RD in school-aged VLBWI was higher than the estimated prevalence of dyslexia in Japan. Even in children with normal intelligence, long-term developmental follow-up including support for reading skills is necessary for VLBWI. Further investigation is desired to elucidate the relations between visual problems and RD in school-aged children. [ABSTRACT FROM AUTHOR]

The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children., (© 2024. Japanese Society of Hematology.)

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs., (© 2024. The Author(s).)

Objectives: To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan., Design: Retrospective study., Setting: Six hundred and thirty-one primary care institutions in Japan., Participants: Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database., Primary and Secondary Outcome Measures: Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3-6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1-25 points)., Results: In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality., Conclusions: The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era., Competing Interests: Competing interests: KI reports grant support from Idorsia Pharmaceuticals Japan Limited. The other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 10 9 /L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences., (© 2021. Japanese Society of Hematology.)

Objective: To examine the current medical and psychosocial status of patients with epilepsy, aiming to facilitate appropriate application of the Intractable/Rare Diseases Act of Japan., Methods: By analysing the cross-sectional data of patients registered in the tertiary hospital-based Epilepsy Syndrome Registry of Japan, we investigated the proportion of patients who met the severity criteria as defined by the Act (seizure frequency of at least once a month, or presence of intellectual/neurological/psychiatric symptoms, or both) and whether there are candidate syndrome/diseases to be added to the existing list in the Act., Results: In total, 2,209 patients were registered. After excluding self-limited/idiopathic epilepsies, 1,851 of 2,110 patients (87.7%) met the severity criteria. The patients were classified into eight main epilepsy syndromes (594 patients), 20 groups based on aetiology (1,078 patients), and three groups without known aetiology (427 patients). Most of the groups classified by syndrome or aetiology had high proportions of patients satisfying the severity criteria (>90%), but some groups had relatively low proportions (<80%) resulting from favourable outcome of surgical therapy. Several small groups with known syndrome/aetiology await detailed analysis based on a sufficiently large enough number of patients registered, some of whom may potentially be added to the list of the Act., Significance: The registry provides data to examine the usefulness of the severity criteria and list of diseases that are operationally defined by the Act. Most epilepsy patients with various syndromes/diseases and aetiology groups are covered by the Act but some are not, and the list of designated syndromes/diseases should be complemented by further amendments, as suggested by future research.

Objective: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan., Methods: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset., Results: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%., Significance: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Background: In Japan there is no consensus on how to efficiently measure quality indicators (QIs), defined as a standard of care, for acute ischemic stroke (AIS). Using information from a health insurance claims database and electronic medical records, we evaluated the feasibility and validity of measuring QIs for AIS patients who received intravenous recombinant tissue plasminogen activator (IV rt-PA) or endovascular therapy (EVT)., Methods and results: AIS patients receiving rt-PA or EVT between 2013 and 2015 were identified. We selected 17 AIS QI measures for primary stroke centers (PSCs) and 8 for comprehensive stroke centers (CSCs). Defined QIs were calculated for each hospital and then averaged. In total, the data of 8,206 patients (rt-PA 83.7%, EVT 34.9%) from 172 hospitals were obtained. Median National Institute of Health Stroke Scale score at admission was 14, and 37.7% of the patients were functionally independent at discharge. All target QIs were successfully measured with fewer missing values, and the accuracy of preset data was about 90%. Adherence rates were low (<50%) in 5 QI measures among PSCs, including door-to-needle time ≤1 h, and in 1 QI measure among CSCs (door-to-brain and vascular imaging time ≤30 min)., Conclusions: Measuring QIs for AIS by this novel approach was feasible and reliable in the provision of a national benchmark.

Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Airway stenting is a procedure in which a stent is inserted into a stenotic site of the airway. The safest method of ventilation for airway stenting is controversial. A prospective randomized interventional study was conducted on airway stenting. We conducted this study to investigate whether controlled ventilation with muscle relaxants (MR) during airway stenting reduces the incidence of desaturation events (percutaneous oxygen saturation [SpO2] <95%) in comparison with spontaneous respiration (SP)., Methods: Sixty-four patients were enrolled at our hospital between April 2016 and August 2018, and were randomly assigned to the controlled ventilation with MR group or SP group. For anesthesia, total intravenous anesthesia with propofol target-controlled infusion and remifentanil was performed. In the SP group, SP was maintained. In the MR group, a rigid bronchoscope was inserted after the administration of MR to perform controlled ventilation. The incidence of desaturation events was analyzed by logistic regression adjusted by the preoperative respiratory state and stenotic site of the airway., Results: The incidence of desaturation events in the SP and MR groups was 75.0% (24/32) and 9.7% (3/31), respectively, with an odds ratio of 0.04 (95% confidence interval, 0.01-0.16, reference = SP group; P < .001). In the SP group, the mean intraoperative pH was lower than that in the MR group (7.2 ± 0.1 vs 7.4 ± 0.1, respectively; P < .001). In this group, the mean partial pressure of arterial carbon dioxide (PaCO2) was higher (70.2 ± 17.0 mm Hg vs 40.5 ± 8.0 mm Hg, respectively; P < .001) and the mean partial pressure of oxygen in the arterial blood/fraction of the inspiratory oxygen ratio was lower (263.1 ± 64.2 mm Hg vs 396.4 ± 69.4 mm Hg, respectively; P < .001)., Conclusions: Controlled ventilation with MR during airway stenting reduced the incidence of desaturation events, maintaining a favorable respiratory status.

Objectives: Comprehensive stroke centre (CSC) capabilities are associated with reduced in-hospital mortality due to acute stroke. However, it remains unclear whether there are improving trends in the CSC capabilities or how hospital-related factors determine quality improvement. This study examined whether CSC capabilities changed in Japan between 2010 and 2018 and and whether any changes were influenced by hospital characteristics., Design: A hospital-based cross-sectional study., Setting: We sent out questionnaires to the training institutions of the Japan Neurosurgical Society and Japan Stroke Society in 2010, 2014 and 2018., Participants: 749 hospitals in 2010, 532 hospitals in 2014 and 786 hospitals in 2018 participated in the J-ASPECT study, a nationwide survey of acute stroke care capacity for proper designation of a comprehensive stroke centre in Japan., Main Outcome Measures: CSC capabilities were assessed using the validated scoring system (CSC score: 1-25 points) in 2010, 2014 and 2018 survey. The effect of hospital characteristics was examined using multiple logistic regression analysis., Results: Among the 323 hospitals that responded to all surveys, the implementation of 13 recommended items increased. The CSC score (median and IQR) was 16 (13-19), 18 (14-20) and 19 (15-21) for 2010, 2014 and 2018, respectively (p<0.001). There was a ≥20% increase in six items (eg, endovascular physicians, stroke unit and interventional coverage 24/7), and a ≤20% decrease in community education. A lower baseline CSC score (OR: 0.82, 95% CI 0.75 to 0.9), the number of beds≥500 (OR: 3.9, 95% CI 1.2 to 13.0) and the number of stroke physicians (7-9) (OR: 2.6, 95% CI 1.1 to 6.3) were associated with improved CSC capabilities, independent of geographical location., Conclusions: There was a significant improvement in CSC capabilities between 2010 and 2018, which was mainly related to the availability of endovascular treatment and multidisciplinary care. Our findings may be useful to determine which hospitals should be targeted to improve CSC capabilities in a defined area., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Improved outcomes in patients with subarachnoid hemorrhage (SAH) treated at high-volume centers have been reported. The authors sought to examine whether hospital case volume and comprehensive stroke center (CSC) capabilities affect outcomes in patients treated with clipping or coiling for SAH., Methods: The authors conducted a nationwide retrospective cohort study in 27,490 SAH patients who underwent clipping or coiling in 621 institutions between 2010 and 2015 and whose data were collected from the Japanese nationwide J-ASPECT Diagnosis Procedure Combination database. The CSC capabilities of each hospital were assessed by use of a validated scoring system based on answers to a previously reported 25-item questionnaire (CSC score 1-25 points). Hospitals were classified into quartiles based on CSC scores and case volumes of clipping or coiling for SAH., Results: Overall, the absolute risk reductions associated with high versus low case volumes and high versus low CSC scores were relatively small. Nevertheless, in patients who underwent clipping, a high case volume (> 14 cases/yr) was significantly associated with reduced in-hospital mortality (Q1 as control, Q4 OR 0.71, 95% CI 0.55-0.90) but not with short-term poor outcome. In patients who underwent coiling, a high case volume (> 9 cases/yr) was associated with reduced in-hospital mortality (Q4 OR 0.69, 95% CI 0.53-0.90) and short-term poor outcomes (Q3 [> 5 cases/yr] OR 0.75, 95% CI 0.59-0.96 vs Q4 OR 0.65, 95% CI 0.51-0.82). A high CSC score (> 19 points) was significantly associated with reduced in-hospital mortality for clipping (OR 0.68, 95% CI 0.54-0.86) but not coiling treatment. There was no association between CSC capabilities and short-term poor outcomes., Conclusions: The effects of case volume and CSC capabilities on in-hospital mortality and short-term functional outcomes in SAH patients differed between patients undergoing clipping and those undergoing coiling. In the modern endovascular era, better outcomes of clipping may be achieved in facilities with high CSC capabilities.

