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Esophageal squamous cell carcinoma (ESCC) has a poor prognosis; therefore, early detection is essential. In Japan, more than 90% of esophageal cancers are ESCC. Endoscopy is effective to detect ESCC in the early stage, but there is a limited number of reports examining its efficacy and effectiveness.This study aimed to evaluate the efficacy of screening endoscopy for detecting ESCC.This retrospective study analyzed the prevalence of ESCC, annual transition of prevalence, and the stage of each ESCC among 128,520 medical check-up patients who underwent esophagogastroduodenoscopy from April 2015 to March 2020 at Yamanashi Koseiren Health Care Center. Furthermore, a case-control study utilized the multivariate logistic regression analysis was performed to assess the risk factor of ESCC.Among a total of 128,520 subjects, 42 ESCC patients were detected, with 95.2% being diagnosed at early stages. Annual prevalence in males was 0.015% (2/13,122) in 2015, 0.044% (6/13,562) in 2016, 0.044% (6/13,676) in 2017, 0.074% (10/13,488) in 2018%, and 0.11% (16/14,386) in 2019. ESCC prevalence has been increasing each year. A significant increase was observed between 2015 and 2018 (p = 0.039). ESCC prevalence was 0.102% (25/24,272) when focusing on males aged over 50 years with a history of smoking and drinking. Regarding the case-control study, the multivariate logistic regression analysis revealed smoking (p = 0.044), mean corpuscular volume (MCV) (p = 0.0018), and severe gastric atrophy (p = 0.048) as positively correlated with ESCC.In conclusion, ESCC has been increasing in our center from 2015 to 2019, and the prevalence has been approaching that of gastric cancer in 2019 in male subjects. ESCC can be detected efficiently by targeting males with high MCV who have a history of drinking and smoking.

Cardiac rehabilitation (CR) is an evidence-based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home-based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT).This study was a single-centre, open-label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II-III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT-based exercise and nutrition guidance using ICT via a Fitbit® device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture-posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 ± 10.1 years, 53% were male, and 87% had non-ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 ± 43.9 m vs. -4.3 ± 38.8 m; P 0.001) at a 73% of adherence rate. There was no significant change in adverse events in either group.Our comprehensive HBCR programme using ICT for HF patients with physical frailty improved exercise tolerance and improved lower extremity muscle strength in our sample, suggesting management with individualized ICT-based programmes as a safe and effective approach. Considering the increasing number of HF patients with frailty worldwide, our approach provides an efficient method to keep patients engaged in physical activity in their daily life.

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.

Myoclonus and ataxia, with or without opsoclonus, have recently been recognized as a central nervous system syndrome associated with coronavirus disease-2019 (COVID-19). A 52-year-old Japanese man developed myoclonus and ataxia 16 days after the onset of COVID-19. Brain single-photon emission computed tomography (SPECT) revealed hyperperfusion in the cerebellum and hypoperfusion in the cerebral cortices with frontal predominance during the acute stage, which improved over two months. This study indicates that brain perfusion SPECT can be effective in detecting functional alterations in COVID-19-related myoclonus and ataxia.

Outside of clinical trials, the prophylactic effect of dihydropyridine calcium channel blockers (CCBs) on ischemic events in patients with nonvalvular atrial fibrillation (NVAF) has not been confirmed. We compared the effect of dihydropyridine CCBs on ischemic events in anticoagulated NVAF patients. We conducted a multicenter historical cohort study at 71 centers in Japan. The inclusion criterion was taking vitamin K antagonists for NVAF. The exclusion criteria were mechanical heart valves and a history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The primary outcomes were ischemic events and ischemic strokes; the secondary outcomes were all-cause mortality, major bleeding, and hemorrhagic strokes. The mean patient age was 73 years old, and 67% of the patients were male. Seventy-eight percent of the patients had hypertension, and dihydropyridine CCBs were used by 2693 (34%) patients (CCB group). The cumulative incidences of ischemic events and ischemic strokes at 4 years in the CCB and No-CCB groups were 5.9% vs. 5.2% and 5.6% vs. 4.8%, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the CCB group for ischemic events and ischemic strokes were 1.22 (0.95-1.57) and 1.32 (1.02-1.71), respectively; the adjusted HRs (95% CIs) of the CCB group for all-cause mortality, major bleeding, and hemorrhagic strokes were 0.85 (0.69-1.04), 1.12 (0.92-1.35), and 1.08 (0.62-1.88), respectively. Dihydropyridine CCB use by anticoagulated NVAF patients significantly increased ischemic strokes in a real-world setting.

