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Aims Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known. Methods We examined the association between ALP levels and the ankle-brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9. Results Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p＜0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively). Conclusions Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.

Although the assessment of nutrition is essential for stroke patients, detailed associations between nutritional status at admission, subsequent complications, and clinical outcomes in patients with acute intracerebral hemorrhage (ICH) are unclear. We aimed to elucidate these associations using the Controlling Nutritional Status (CONUT) score. Consecutive patients with acute ICH were investigated. Nutritional status was evaluated using the CONUT score, calculated from the serum albumin level, lymphocyte count, and total cholesterol level. Subsequent complications, such as hemorrhage expansion (HE) during the acute stage and aspiration pneumonia during hospitalization, were evaluated. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3 months. Of the 721 patients, 49 had HE, 111 had aspiration pneumonia, and 409 had poor outcomes. Patients with HE had significantly lower total cholesterol levels than those without HE. Patients with aspiration pneumonia had significantly lower albumin levels, lower lymphocyte counts, and higher CONUT scores than those without aspiration pneumonia. Patients with poor outcomes had significantly lower albumin levels, lower lymphocyte counts, lower total cholesterol levels, and higher CONUT scores than those with good outcomes. Multivariable logistic analysis showed that higher CONUT scores were independently associated with poor outcome (odds ratio, 1.28; 95% confidence interval, 1.09-1.49; P = 0.002) after adjusting for baseline characteristics, HE, and aspiration pneumonia. Each component of CONUT was a useful predictor of subsequent complications. Malnutrition, determined using the CONUT score, was independently associated with poor outcomes in patients with ICH after adjusting for these complications.

Cancer-associated ischemic stroke (CAS) refers to a hypercoagulation disorder related to malignant tumors, especially adenocarcinoma. Carbohydrate antigen (CA) 125 is a mucinous serum marker that might reflect hypercoagulation status, but the association between CA 125 and CAS is unclear across various types of cancer. The aim of this study was to investigate the associations among tumor markers, coagulation markers, and clinical factors in acute ischemic stroke (AIS) patients with active cancer. Consecutive AIS patients with active cancer (a diagnosis or ongoing active therapy for cancer within 6 months) were prospectively enrolled at four hospitals. D-dimer, C-reactive protein (CRP), carcinoembryonic antigen (CEA), CA19-9, and CA 125 levels were measured. Of 120 AIS patients with active cancer, 47 were diagnosed with CAS. CA 125 had the strongest correlations with D-dimer and CRP (ρ = 0.543, p

A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.

Purpose Various immune mediators have crucial roles in the pathogenesis of intraocular diseases. Machine learning can be used to automatically select and weigh various predictors to develop models maximizing predictive power. However, these techniques have not yet been applied extensively in studies focused on intraocular diseases. We evaluated whether 5 machine learning algorithms applied to the data of immune-mediator levels in aqueous humor can predict the actual diagnoses of 17 selected intraocular diseases and identified which immune mediators drive the predictive power of a machine learning model. Design Cross-sectional study. Participants Five hundred twelve eyes with diagnoses from among 17 intraocular diseases. Methods Aqueous humor samples were collected, and the concentrations of 28 immune mediators were determined using a cytometric bead array. Each immune mediator was ranked according to its importance using 5 machine learning algorithms. Stratified k-fold cross-validation was used in evaluation of algorithms with the dataset divided into training and test datasets. Main Outcome Measures The algorithms were evaluated in terms of precision, recall, accuracy, F-score, area under the receiver operating characteristic curve, area under the precision-recall curve, and mean decrease in Gini index. Results Among the 5 machine learning models, random forest (RF) yielded the highest classification accuracy in multiclass differentiation of 17 intraocular diseases. The RF prediction models for vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma achieved the highest classification accuracy, precision, and recall. Random forest recognized vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma with the top 5 F-scores. The 3 highest-ranking relevant immune mediators were interleukin (IL)-10, interferon-γ-inducible protein (IP)-10, and angiogenin for prediction of vitreoretinal lymphoma; monokine induced by interferon γ, interferon γ, and IP-10 for acute retinal necrosis; and IL-6, granulocyte colony-stimulating factor, and IL-8 for endophthalmitis. Conclusions Random forest algorithms based on 28 immune mediators in aqueous humor successfully predicted the diagnosis of vitreoretinal lymphoma, acute retinal necrosis, and endophthalmitis. Overall, the findings of the present study contribute to increased knowledge on new biomarkers that potentially can facilitate diagnosis of intraocular diseases in the future.

Introduction Bladder pleomorphic giant cell carcinoma is a rare and aggressive malignancy with a poor prognosis. There are no reports of immune checkpoint inhibitors for bladder pleomorphic giant cell carcinoma to date. Case presentation A 72-year-old man presented with gross hematuria due to multiple bladder cancers. Despite transurethral bladder resection and intravesical injection of Bacillus Calmette-Guerin, bladder cancer recurred. Nineteen months later, he underwent total cystectomy. Pathological examination revealed bladder giant cell carcinoma. Twenty-eight months later, pembrolizumab was administered due to para-aortic lymph node metastasis. Forty-four months later, the lymph node metastasis disappeared, and pembrolizumab administration was terminated. Fifty-eight months later, the patient has remained in remission at the time of writing. Conclusion Immune checkpoint inhibitors manifest a therapeutic potential in bladder pleomorphic giant cell carcinoma.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

A 65-year-old man presented with a slight headache and transient visual disturbance. Magnetic resonance imaging (MRI) revealed occlusion of the left internal carotid artery (ICA) and acute brain infarctions in both hemispheres, and a blood examination indicated inflammation. Gadolinium enhancement was observed in the walls of the temporal arteries and ICAs. After we diagnosed giant cell arteritis (GCA) by a temporal artery biopsy, aspirin and corticosteroids were administered. The typical symptoms of GCA, such as jaw claudication and temporal artery tenderness, were absent during the entire clinical course, and the findings of contrast-enhanced MRI contributed to the diagnosis.