Outcomes of children treated for relapsed acute lymphoblastic leukemia (ALL) remain poor. Bortezomib (BZM), a proteasome inhibitor, has shown promising activity against lymphoid malignancies. We conducted a phase I study to evaluate the safety and tolerability of multidrug chemotherapy including BZM in Japanese children with relapsed ALL. Three of five children with relapsed ALL enrolled in the study between November 2014 and April 2016 were evaluated. BZM (1.3 mg/m 2 ) was administered on days 8, 11, 15, and 18 of multidrug induction chemotherapy. Pharmacokinetic studies were performed. Age at study entry was 5, 7, and 7 years old, respectively. Two patients had hyperdiploid B-precursor ALL, and one had T cell ALL. Although all patients experienced grade 3-4 hematologic toxicity and grade 3 elevation of aminotransferases, no dose-limiting toxicities were observed. The maximum tolerated dose was defined as 1.3 mg/m 2 . Peripheral neuropathy and respiratory complications were not observed. Complete remission was achieved in all three patients. The mean maximum plasma concentration and area under the concentration-time curve was 74.0 ng/mL and 73.9 ng h/mL, respectively. Thus, adding BZM to 5-drug induction chemotherapy appears safe and well-tolerated in Japanese children with relapsed ALL.

Background: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database., Methods and results: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics., Conclusions: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Background: The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients., Methods: Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients., Results: Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P < 0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at >7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P < 0.001), and incidence of acute subdural hematoma (OR, 1.89; P < 0.001) were associated with in-hospital mortality in elderly patients with TBI., Conclusions: Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Combination chemotherapy with platinum preparations is the standard first-line treatment for stage IIIB/IV non-small-cell lung cancer. However, the median survival in patients receiving this therapy is 8 to 10 months, and it is essential to improve the results of chemotherapy in non-small-cell lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors hinder EGFR signal transmission by binding to the adenosine triphosphate binding site of intracellular tyrosine kinase and inhibiting the autophospholylation of EGFR. They are a standard initial treatment option in EGFR gene mutation-positive patients. In Japan, gefitinib is routinely used. A combination of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and another antineoplastic drug may be a strategy to further improve treatment outcomes. We planned a randomized phase 2 trial to assess the efficacy and safety of gefitinib plus bevacizumab in such patients. In this study, subjects will be assigned to receive monotherapy with gefitinib (GEF group) or combination therapy with gefitinib and beva cizumab (GEF+BEV group) as the initial treatment at a ratio of 1:1. EGFR gene mutations are frequently detected in Asian patients with non-small-cell lung cancer. This study may be significant for establishing a new standard treatment.

Introduction: To detect patients at high risk of developing myocardial infarction, plaque characteristics as well as the degree of stenosis in coronary arteries should be evaluated. However, unstable plaque or severe calcification detected via coronary artery CT (CACT) is not reflected in risk stratification according to current guidelines. It is hypothesised that patients with high-risk findings on CACT (even those without proven history of coronary artery diseases; CAD) should be strictly managed to lower their low-density lipoprotein cholesterol (LDL-C) levels to targets of secondary prevention. Currently, however, there is no evidence based on prospective randomised intervention studies to prove this hypothesis., Methods and Analysis: Patients with mild-to-moderate stenotic lesions with positive remodelling or severe calcification, but without any history of CAD, will be randomly allocated to group A (reduce LDL-C to <120~160 mg/dL according to the primary prevention criteria based on the Japan Atherosclerosis Society (JAS) Guideline for Prevention of Atherosclerotic Cardiovascular Diseases 2017) and group B (reduce LDL-C to <70 mg/dL according to the secondary prevention criteria for high risk based on the JAS Guideline). They will be strictly managed to achieve the LDL-C targets. We will follow-up and evaluate the composite endpoints consisting of major cardiovascular events (death from CAD, non-fatal myocardial infarction, operation for coronary revascularisation and stroke) and stenosis progression or new stenosis development for 3 years., Ethics and Dissemination: The study was approved by the National Hospital Organization Central Research Ethics Committee. The results of this study are scheduled to be published within 2 years after study completion via conference presentation or journal publication., Trial Registration Number: UMIN000031136., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.