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.

Although associations between malnutrition status at stroke admission and poor stroke outcomes have been established, the effect of nutritional intake during the acute phase remains unclear. We aimed to evaluate the associations between nutritional intake one week after admission and the outcome at three months among acute ischemic stroke (AIS) patients.Consecutive AIS patients were investigated. Nutritional status at admission was evaluated using the Controlling Nutritional Status score, calculated from the serum albumin, lymphocyte count, and total cholesterol. We retrospectively evaluated nutritional intake (energy and protein) one week after admission, and the cutoff value of each nutritional intake level for good outcome was defined as the modified Rankin Scale 0-2 at three months after stroke onset using the receiver operating characteristic curve.Of the 205 patients, 146 patients had good outcomes. Mild initial neurological symptoms and good nutritional status at admission were associated with good outcome. The cutoff value of good outcome for protein intake was 0.812 g/kg/day (sensitivity: 0.884, specificity: 0.509) and that for energy intake was 19.0 kcal/kg/day (sensitivity: 0.918, specificity: 0.424). Those nutritional intake indicators were independently associated with good outcome after adjusting for baseline confounders, including stroke severity and nutritional status at admission (protein intake: odds ratio (OR), 4.04; 95% confidence intervals (CIs), 1.14-13.1, and energy intake: OR, 5.00; 95% CIs, 1.41-17.8, respectively).Adequate nutritional intake at one week after admission was independently associated with good outcome regardless of the nutritional status at admission or stroke severity.

Acid-suppressive drugs (ASDs) are often prescribed for patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs). However, the risk-benefit balance of ASDs prescription for patients with NVAF taking OACs is still unclear. This study aimed to assess the association between ASDs and clinical outcomes in patients taking OACs for NVAF.This study is a subanalysis of an historical registry study from 71 centers in Japan. We included patients taking vitamin K antagonists for NVAF and excluded those with mechanical heart valves or a history of pulmonary thrombosis or deep vein thrombosis. We registered consecutive patients in February 2013 and followed them up until February 2017. The primary outcomes were ischemic events, major bleedings, and all-cause mortality. Ischemic stroke, acute myocardial infarction, and hemorrhagic stroke comprised the secondary outcomes.We included 7826 patients with a mean age of 73 years, 5274 (67%) of whom were males. The adjusted hazard ratios (95% confidence intervals) for ischemic events, major bleedings, and all-cause mortality in the ASD group compared with the no-ASD group were 0.998 (0.78-1.27), 0.98 (0.81-1.18), and 1.22 (1.02-1.47), respectively, while those for ischemic stroke, acute myocardial infarction, and hemorrhagic stroke were 0.96 (0.74-1.24), 0.82 (0.36-1.88), and 1.17 (0.69-1.99), respectively.ASDs were significantly associated with all-cause mortality in patients with NVAF taking OACs.