Evidence-based practice (EBP) models have been developed, in part, to enhance the likelihood that the outcome of health care treatment, including psychotherapy, leads to positive improvement. However, two additional outcomes can occur: no change and poor outcome (e.g., harm, worsening of symptoms). What does the clinician do when psychotherapy is not working? When faced with various treatment decisions, such as this, the EBP model posits that therapists should apply their clinical expertise in considering the “best available research” within the context of various patient characteristics. In part because of various limitations of this approach, I suggest that another important set of principles are important to consider in tandem when faced with this clinical dilemma—that is, ethical concerns. Borrowing from the American Psychological Association’s (2017a) Ethics Code, I discuss how the following issues exist when clinicians wrestle with this question: avoidance of harm, competence, conflicts of interest, and informed consent. I conclude this paper with a list of suggestions that can potentially foster the application of ethical principles when making treatment decisions.

Carotid ultrasonography is useful for the assessments of the risk stratification for stroke or coronary artery disease, because it is a simple, repeatable, and noninvasive procedure. The carotid intima-media thickness (IMT), which is assessed using carotid ultrasonography, is a widely used surrogate marker for the severity of atherosclerosis. Several large clinical studies showed that increased carotid IMT is associated with the future stroke or cardiovascular events. In addition, in many clinical trials, it has been adopted for surrogate markers of clinical endpoints of medical intervention. Moreover, carotid ultrasonography allows the measurement of the presence and characteristics of plaques and the severity of carotid artery stenosis. The unstable morphology of plaque, such as hypoechoic, ulcer, and mobility, is associated with future ischemic stroke events. The screening tool of asymptomatic carotid artery stenosis is also important, although whether routine carotid ultrasonography assessment is recommended in the general population remains controversial. The screening of carotid artery stenosis using ultrasonography is essential for not only daily clinical settings but also management of patients with acute ischemic stroke. The patients with atherothrombotic stroke with severe internal carotid artery stenosis should be considered to surgical intervention, and duplex ultrasound approach is important to estimate for the severity of carotid stenosis. Physicians should keep in mind the usefulness of carotid ultrasonography for risk stratification of cerebral and cardiovascular disease based on various aspects. In addition, visual assessment or dynamic changes using carotid ultrasonography could provide the various and valuable insights in clinical settings.

Introduction Mucinous urethral adenocarcinoma is a rare and progressive cancer of the prostatic urethra. Reports on palliative systemic treatment for mucinous urethral adenocarcinoma are few. We present a case of coexisting mucinous urethral and prostate adenocarcinomas managed with systemic treatment. Case presentation A 66-year-old man presented with gross hematuria and urinary retention. Prostate-specific antigen level was elevated, at 99 ng/mL, and prostate biopsy revealed moderately to poorly differentiated adenocarcinoma. Hormone therapy and standard chemotherapy for prostate adenocarcinoma were ineffective. Prostate re-biopsy revealed coexisting mucinous urethral and prostate adenocarcinomas. Gemcitabine + cisplatin chemotherapy and folinic acid + 5-fluorouracil + irinotecan chemotherapy temporarily suppressed the cancer, but 14 months after presentation, he developed liver metastasis and died. Autopsy revealed metastasis of both mucinous urethral adenocarcinoma and carcinosarcoma. Conclusion Mucinous urethral adenocarcinoma is difficult to diagnose in coexistence with prostate adenocarcinoma. This was an extremely rare case showing chemoresistance due to epithelial-mesenchymal transition.

Objectives The efficacy of negative pressure wound therapy (NPWT) and its application to severely contaminated wounds sustained during surgery remain to be established. Here, we evaluated the efficacy of utilizing NPWT until delayed primary closure (DPC) by assessing the infection rates in patients with lower gastrointestinal perforations. Methods This prospective multicenter cohort study included 56 patients that underwent abdominal surgery for lower gastrointestinal perforations in eight institutions, from February 2016 to May 2017. All patients received NPWT after surgery before attempting DPC. The extent of peritonitis was categorized according to Hinchey's classification. Patients in stages II-IV were included. Results Five patients had surgical site infections (SSIs) during NPWT and did not receive a DPC (9%). Of the 51 patients that received DPCs, 44 had no infection (91%) and 7 developed SSIs after the DPC (13.7%). For stages II, III, and IV, the SSI rates were 0%, 22.6%, and 35.7%, respectively; the median (range) times to wound healing were 15 (10-36), 19 (11-99), and 19 (10-53) days, respectively. There were no significant differences between the stages. Conclusions NPWT followed by DPC resulted in low infection rates in each peritonitis stage. This approach appears promising as an alternative to traditional DPC alone for treating lower gastrointestinal perforations.

Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders. Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently. Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation. Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

Aim: Posterior circulation stroke (PCS) has different clinical features and prognosis compared with anterior circulation stroke (ACS), and whether the effect of statin therapy on stroke prevention differs according to infarction location remains unclear. This post hoc analysis of the J-STARS study aimed to compare the usefulness of statin at different infarction locations (i.e., ACS and PCS). Methods: In the J-STARS study, 1578 patients were randomly assigned to the pravastatin or control group. The subjects were divided into two subgroups (ACS and PCS groups) based on the arteries responsible for the infarction. Cox proportional hazards models were used to investigate whether the all stroke recurrence rate was different between the ACS and PCS groups. Results: The PCS group (n = 499) had a significantly higher prevalence of diabetes than the ACS group (n = 1022) (30.7% vs. 19.8%, P < 0.001). During the follow-up (4.9 ± 1.4 years), the incidence of all stroke was significantly lower in the pravastatin group than in the control group among patients with PCS (adjusted hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25–0.83, P = 0.009); however, the stroke recurrence rates were not significantly different between both groups among patients with ACS (adjusted HR 1.32, 95% CI 0.93–1.88, P = 0.123). A significant interaction between the ACS and PCS groups in terms of pravastatin effects was noted (P = 0.003 for interaction). Conclusions: Pravastatin significantly reduced the recurrence rate of all stroke among patients with PCS. Thus, the effect of statin on the recurrence of stroke may differ according to infarction location.