Background: The quality of cardiopulmonary resuscitation (CPR) performed by emergency medical services (EMS) personnel affects patient outcomes after cardiac arrest. A CPR feedback device with an accelerometer mounted on a defibrillator can monitor the motion of the patient's sternum to display and record CPR quality in real time. To evaluate the utility of real-time feedback, debriefing, and retraining using a CPR feedback device outside of the hospital, an open-label, cluster randomized controlled trial will be conducted in five municipalities of Osaka Prefecture, Japan., Methods: Each EMS station within a fire department will be randomly assigned to: 1) the treatment group with real-time feedback, debriefing, and retraining using the CPR feedback device (intervention group); or 2) the conventional treatment group without real-time feedback, debriefing, and retraining (control group). This trial will include 2850 to 3020 patients over about 4 years. The primary outcome of the trial is 1-month favorable neurological survival, defined as cerebral performance category scale score 1 or 2. Secondary outcomes are 1-month survival, survival to hospital discharge, return of spontaneous circulation, and quality of CPR including fraction, depth, tempo, and ventilation rate., Discussion: The trial will assess whether treatment monitored by the CPR feedback device, which allows for real-time feedback, debriefing, and retraining using CPR quality data, outperforms conventional treatment without real-time feedback, debriefing, and retraining in terms of 1-month favorable neurological survival in cardiac arrest patients receiving CPR outside the hospital., Trial Registration: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000021431 . Registered on 11 March 2016.

OBJECTIVE Although heterogeneity in patient outcomes following subarachnoid hemorrhage (SAH) has been observed across different centers, the relative merits of clipping and coiling for SAH remain unknown. The authors sought to compare the patient outcomes between these therapeutic modalities using a large nationwide discharge database encompassing hospitals with different comprehensive stroke center (CSC) capabilities. METHODS They analyzed data from 5214 patients with SAH (clipping 3624, coiling 1590) who had been urgently hospitalized at 393 institutions in Japan in the period from April 2012 to March 2013. In-hospital mortality, modified Rankin Scale (mRS) score, cerebral infarction, complications, hospital length of stay, and medical costs were compared between the clipping and coiling groups after adjustment for patient-level and hospital-level characteristics by using mixed-model analysis. RESULTS Patients who had undergone coiling had significantly higher in-hospital mortality (12.4% vs 8.7%, OR 1.3) and a shorter median hospital stay (32.0 vs 37.0 days, p < 0.001) than those who had undergone clipping. The respective proportions of patients discharged with mRS scores of 3-6 (46.4% and 42.9%) and median medical costs (thousands US$, 35.7 and 36.7) were not significantly different between the groups. These results remained robust after further adjustment for CSC capabilities as a hospital-related covariate. CONCLUSIONS Despite the increasing use of coiling, clipping remains the mainstay treatment for SAH. Regardless of CSC capabilities, clipping was associated with reduced in-hospital mortality, similar unfavorable functional outcomes and medical costs, and a longer hospital stay as compared with coiling in 2012 in Japan. Further study is required to determine the influence of unmeasured confounders.

Background: Patients with late referral and positive history of volume overload may have a poor prognosis after initiating dialysis due to insufficient and/or inadequate management of complications of renal failure and the lack of better dialysis preparation. Little is known about the influence of the relationship between history of volume overload and late referral on prognosis., Methods: We analyzed 1475 patients who had initiated dialysis for the first time from October 2011 to September 2013. late referral was defined as referral to a nephrologist < 3 months before dialysis initiation. The major outcomes were all-cause death and deaths due to cardiovascular diseases (CVD). The impact of late referral and history of volume overload on all-cause mortality was assessed by Cox proportional hazards models., Results: Among 1475 patients, the mean patient age was 67.5 years. During the median follow-up of 2.2 years, 260 deaths occurred; 99 were due to CVD. Cox proportional hazards models demonstrated that late referral (adjusted hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00-1.82) and history of volume overload (adjusted HR, 1.39; 95% CI, 1.06-1.81) were risk factors for all-cause mortality. Furthermore, late referral coexisting was associated with a history of volume overload increased mortality (adjusted HR, 2.10; 95% CI, 1.39-3.16 versus absence of late referral without history of volume overload) after adjusting for age, sex, diabetes, atherosclerotic disease, and laboratory values., Conclusions: Both late referral and history of volume overload were associated with increased risks of all-cause mortality., Trial Registration: University Hospital Medical Information Network (UMIN000007096). Registered 18 January 2012, retrospectively registered. https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000008349 .