A conventional antibody targeting a soluble antigen in circulation typically requires a huge dosage and frequent intravenous administration to neutralize the antigen. This is because antigen degradation is reduced by the formation of antigen-antibody immune complexes, which escape from lysosomal degradation using neonatal Fc receptor (FcRn)-mediated recycling. To address this, we developed an antigen-sweeping antibody that combines pH-dependent antigen binding and Fc engineering to enhance Fc receptor binding. The sweeping antibody actively eliminates the plasma antigens by increasing the cellular uptake of the immune complex and dissociating the antigens in the acidic endosome for degradation. Strong antigen sweeping can reduce the dosage, potentially achieve higher efficacy, and expand the scope of antigen space available for targeting by antibodies. In this study, to further improve the sweeping efficacy, we developed a novel antibody Fc variant by enhancing Fcγ receptor IIb (FcγRIIb) binding and modulating charge characteristics for increased cellular uptake of the immune complex, together with enhancing FcRn binding for efficient salvage of the antigen-free antibodies. Our Fc variant achieved strong antigen sweeping in cynomolgus monkeys with antibody pharmacokinetics comparable to a wild-type human IgG

Emergency medical service (EMS) providers play an important role in determining which hospital to choose. To date, there is no evidence-based guideline to support their decisions, except for major trauma cases. Secondary transport is considered when a patient needs further investigation or treatment after primary transport, but this can delay treatment and put patients at unnecessary risk. The objective of this study was to investigate the outcomes of pediatric secondary transport patients to tertiary hospitals.This was a citywide population-based observational study conducted in Kobe, Japan. We reviewed the EMS registry to identify secondary transport patients younger than 19 years and investigated their clinical characteristics. We excluded cases of unknown hospital destinations, nontransported cases, and major trauma patients who followed a different protocol for a hospital destination. The primary endpoint was the hospital outcome 12 hours after transport. Because there was no link between the EMS patient transport data and the hospital medical records, a probabilistic linkage was performed to obtain the hospital outcomes. Patients who required secondary transport were compared with patients transported directly to tertiary hospitals.A total of 13,720 pediatric patients were transported from the field by Kobe EMS between January 2013 and December 2015. Among them, 81 pediatric patients (0.6%) required secondary transport to tertiary hospitals within 24 hours of the primary transport, whereas a total of 3673 patients (27%) were transported directly to tertiary hospitals. Despite no apparent difference in prehospital severity, secondary transport patients were associated with higher hospitalization rates and a need for critical care compared with those who had direct transport. Seizure was the most common reason for the use of secondary transport, and 89% of the seizure patients were hospitalized after undergoing secondary transport; minor trauma was the second most common reason for the use of secondary transport, and 53% of the patients were hospitalized.In this study, the characteristics of the secondary transport patients and hospital outcomes revealed a heterogeneity in pediatric prehospital transport. It is recommended that the development of pediatric EMS destination guidelines cover children's diverse conditions. Further studies are required, and linkages between prehospital and hospital data will help promote a better understanding of appropriate hospital destinations.

© 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.

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.

Vital signs are important for patient assessment, but little is known about interpreting those of children in prehospital settings. We conducted an observational study to investigate the association between prehospital vital signs of children and their clinical outcomes in hospitals. We plotted the data of patients with critical outcomes on published reference ranges, such as those of healthy children to evaluate the clinical relevance. Of the 18,493 children screened, 4477 transported to tertiary hospitals were included in the analysis. The outcomes 12 h after being transported to a tertiary hospital were as follows: deceased, 41; hospitalization with critical deterioration events, 65; hospitalization without critical deterioration events, 1086; returned home, 3090; and unknown, 195. The reference ranges of the heart rates (sensitivity: 57.7%, specificity: 67.5%) and respiratory rates (sensitivity: 54.5%, specificity: 67.7%) of healthy children worked best to detect the critical outcomes. Therefore, the reference ranges of healthy children were concluded to be suitable in prehospital settings; however, excessive reliance on vital signs carried potential risks due to their limited sensitivities and specificities. Future studies are warranted to investigate indicators with higher sensitivities and specificities.