Aims To understand the different influences of statins on the incidence rate of each stroke subtype in association with low-density lipoprotein (LDL) cholesterol levels, we performed a post hoc analysis on the data from the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study. Methods Subjects (n=1,578) were divided into three groups according to their mean postrandomized LDL cholesterol level (＜100, 100-120, and ≥ 120 mg/dL) until the last observation before the event or the end of follow-up. A Cox proportional hazard model for time to events was used for calculating adjusted hazard ratios, 95% confidence intervals, and the trend tests. Results The event rates for atherothrombotic stroke did not decrease in accordance with the postrandomized LDL cholesterol level subgroups of either the control or the pravastatin group (p=0.15 and 0.33 for the trend, respectively). In the control group, however, no atherothrombotic stroke event was observed in the subgroup of the low postrandomized LDL cholesterol level (less than 100 mg/dL). The event rates for atherothrombotic stroke were lower in the middle postrandomized LDL cholesterol level subgroup (100-120 mg/dL) of the pravastatin group than that of the control group. The event rates for lacunar stroke decreased in the lower postrandomized LDL cholesterol level subgroup of the control group but not of the pravastatin group (p=0.004 and 0.06 for the trend, respectively). Conclusions Statins showed different influences on the risks of atherothromobotic and lacunar stroke according to postrandomized LDL cholesterol levels.

This study aims to investigate whether it is possible to predict the modulus of elasticity (MOE) and modulus of rupture (MOR) of lumber produced from different heights using the stress-wave velocit...

Background School refusal behavior (SRB), which is the refusal to attend or remain in school, has been associated with emotional, psychological, and other behavioral problems, as well as a lower health-related quality of life (HRQOL). However, the effects of self-esteem and a psychiatric diagnosis in students with SRB on HRQOL are not yet known. Understanding these relationships could help to develop more effective therapeutic interventions. Methods A total of 175 young people (aged 8-18 years old) who visited our medical centers and outpatient clinics participated in the study. This comprised the SRB group (n = 70) and an age- and sex-matched control group (n = 105). Information about any psychiatric diagnosis was collected from medical records, HRQOL was measured using the J-KIDSCREEN-52, SRB was assessed using the School Refusal Assessment Scale-Revised for Japanese Attendance at School, self-esteem was measured using the Rosenberg Self-Esteem Scale, children's mental health status was measured using the Strengths and Difficulties Questionnaire, and social support was measured using the Oslo 3-item Social Support Scale. We performed between-group comparisons and multiple regression analysis. Results The SRB had a significantly lower HRQOL than the control group in several of the KIDSCREEN-52 dimensions. In the SRB group, 35.7% had chronic disease and 35.7% of their parents had health problems and were receiving treatment. The multiple regression analysis revealed that, within the SRB group, a psychiatric diagnosis was associated with a lower HRQOL. However, this was not the case for a diagnosis of autistic spectrum disorder. Self-esteem positively affected HRQOL in six dimensions of the KIDSCREEN-52 within the SRB group. Conclusion Our results could inform the development of support strategies for young people with SRB. Namely, support that enhances self-esteem could be used to increase HRQOL in young people with SRB. Furthermore, the presence of psychiatric disorders should be assessed as early as possible.

Background:Veterans enrolled in Veterans Health Administration (VHA) Home Based Primary Care (HBPC), a program providing in-home medical and mental health care by an interdisciplinary care team, often face substantial physical, cognitive, and mental health challenges. This program evaluation examined the impact of a brief problem-solving intervention on depressive symptoms, quality of life, and problem-solving abilities for Veterans enrolled in HBPC.Design:Pre- and post-intervention outcomes for Veterans, and qualitative feedback from Veterans and clinicians regarding program satisfaction.Participants and Setting:A total of 230 HBPC patients (mean age in years = 72.1, SD = 11.6) within the U.S. national VHA health care system.Intervention:Six-session, individual Problem-Solving Training (PST-HBPC).Method:Licensed psychologists and social workers (n = 115) completed training and administered the treatment with HBPC Veterans between 2014 and 2017.Measurements and Results:From baseline to post-intervention, Veterans completing five or more PST-HBPC sessions (n = 199) reported significant reductions in depressive symptoms on the Patient Health Questionnaire 9-item (PHQ-9), in difficulty functioning due to depressive symptoms (PHQ-9 item 10), and in thoughts of death (PHQ-9 item 9). They also reported more effective problem-solving on the Social Problem-Solving Inventory – Revised: Short form (total score and subscales), and improved quality of life across life domains on the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale. Both clinicians and Veterans also reported satisfaction with the program.Conclusions:Preliminary findings support the continued dissemination and implementation of this brief PST intervention for HBPC Veterans, and its potential for use with non-VA home care populations with complex comorbidities.

Purpose The Informing the Pathway of COPD Treatment (IMPACT) study demonstrated that single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduces moderate/severe exacerbation rates and improves lung function and health status versus FF/VI or UMEC/VI dual therapy in patients with symptomatic COPD and a history of exacerbations. This analysis evaluated the efficacy and safety of FF/UMEC/VI in patients enrolled in Japan. Patients and methods IMPACT was a 52-week, randomized, double-blind, multicenter study comparing FF/UMEC/VI 100/62.5/25 µg with FF/VI 100/25 µg or UMEC/VI 62.5/25 µg in patients ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the previous year. Endpoints included annual rate of on-treatment moderate/severe exacerbations (primary endpoint), time-to-first on-treatment moderate/severe exacerbation and change from baseline at Week 52 in trough FEV1, post-bronchodilator FEV1, St. George's Respiratory Questionnaire, and COPD Assessment Test score. Safety was also assessed. Results The Japan subgroup accounted for only 4% (378/10,355) of the overall IMPACT intent-to-treat (ITT) population. In the Japan subgroup, FF/UMEC/VI reduced the annual rate of on-treatment moderate/severe exacerbations by 15% (95% CI: -20, 40) versus FF/VI (compared with 15% [10, 20] in the ITT) and 36% (95% CI: 6, 57) versus UMEC/VI (compared with 25% [19, 30] in the ITT). FF/UMEC/VI reduced moderate/severe exacerbation risk (time-to-first), improved lung function and health status at Week 52 versus both dual therapies. These results were in the same direction and of a generally similar magnitude to those seen in the overall ITT population. No new safety signals were identified in the Japan subgroup compared with the ITT population. Pneumonia incidence was higher with FF/UMEC/VI and FF/VI versus UMEC/VI. Conclusion These results highlight the favorable benefit-risk profile of FF/UMEC/VI single-inhaler triple therapy compared with FF/VI or UMEC/VI dual therapy in patients in Japan with symptomatic COPD and ≥1 exacerbation in the prior year.