Background: Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) are the two most common tumors expressing CD30. Internationally, a clinical study that is being conducted involving adults with recurrent or refractory HL or ALCL suggests efficacy of brentuximab vedotin (SGN-35). Pediatric patients should be given medicines that have been appropriately evaluated for their use. In the past, however, new approved drugs have been used for pediatric patients without the confirmation of safety and efficacy in pediatric patients. Therefore, it is important to examine the safety and efficacy of SGN-35 in Japanese children., Methods: Phase I clinical study of SGN-35 involving children with recurrent or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma (BV-HLALCL study) is being conducted for pediatric patients in order to evaluate the safety, feasibility and preliminary clinical effectiveness of brentuximab vedotin. SGN-35 is intravenously administered on Day 1 of each cycle (21 days/cycle). The dose of SGN-35 is calculated based on the body weight at the baseline. The primary endpoint is dose limiting toxicity and incidence of adverse events. The secondary endpoints are pharmacokinetics, response rate, complete remission rate, response duration, progression-free survival and event-free survival. The reduction rate of tumor will be calculated according to revised response criteria for malignant lymphoma for measurable tumor. Six pediatric patients will be enrolled in this study., Discussion: This study aims to expand indication of SGN-35 in Japan by assessing its safety and efficacy in pediatric patients., Trial Registration: JMACCT ID: JMA-IIA00229 . Registered on 17 Nov 2015.

Background: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances., Methods: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis., Results: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs., Conclusions: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Background: The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically., Methods and Results: Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP., Conclusions: Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS.

Background: Poor outcomes have been reported for stroke patients admitted outside of regular working hours. However, few studies have adjusted for case severity. In this nationwide assessment, we examined relationships between hospital admission time and disabilities at discharge while considering case severity., Methods and Results: We analyzed 35 685 acute stroke patients admitted to 262 hospitals between April 2010 and May 2011 for ischemic stroke (IS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). The proportion of disabilities/death at discharge as measured by the modified Rankin Scale (mRS) was quantified. We constructed 2 hierarchical logistic regression models to estimate the effect of admission time, one adjusted for age, sex, comorbidities, and number of beds; and the second adjusted for the effect of consciousness levels and the above variables at admission. The percentage of severe disabilities/death at discharge increased for patients admitted outside of regular hours (22.8%, 27.2%, and 28.2% for working-hour, off-hour, and nighttime; P<0.001). These tendencies were significant in the bivariate and multivariable models without adjusting for consciousness level. However, the effects of off-hour or nighttime admissions were negated when adjusted for consciousness levels at admission (adjusted OR, 1.00 and 0.99; 95% CI, 1.00 to 1.13 and 0.89 to 1.10; P=0.067 and 0.851 for off-hour and nighttime, respectively, versus working-hour). The same trend was observed when each stroke subtype was stratified., Conclusions: The well-known off-hour effect might be attributed to the severely ill patient population. Thus, sustained stroke care that is sufficient to treat severely ill patients during off-hours is important., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The effectiveness of comprehensive stroke center (CSC) capabilities on stroke mortality remains uncertain. We performed a nationwide study to examine whether CSC capabilities influenced in-hospital mortality of patients with ischemic and hemorrhagic stroke., Methods and Results: Of the 1,369 certified training institutions in Japan, 749 hospitals responded to a questionnaire survey regarding CSC capabilities that queried the availability of personnel, diagnostic techniques, specific expertise, infrastructure, and educational components recommended for CSCs. Among the institutions that responded, data on patients hospitalized for stroke between April 1, 2010 and March 31, 2011 were obtained from the Japanese Diagnosis Procedure Combination database. In-hospital mortality was analyzed using hierarchical logistic regression analysis adjusted for age, sex, level of consciousness on admission, comorbidities, and the number of fulfilled CSC items in each component and in total. Data from 265 institutions and 53,170 emergency-hospitalized patients were analyzed. Mortality rates were 7.8% for patients with ischemic stroke, 16.8% for patients with intracerebral hemorrhage (ICH), and 28.1% for patients with subarachnoid hemorrhage (SAH). Mortality adjusted for age, sex, and level of consciousness was significantly correlated with personnel, infrastructural, educational, and total CSC scores in patients with ischemic stroke. Mortality was significantly correlated with diagnostic, educational, and total CSC scores in patients with ICH and with specific expertise, infrastructural, educational, and total CSC scores in patients with SAH., Conclusions: CSC capabilities were associated with reduced in-hospital mortality rates, and relevant aspects of care were found to be dependent on stroke type.