The Bayesian penalized likelihood (BPL) reconstruction algorithm, Q.Clear, can achieve a higher signal-to-noise ratio on images and more accurate quantitation than ordered subset-expectation maximization (OSEM). The reconstruction parameter (β) in BPL requires optimization according to the radiopharmaceutical tracer. The present study aimed to define the optimal β value in BPL required to diagnose Alzheimer disease from brain positron emission tomography (PET) images acquired usingImages generated from Hoffman 3D brain and cylindrical phantoms were acquired using a Discovery PET/computed tomography (CT) 710 and reconstructed using OSEM + time-of-flight (TOF) under clinical conditions and BPL + TOF (β = 20-1000). Contrast was calculated from images generated by the Hoffman 3D brain phantom, and noise and uniformity were calculated from those generated by the cylindrical phantom. Five cognitively healthy controls and five patients with Alzheimer disease were assessed using [The contrast in BPL satisfied the Japanese Society of Nuclear Medicine (JSNM) criterion of ≥55% and exceeded that of OSEM at ranges of β = 20-450 and 20-600 for [The BPL achieved better image contrast and less image noise than OSEM, while maintaining quantitative standardized uptake value ratios (SUVR) due to full convergence, more rigorous noise control, and edge preservation. The optimal β values for [

Although hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer.Consecutive acute ischemic stroke patients with cancer (n = 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed.Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.00-1.08, and aOR: 0.50, 95% CI: 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio [aHR]: 2.65, 95% CI: 1.37-5.12, and aHR: 2.29, 95% CI: 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer.Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

In 2008, a familial noradrenergic pheochromocytoma (PCC) with a KIF1B germline mutation in exon 41 was reported in a 24-year-old female proband and her family. However, in 2020, the same research group reported that the cause of PCC in this family was a MAX germline mutation and was not due to the KIF1B mutation. In this study, we investigated the pathogenicity of a KIF1B germline mutation detected in a 26-year-old woman with juvenile-onset noradrenergic PCC. She was surgically treated and did not have a family history of PCC. We performed whole-exome sequencing, Sanger sequencing, and immunohistochemical and gene expression analyses of catecholamine-synthesizing enzymes. Three tumors with associated somatic mutations were used as the control group. Whole-exome sequencing revealed a p.V1529M KIF1B germline mutation in exon 41 in our patient, and no other associated germline and somatic mutations, including MAX, were detected. Sanger sequencing confirmed the presence of both mutant and wild-type alleles in the tumor. Among the catecholamine-synthesizing enzymes, the expression of phenylethanolamine-N-methyl transferase was suppressed. An in silico analysis of the p.V1529M mutation showed a score suggestive of pathogenicity. After evaluation with the international guideline for sequence variants, p.V1529M mutation was still classified as a variant with uncertain significance; however, our data, including the in silico analysis data, provided certain evidences that met the criteria supporting its pathogenicity. Therefore, this study can support future studies in proving the pathogenicity of the KIF1B p.V1529M mutation.

Factors that influence the decision of voluntary driving cessation in patients living with Parkinson’s disease (PD) are still unclear. We aimed to reveal the factors affecting the decision of voluntary driving cessation in patients with PD. This hospital-based cross-sectional study recruited consecutive outpatients with PD. Data on sociodemographic and clinical characteristics and medication use were collected from the patients using semistructured interviews. Cognitive function was evaluated using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). We excluded patients with dementia or motor impairment ( Hoehn − Yahr stage > 3 ). We divided the patients into two groups, with and without voluntary driving cessation (D: driver; RD: retired driver), and conducted investigations using multivariate logistic regression analyses. Of the 40 patients, 8 (20.0%) voluntarily retired from driving. Patients who decided on driving cessation had a higher prevalence of freezing of gait (FOG) (D vs. RD, 25.0% vs. 87.5%; P = 0.001 ) and tended to have lower scores for attention in the MoCA-J (D vs. RD, 5.0 ± 1.2 vs. 4.1 ± 1.4 ; P = 0.086 ). Multivariable analysis showed that FOG was independently associated with driving cessation (odds ratio: 14.46, 95% confidence interval: 1.91–303.74). FOG was associated with voluntary driving cessation in patients with PD without dementia or severe motor impairment. Physicians should consider providing extensive social support to maintain patients’ mobility and independence, especially if the patients have these clinical factors.