This study aimed to reveal the relationship between quality of life (QOL) and sleep quality in patients with type 1 diabetes mellitus (T1DM). Overall, 202 patients with T1DM were registered in our study, and 192 were eligible for analysis. Baseline characteristics and laboratory values were determined. Patients completed the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Therapy-Related QOL (DTR-QOL) questionnaires. We investigated the relationship between the global PSQI and DTR-QOL total scores by using linear regression analysis. In univariate regression analysis, DTR-QOL total scores were associated with body mass index, alcohol consumption, hypertension, hemoglobin A1c (HbA1c), and global PSQI score (all p-value

The coronavirus disease 2019 (COVID-19) pandemic has caused a wide range of unprecedentedconsequences, including social, economic, and health disruptions. From the point of view ofhealthcare assistance, COVID-19 has deeply impacted usual practice at all levels since the beginningof 2020. In this setting, neurological assistance has adapted to the circumstances of the pandemic. Infact, because COVID-19 involves neurological symptoms, affected patients require the attention ofneurologists, and the high demand for clinical care entailed the recruitment ofmany neurologists tofrontline assistance (1). In addition, the pandemic has impacted the management of patients withneurological disorders, with changes in the management of relapses, usual follow-up, diagnosticprocedures, implementation or generalization of telemedicine, etc. Lockdown and social isolationwere also very harmful in patients with neurological disorders (2). Furthermore, the treatment ofneurological emergencies, such as stroke, was also compromised because of resource re-allocationduring the emergency, and the fear of patients to attend the hospital.The neurological community needed to share experiences about how to face this globalchallenge. Accordingly, this Research Topic was launched in April 2020 to address these issues.Over 117 manuscripts were submitted, and 76 papers have been published, including originals,reviews, and case reports. Studies have covered the main areas of neurological care, includinggeneral neurological care, stroke, epilepsy, multiple sclerosis, movement disorders, cognitiveneurology, neuromuscular disorders, headache, and neuropediatrics Fil: Matias Guiu, Jordi A.. Universidad Complutense de Madrid; España Fil: Sung, Sheng Feng. No especifíca; Fil: Hsieh, Cheng Yang. No especifíca; Fil: Nezu, Tomohisa. No especifíca; Fil: Porta Etessam, Jesús. Universidad Complutense de Madrid; España Fil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Background: Mepolizumab reduces exacerbations and oral corticosteroid (OCS) use in randomized controlled trials of patients with severe eosinophilic asthma. This study evaluated the effectiveness of mepolizumab in patients with severe asthma in real-world clinical practice in Japan. Methods: This was a retrospective, observational, self-controlled study (GSK ID: 213221) of patients (aged ≥12 years) with asthma from the JMDC Claims Database. Data were gathered for 12 months prior to (baseline) and 12 months following (follow-up) index (mepolizumab initiation date). Outcomes (compared annually or quarterly during baseline and follow-up) included the rate of exacerbations, the proportions of patients experiencing an asthma exacerbation, receiving maintenance OCS, and achieving a ≥50% reduction from baseline in daily OCS dose, and median daily OCS dose. Results: Sixty-one patients were included. During follow-up versus baseline, exacerbation incidence was significantly reduced by 43% (incidence rate ratio: 0.57 [95% confidence interval: 0.43, 0.74]) and the proportion of patients with any exacerbation fell from 89% to 62%. In the final quarter of follow-up, the proportion of patients receiving OCS maintenance therapy decreased to 16% (from 26% in the 3 months prior to index), 60% of patients achieved a ≥50% reduction from baseline in daily OCS dose, and median (interquartile range) prednisone-equivalent OCS dose reached 3 (1–5) mg/day, a 55% reduction from baseline dose (8 [7–11] mg/day). Conclusions: Patients with asthma receiving mepolizumab treatment in routine clinical practice in Japan experienced clinically significant reductions in asthma exacerbations and maintenance OCS use, supporting the effectiveness of mepolizumab in real-world settings.

Background Recently, the prevalence of venous thromboembolism (VTE) in Asian patients with inflammatory bowel disease (IBD) is gradually increasing. IBD surgery is a well-recognized risk factor for VTE. However, there are no prospective studies about VTE after surgery for ulcerative colitis (UC) in Asia. This multicenter prospective study aimed to clarify the prevalence and risk factors for perioperative VTE in UC surgery in Japan. Methods A total of 134 patients with UC were included from January 1, 2013 to December 31, 2014. Preoperative screening was performed in all patients. In the perioperative period, standard VTE prophylaxis based on risk assessment was administered. The prevalence of pre- and postoperative VTE, its risk factors, and mortality rates were investigated. Results Perioperative deep vein thrombosis and pulmonary embolism were diagnosed in 15 (11.1%) and 1 patient (0.7%), respectively. All patients were asymptomatic. No surgery-related deaths were found (mortality rate 0%). Seven patients (5.2%) were diagnosed, and 8 (6.4%) during postoperative follow-up by ultrasonography or computed tomography. Forty-seven percent of VTE cases was developed preoperatively. A preoperative hospital length stay of over 5 days was a significant risk factor [P = 0.04; odds ratio: 8.26 (1.06–64.60)] for preoperative VTE. Postoperative deep vein thrombosis occurred in 8 of the 127 patients (6.4%). Six out of these 8 (75.0%) occurred after postoperative day 14. Perioperative blood transfusion was a significant risk factor [P = 0.04; odds ratio: 8.26 (1.06–64.60)] for postoperative VTE. Conclusion A VTE-conscious perioperative management is as necessary in Asia as in Western countries.