Background: Burnout is common among physicians and affects the quality of care. We aimed to determine the prevalence of burnout among Japanese physicians working in stroke care and evaluate personal and professional characteristics associated with burnout., Methods and Results: A cross-sectional design was used to develop and distribute a survey to 11 211 physicians. Physician burnout was assessed using the Maslach Burnout Inventory General Survey. The predictors of burnout and the relationships among them were identified by multivariable logistic regression analysis. A total of 2724 (25.3%) physicians returned the surveys. After excluding those who were not working in stroke care or did not complete the survey appropriately, 2564 surveys were analyzed. Analysis of the participants' scores revealed that 41.1% were burned out. Multivariable analysis indicated that number of hours worked per week is positively associated with burnout. Hours slept per night, day-offs per week, years of experience, as well as income, are inversely associated with burnout. Short Form 36 mental health subscale was also inversely associated with burnout., Conclusions: The primary risk factors for burnout are heavy workload, short sleep duration, relatively little experience, and low mental quality of life. Prospective research is required to confirm these findings and develop programs for preventing burnout., (© 2014 American Heart Association, Inc.)

Background: The association between comprehensive stroke care capacity and hospital volume of stroke interventions remains uncertain. We performed a nationwide survey in Japan to examine the impact of comprehensive stroke care capacity on the hospital volume of stroke interventions., Methods: A questionnaire on hospital characteristics, having tissue plasminogen activator (t-PA) protocols, and 25 items regarding personnel, diagnostic, specific expertise, infrastructure, and educational components recommended for comprehensive stroke centers (CSCs) was sent to 1369 professional training institutions. We examined the effect of hospital characteristics, having a t-PA protocol, and the number of fulfilled CSC items (total CSC score) on the hospital volume of t-PA infusion, removal of intracerebral hemorrhage, and coiling and clipping of intracranial aneurysms performed in 2009., Results: Approximately 55% of hospitals responded to the survey. Facilities with t-PA protocols (85%) had a significantly higher likelihood of having 23 CSC items, for example, personnel (eg, neurosurgeons: 97.3% versus 66.1% and neurologists: 51.3% versus 27.7%), diagnostic (eg, digital cerebral angiography: 87.4% versus 43.2%), specific expertise (eg, clipping and coiling: 97.2% and 54% versus 58.9% and 14.3%, respectively), infrastructure (eg, intensive care unit: 63.9% versus 33.9%), and education (eg, professional education: 65.2% versus 20.7%). On multivariate analysis adjusted for hospital characteristics, total CSC score, but not having a t-PA protocol, was associated with the volume of all types of interventions with a clear increasing trend (P for trend < .001)., Conclusion: We demonstrated a significant association between comprehensive stroke care capacity and the hospital volume of stroke interventions in Japan., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti-platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score ≥4 points, positive-ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64·4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12·8%) in the heparin group. Seven patients had 4Ts ≥ 4 points. Among them, three patients (1·7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16-23) and in-hospital mortality was very high (66·7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1·7% (95% confidence interval: 0·4-5·0). The clinical severity and outcome of definite HIT were unfavourable., (© 2011 Blackwell Publishing Ltd.)

Background: Nifekalant hydrochloride (NIF) is an intravenous class-III antiarrhythmic agent that purely blocks the K(+)-channel without inhibiting β-adrenergic receptors. The present study was designed to investigate the feasibility of NIF as a life-saving therapy for out-of-hospital ventricular fibrillation (VF)., Methods and Results: The Japanese Population-based Utstein-style study with basic and advanced Life Support Education study was a multi-center registry study with 4 participating institutes located at the northern urban area of Osaka, Japan. Eligible patients were those treated with NIF because of out-of-hospital VF refractory to 3 or more precordial shocks and intravenous epinephrine. Between February 2006 and February 2007, 17 patients were enrolled for the study. The time from a call for emergency medical service to the first shock was 12(6-26)min. The time from the first shock to the NIF administration was 25.5(9-264)min and the usage dose of NIF was 25(15-210)mg. When excluding 3 patients in whom percutaneous extracorporeal membrane oxygenation was applied before NIF administration, the rate of return of spontaneous circulation was 86% and the rate of admission alive to the hospital was 79%. One patient developed torsade de pointes., Conclusions: Intravenous administration of NIF seems to be feasible as a potential therapy for advanced cardiac life-support in patients with out-of-hospital VF, and therefore further study is warranted.