In order to reduce maintenance labor of overhead contact lines (OCL), a contactless measurement device for OCL was developed. This device is mounted on a roof of a vehicle of a train and measures static three-dimensional positions of wires of OCL and detects positions of OCL fittings without touching the OCL while the train is running. We proposed hybrid sensing method that combines stereo measurement by image processing with structure measurement by laser range scanners and it realized to measure OCL geometry with high-precision even in sections with complicated OCL structure. In addition, we developed position detection method of the OCL fittings that can cope with changes in height and stagger of OCL by using machine learning. Measurement data of OCL contactless measurement device is static position of OCL without influence of a probe such as a pantograph. With this device, the OCL static position can be measured continuously instead of at each support point or dropper point. For maintenance of OCL, the criterion of OCL is defined as a static position. The device is utilizable for OCL maintenance and it sophisticate maintenance of OCL. For example, this device realize the height difference measurement of the crossing section, which has been conventionally measured by maintenance workers. In addition, the device are utilizable for OCL fittings inspection. Maintenance workers can check the image of OCL fittings without on foot into the field. Furthermore the static position data of OCL can be used to create simulation model of OCL dynamic behavior. Using this model, it is possible to know the dynamic response of cases where various pantographs pass at various speeds. Running tests was conducted on commercial line, and the performance of the device was verified when running at a speed of 130 km/h. The results shown that the repeated measurement accuracy is within 10 mm, and the OCL fitting detection rate is 90 % or more.

BackgroundThe Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria.MethodsWe conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0–10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24.ResultsBaseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P P P P = 0.0079 for systolic BP,P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR.ConclusionsIn Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction.Trial registrationThe study is registered at the UMIN Clinical Trials Registry (UMIN000018930;http://www.umin.ac.jp/ctr/index-j.htm). The study was conducted from July 1, 2015 to August 1, 2018.

Introduction Atypical femoral fractures are atraumatic or minimally traumatic fractures and rare side effects of bone resorption inhibitors. Bone resorption inhibitors are frequently used in the treatment of prostate cancer. Case presentation A 62-year-old man complained of difficulty in walking and left lower limb pain. Androgen deprivation and denosumab therapy for prostate cancer-induced bone metastasis was initiated 27 months ago. Even though the prostate-specific antigen level did not increase, imaging studies indicated the possibility of bone metastasis. The patient underwent bone biopsy; however, no malignancy was detected. Afterward, he had a fall, causing a complete fracture in his left femur. Conclusion Atypical femoral fractures occasionally mimic typical imaging findings and outcomes of bone metastasis. This case is important for recognizing such cases.

Background and Purpose— As a prespecified post hoc analysis of the J-STARS (Japan Statin Treatment Against Recurrent Stroke) Echo Study, the 5-year stroke recurrence rate according to the baseline mean carotid intima-media thickness (IMT) with and without pravastatin treatment was investigated. Methods— Patients were randomly assigned to receive pravastatin 10 mg/day (pravastatin group) or control group (nonstatin treatment; 1:1) for 5 years. Baseline mean IMT of the common carotid artery was measured by ultrasonography. Cox proportional hazards models were used to investigate whether the stroke (any ischemic stroke, atherothrombotic brain infarction, or lacunar infarction) recurrence rate was different according to tertiles of baseline mean IMT. Results— A total of 793 patients, including 388 in the pravastatin group and 405 in the control group, were investigated. In the control group, Cox proportional hazards models showed that participants in the highest tertile IMT group (≥0.931 mm) had a higher rate of atherothrombotic brain infarction than those in the lowest tertile IMT group (P value=0.045). Conclusions— Long-term pravastatin administration may prevent the occurrence of atherothrombotic brain infarction in noncardioembolic infarction patients with the highest tertile IMT. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00361530.

Background Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. Methods A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. Results The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732–1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670–0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575–0.919). The incidence of overall grade 3–4 adverse events was almost comparable in both groups. Conclusions Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.

Background A spontaneous iliopsoas muscle hematoma is relatively rare and often associated with abnormal coagulation. Nafamostat mesilate is an anticoagulant agent that is sometimes used to treat hemodialysis patients at high risk of bleeding. Although severe drug allergy caused by nafamostat mesilate was previously reported, spontaneous iliopsoas muscle hematoma secondary to disseminated intravascular coagulation caused by nafamostat mesilate allergy has not yet been reported. Case presentation Severe nafamostat mesilate allergy occurred in a 78-year-old male patient with a 2-year history of hemodialysis. During hospitalization, disseminated intravascular coagulation occurred followed by a progressive iliopsoas muscle hematoma a few days later. Emergent transarterial lumbar artery embolization was successfully performed. Conclusion For dialysis patients, a detailed medical history including repeated nafamostat mesilate use and considering an allergy to nafamostat mesilate in differential diagnosis are critical. In addition to early diagnosis, when an iliopsoas hematoma occurs, early intravascular treatment is important.

Aims/Introduction The present study investigated the relationship between the macronutrient energy ratio, dietary carbohydrate and glycated hemoglobin levels in Japanese patients with type 2 diabetes, to generate a potential optimal dietary intake of macronutrients for such patients. Materials and Methods In total, 3,032 patients participating in the Sleep and Food Registry in Kanagawa study were evaluated. Their diets were assessed for macronutrient content through a brief self‐administered dietary history questionnaire. Relevant biochemical assays were carried out. Results The mean energy intake (±standard deviation) was 1,711 ± 645 kcal/day. The proportion of energy supplied by protein, fat and carbohydrate were 16.3, 26.8 and 52.3%, respectively. Total fiber intake was 12.6 ± 5.7 g/day. The high glycated hemoglobin (HbA1c) group (HbA1c >8%) had significantly lower protein and higher carbohydrate intake than the low HbA1c group (HbA1c 60%) were most likely to have high HbA1c levels. HbA1c was significantly correlated with carbohydrate (%E) in all age groups and in patients taking one or two antidiabetic drugs. Conclusions The dietary carbohydrate:energy ratio has a positive correlation with HbA1c, suggesting that avoiding excessive carbohydrate intake (>60%) might help foster glycemic control.

Aim Appendiceal mucinous neoplasms are rare, and thus the literature is sparse with regard to histological types, staging, and prognosis. In particular, it is unclear how long‐term outcome may differ between mucinous adenocarcinomas and other adenocarcinomas. In the present study, we aimed to investigate the histological types and stages of appendiceal neoplasms, and to evaluate the prognostic impacts of these factors in patients with mucinous adenocarcinomas and non‐mucinous adenocarcinomas. Methods Patients with appendiceal tumors diagnosed between 2007 and 2016 were retrospectively identified from the databases of 19 institutions in the Clinical Study Group of Osaka University, Colorectal Group. Results A total of 266 patients with appendiceal tumors were identified, of whom 130 had pathologically diagnosed adenocarcinomas, including 57 with mucinous adenocarcinomas and 73 with non‐mucinous adenocarcinomas. Five‐year overall survival (OS) rates were 64.5% for mucinous adenocarcinomas, and 49.0% for non‐mucinous adenocarcinomas. OS was significantly shorter among patients with non‐mucinous adenocarcinomas compared to mucinous adenocarcinomas. Among patients with mucinous adenocarcinomas, 5‐year OS rates were 53.6% for stage 0/I, 82.6% for II/III, and 48.4% for IV. Among patients with non‐mucinous adenocarcinomas, 5‐year OS rates were 90.9% for stage 0/I, 68.8% for II/III, and 7.1% for IV. Analysis of patients with stage IV disease revealed significantly shorter OS among patients with non‐mucinous adenocarcinomas compared to mucinous adenocarcinomas. Conclusion Our present findings showed a better prognosis in patients with mucinous adenocarcinomas compared to non‐mucinous adenocarcinomas. In this setting, Union for International Cancer Control staging was associated with prognosis for non‐mucinous adenocarcinomas, but not for mucinous adenocarcinomas.

Hypothalamic obesity is a clinical syndrome characterized by severe and refractory obesity that is caused by hypothalamic function impairment. Recently, bariatric surgery has been attempted for patients with hypothalamic obesity after craniopharyngioma, but experiences have not yet been accumulated in other hypothalamic disorders. Here, we report the case of a 39-year-old male patient with panhypopituitarism who received laparoscopic sleeve gastrectomy (LSG) after intracranial germinoma treatment. The patient was diagnosed with intracranial germinoma at age 15 and achieved complete remission after radiotherapy (total 50 Gy). He was obese during diagnosis [body mass index (BMI), 29.2 kg/m2], and his obesity gradually worsened after the intracranial germinoma treatment, and LSG was considered when his BMI was 48.6 kg/m2. After 1 month of hospitalized diet-exercise program, LSG was performed. After LSG, his BMI gradually decreased and reached 38.8 kg/m2 on the day of discharge (6 weeks after the surgery). Five months after LSG, his insulin resistance improved, but insulin hypersecretion remained. Fifteen months after the surgery, his BMI was 31.2 kg/m2, with marked decrease in visceral and subcutaneous fat areas (from 393.8 cm2 and 168.2 cm2 before the surgery to 111.5 cm2 and 56.3 cm2, respectively.). To our knowledge, this is the first case of LSG for hypothalamic obesity after intracranial germinoma treatment. Although the pathophysiology of hypothalamic obesity is different from that of primary obesity, LSG could be a successful therapeutic choice for patients with hypothalamic obesity after the intracranial germinoma treatment.

Background Malnutrition is an independent risk factor for poor outcomes in patients with acute ischemic stroke. However, the indicator of malnutrition has not yet been established. We investigated the relationship between the Controlling Nutritional Status score, a useful prognostic measure of malnutrition in patients with cardiovascular diseases and malignant tumors, and functional outcomes in patients with acute ischemic stroke. Methods Patients with acute ischemic stroke (n = 264, 71 ± 12 y old) were consecutively evaluated within 7 d of stroke onset. The Controlling Nutritional Status score was calculated from the serum albumin, total peripheral lymphocyte count, and total cholesterol; a Controlling Nutritional Status score of 5 to 12 was defined as malnutrition. Poor functional outcome was defined as a modified Rankin Scale score of 3 to 6 at 3 mo. Results Of the total cohort, 230 patients (87.1%) were assessed. The patients with poor functional outcome (n = 85) were older; had a lower body mass index; had a higher frequency of atrial fibrillation, chronic heart failure, and anemia; and had a lower frequency of dyslipidemia and a current smoking status. In addition, the Controlling Nutritional Status score and National Institutes of Health Stroke Scale score at admission were significantly higher for the patients with poor functional outcome. After multivariate analysis, adjusted for baseline characteristics, a Controlling Nutritional Status score of 5 to 12 was found to be independently associated with poor outcome (odds ratio: 4.15, 95% confidence interval: 1.52–11.67, P = 0.005). Conclusions The Controlling Nutritional Status score at admission could be a useful prognostic marker of 3-mo functional outcomes in patients with acute ischemic stroke.

PURPOSE: Breast cancer (BC) is a risk factor for major depressive disorder (MDD), yet little research has tested the efficacy of different psychotherapies for depressed women with BC. This study, the largest to date, compared outcomes of three evidence-based, twelve-week therapies in treating major depressive disorder among women with breast cancer. METHODS: This randomized trial compared interpersonal psychotherapy (IPT), problem solving therapy (PST), and brief supportive psychotherapy (BSP). Conducted at the outpatient clinic of the New York State Psychiatric Institute/Columbia University, the trial offered bilingual treatment by treatment-specific psychotherapists supervised by treatment experts. The primary outcome was change in the Hamilton Depression Rating Scale (HAM-D) at 12 weeks. Secondary outcomes included other validated patient-reported outcomes for depression and quality of life. RESULTS: Of 179 women with breast cancer screening positive for depression at the Columbia Cancer Center, 134 eligible patients signed informed treatment consent. Half of patients were Hispanic and economically disadvantaged. Most women had stage I (35.2%) or II (36.9%) BC; 9% had stage IV. The three brief psychotherapies showed similar improvements on the HAM-D, with large pre-post effect sizes (d~ 1.0); a priori defined response rates were 35% for IPT, 50% for PST and 31% for BSP, and remission rates 25%, 30% and 27%, respectively. The three treatments also showed similar improvements in the Quality of Life Enjoyment and Satisfaction Questionnaire. Dropout was high, ranging from 37–52% across treatments. Predictors of dropout included having

Introduction/aims Cross-sectional area (CSA) reference values using ultrasonography vary widely for lower extremity peripheral nerves. In addition, there is a lack of data on the muscular branches of the tibial nerve and the anatomical variations of the sural nerve. We aimed to evaluate the ultrasonographic reference values for lower extremity peripheral nerves considering different anatomical variations and physical factors. Methods The CSA of the lower extremity nerve was measured at 10 sites. In addition to establishing reference values, differences in the CSA owing to anatomical variations were verified. The relationship between CSA and physical factors, such as age, height, weight, body mass index, and ankle circumference, was also examined. Results A total of 100 healthy Japanese volunteers were recruited. The mean CSA of the sural nerve significantly differed depending on its formation pattern (1.4-1.8 mm2 ). The mean decreases in CSAs from the proximal to distal tibial and fibular nerves within the popliteal region significantly differed based on the fine branching pattern. The maximum value of the mean decreases in CSAs in the tibial and fibular nerves reached 7.2 and 2.5 mm2 , respectively. With respect to physical factors, age and ankle circumferences were associated with CSA at several measurement sites. Discussion Fine branching from the tibial and fibular nerves and sural nerve formation may affect CSA measurements. The establishment of accurate CSA reference values requires consideration of anatomical variations in the peripheral nerves of the lower extremity.

Introduction: Post-synaptic dopamine receptor supersensitivity (DARSS) has been extensively researched by Dr. Masaya Segawa, who has investigated the efficacy of very-low-dose levodopa therapy (VLDT; 0.5–1 mg/kg/day). Considerable Japanese research supports the possibility that VLDT could be used to treat pediatric neurological disorders. We conducted an on-line survey in 2014 to collect real-world data on the use of VLDT to treat DARSS.Methods: A two-step survey, including a screening test and questionnaire, was posted on a private internet site that could be accessed via the VLDT Research Group home page, and 1,165 pediatric neurologists across Japan were invited to complete it.Results: A total of 25 respondents reported prescribing VLDT; 19 used VLDT to treat autism spectrum disorder, 14 for tics, 12 for speech delay, 9 for Rett syndrome, 7 for attention-deficit/hyperactivity disorder, intellectual disability, and 6 for sleep problems. Twelve respondents reported prescribing a dose of 0.5 mg/kg. Twenty-two reported that VLDT was effective for treating behavioral problems, and twenty reported a good efficacy for treating motor symptoms. Adverse events had a low incidence. Notably, respondents chose VLDT for its possible action in DARSS and for its safety. VLDT was commonly used for behavioral problems in patients younger than 5 years, and for motor symptoms in aged 5–9 years.Conclusion: VLDT could safely treat behavioral and motor symptoms in pediatric neurological disorders. In contrast, dopamine antagonists are associated with potent efficacy, but with adverse effects such as sleepiness and obesity. Further surveys should be conducted with a broader participants.

Biliary peritonitis is a rare cause of acute abdomen with life threatening consequences, ant it is usually associated with the perforation of biliary tract or upper gastrointestinal tract...

Objective We aimed to test our hypothesis that traditional Japanese (Kampo) medicine, hochuekkito (Hochu-ekki-to: HET) has a preventive effect for the symptoms on COVID-19. Trial design The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator sponsored, two-arm study. Participants Six thousand participants will be recruited from healthy hospital workers in 7 Japanese University Hospitals. Inclusion criteria: 1. Age from 20 to 75 years old at the time of registration 2. Asymptomatic and body temperature below 37°C at the time of registration 3. Capable of eating orally Exclusion criteria: 1. Previous upper respiratory inflammation due to viral infection (including suspected COVID-19) 2. Taking immunosuppressants 3. Allergic to the Kampo medicines used in this study 4. History of hypokalaemia, severe hypertension, severe liver dysfunction, and interstitial pneumonia 5. Regularly taking other Kampo medicines 6. Pregnant or possibly pregnant 7. Participating in other research 8. Judged to be unsuitable for this study by the doctor in charge Intervention and comparator Kampo group: participants receive HET in 9 tablets 2 times per day for 8 weeks. Control group: participants receive placebo in the same dosage as the Intervention group - 9 tablets 2 times per day for 8 weeks. Placebo tablets are identical in appearance and package to HET. Taste of placebo is different from that of HET. The Ohsugi Pharmaceutical Co. Ltd, Osaka, Japan manufactured the placebo and HET. Main outcomes Primary outcome: Number of patients with a SARS-CoV-2 RNA by ploymerase chain reaction (PCR) positive result with at least one symptom (fever, cough, sputum, malaise, shortness of breath) during the 12-week study period (including the 4-week observation period after oral administration). Secondary outcomes: 1. Period from infection to onset 2. Period from the appearance of symptoms to the disappearance of PCR positive 3. Number of days until the appearance or improvement of symptoms 4. Severe stage: presence of hospitalization 5. Shock stage: ICU management required for mechanical ventilation, shock vitals or failure of organ(s) other than lungs Safety endpoints include numbness in the hands and/or feet, edema, skin rash or other allergic symptoms, and gastric discomfort. Randomisation Patients are randomized (1:1 ratio) to each group using minimization implemented with the Electric data capture system (DATATRAK Enterprise Cloud), with balancing of the arms with age range (under 50 years of age or not) and having a history of risk factors for COVID-19 (cardiovascular disease, hypertension, diabetes, respiratory diseases). Blinding (masking) Only participants will be randomized. Numbers to be randomised (sample size) The main research hypothesis of this study is that Kampo medicines significantly prevent the onset of COVID-19. It is assumed that the infection rate before the administration of the drug under consideration will be 0% and that the incidence of COVID-19 thereafter will be 2- 3%, of which 70%-80% will show symptoms of COVID-19. Assuming that the pharmaceutical effect of the drug will be effective in 50% of patients and that the incidence rates in the placebo and drug groups will be 1.4%-2.4% and 0.7%-1.2%, respectively, the placebo is calculated at 2%, and the study drug at 1%. Since the frequency of verification is low and the number of cases will be large, we set a total of 10 analyses (9 interim analyses and a final analysis). Since the number of cases at the time of the final analysis will be 4,986 under the conditions of α = 0.05 and a power of 80% by the Peto method. We set at 600 cases in each interim analysis with an estimated dropout rate of 16.9%. Finally, the total number of cases is set to 6,000 with 3,000 in the placebo group and 3,000 in the HET group. Trial status Protocol version 1.3 of October 23rd , 2020. Recruitment start (expected): December 1st, 2020. Recruitment finish (expected): December 31st, 2022. Trial registration This trial is registered in the Japan Registry of Clinical Trials (jRCT) (jRCTs031200150) on 14 October 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Objectives The present study aimed to examine the effectiveness of proton magnetic resonance spectroscopy (1HMRS) in determining the progression of neurological symptoms resulting in acute ischemic stroke in patients with lenticulostriate artery (LSA) infarction. Materials and Methods 1HMRS was performed within 72 h after neurological symptom onset. Voxel of interest was placed in tissue that included the pyramidal tract and identified diffusion weighted echo planar spin-echo sequence (DWI) coronal images. Infarct volume in DWI was calculated using the ABC/2 method. 1HMRS data (tNAA, tCr, Glx, tCho, and Ins) were analyzed using LCModel. Progressive neurological symptoms were defined as an increase of 1 or more in the NIHSS score. Patients who underwent 1HMRS after progressive neurological symptoms were excluded. Results In total, 77 patients were enrolled. Of these, 19 patients had progressive neurological symptoms. The patients with progressive neurological symptoms were significantly more likely to be female and had higher tCho/tCr values, higher rates of axial slices ≥ 3 slices on DWI, higher infarct volume on DWI, higher maximum diameter of infarction of axial slice on DWI, and higher SBP on admission compared to those without. Multivariable logistic analysis revealed that higher tCho/tCr values were independently associated with progressive neurological symptoms after adjusting for age, sex, and initial DWI infarct volume (tCho/tCr per 0.01 increase, OR 1.26, 95% CI 1.03–1.52, P = 0.022). Conclusions Increased tCho/tCr score were associated with progressive neurological symptoms in patients with LSA ischemic stroke. Quantitative evaluation of 1HMRS parameters may be useful for predicting the progression of neurological symptoms.

Strains of Streptococcus mutans expressing the cell surface collagen-binding protein, Cnm, encoded by cnm (cnm-positive S. mutans), are associated with hypertensive intracerebral hemorrhage (ICH) and the occurrence of cerebral microbleeds (CMBs). Small diffusion-weighted imaging (DWI) hyperintensities in patients with acute ICH are also associated with CMBs. However, the association between cnm-positive S. mutans and DWI hyperintensities is unclear. Hence, this study aimed to investigate the association between cnm-positive S. mutans and DWI hyperintensities in patients with acute ICH.Patients with acute ICH were prospectively registered at three hospitals. Dental plaque specimens were collected within 4 days after admission, and cnm-positive S. mutans was detected using the polymerase chain reaction. Magnetic resonance imaging at 14 ± 5 days after admission was used to evaluate DWI hyperintensities and CMBs.A total of 197 patients were enrolled in this study. cnm-positive S. mutans was detected in 30 patients (15.2%), and DWI hyperintensities were observed in 56 patients (28.4%). Patients with cnm-positive S. mutans had a higher frequency of DWI hyperintensities (50.0% vs 24.6%; p = 0.008) and a higher number of CMBs (5.5 vs 1.5; p 0.001) than those without cnm-positive S. mutans. Multivariable logistic analysis revealed that the presence of cnm-positive S. mutans was independently associated with DWI hyperintensities (OR 2.38; 95% CI 1.01-5.61; p = 0.047) after adjusting for several confounding factors.This study found an association between the presence of cnm-positive S. mutans and DWI hyperintensities in patients with acute ICH.

This chapter analyzed how Japanese teachers' qualifications and abilities, as well as educational policies, have been promoted since the postwar period to the present day and summarized these results. There are discrepancies between the needs of students' families and the real world and the ideas and contents required by the Course of Study. Teachers have tried to play a positive role in bridging the gap and in merging the reality and the ideals. In order to bridge the “difference” faced by school sites, it is necessary to start by examining the contents of the reforms required from the bottom and reforms required from the top. As an initiative from below, in most elementary schools in Japan, groups of teachers have voluntarily gathered, and “Jugyo-Kenkyu” have been conducted for many years to analyze the challenges of their own school's students as a team. Although Jugyo-Kenkyu has achieved some positive results, the way to measure the effectiveness of the research is still an issue.

Aim The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome. Methods Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission. Results Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02- 1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome. Conclusion Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.