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.

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.

One of the most persistent health disparities is the underutilization of mental health services by people of color. Neither evidence-based treatments (universal focus) nor culturally adapted treatments (group focus) have reduced these disparities. We propose the personal relevance of psychotherapy (PROP) model, which integrates universal, group, and individual dimensions to determine the personal relevance of interventions. A cultural example of personal relevance among people of East Asian ancestry involves "face" (i.e., one's prestige and position in society), which may moderate treatment outcomes. Pragmatic intervention approaches focused on helping individuals cope with specific external problems, compared to managing a "personal" disease, can effectively "restore" face. Thus, social problem-solving interventions may be more personally relevant to many people of East Asian ancestry than are approaches that are internally focused. In addition, we posit that social neuroscience can offer unique opportunities above and beyond self-report measures when assessing the impact of PROP and the personal relevance of interventions for diverse populations. Our preliminary evidence upon testing this hypothesis indicated that among Asian Americans, exposure to problem-solving therapy content elicited significantly greater neural activity in brain areas associated with personal relevance compared to exposure to cognitive-behavioral therapy content. Identifying personally relevant interventions has the potential to reduce mental health disparities by increasing engagement with mental health services for diverse groups. The increased client engagement produced by personally relevant interventions also has the potential to make mental health services more effective for diverse groups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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.

Mitochondria uncoupling protein2 (UCP2) expressed ubiquitously is a key molecule of energy metabolism. Insulin-like growth factor-1 (IGF-1) is a hormone, a target molecule of growth hormone (GH) signal pathway, which is also known as the drug "mecasermin" for clinical usages. IGF-1 is seemed to be closely related to metabolic diseases, such as adult GH deficiency. However, there has not been reports depicted possible relationship with each other. So, we sought to elucidate the mechanisms by which expression of UCP2 is regulated by IGF-1 via FOXO1. The findings suggested that three sequences in the consensus UCP2 promoter play complementary functional roles in the functional expression of FOXO1. So, we found that FOXO1 is involved in IGF-1-mediated energy metabolism greater than that of direct action of GH via STAT5. Our findings suggested that IGF-1 was involved in energy metabolism by regulating the expression of UCP2 via the PI3K/Akt/FOXO1 pathway.

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

There is accumulating evidence that periodontal disease is associated with atrial fibrillation (AF) or stroke, but it is unclear which causative species of periodontal disease are present in stroke patients with AF. We aimed to investigate the associations between AF and specific periodontal pathogens using serum titers of IgG antibodies of bacteria in acute stroke patients.Acute stroke patients were registered at two hospitals. Serum samples were evaluated for titers of antibodies against 9 periodontal pathogens (16 genotypes) using ELISAs. We identified AF in patients according to the following criteria: (1) a history of sustained or paroxysmal AF or (2) AF detection upon arrival or during admission. We carried out propensity score matching to categorize the patients as those with AF and those without.Of the 664 acute stroke patients, 123 (18.5%) had AF. After propensity score matching, 234 patients were selected. Patients with AF had a higher prevalence of positive serum titers of antibodies against Porphyromonas gingivalis (FimA type III) and Porphyromonas gingivalis (FimA type V) than those without AF (59.0% vs. 39.3%, p=0.004 and 58.2% vs. 40.2%, p=0.009, respectively).Porphyromonas gingivalis, especially FimA type III and type V, might be associated with AF in stroke patients.

Diffusion-weighted imaging hyperintensities are observed in intracerebral hemorrhage patients at times and might be associated with unfavorable functional outcomes. However, the suitable time to evaluate diffusion-weighted imaging hyperintensities to influence stroke outcome remains unclear. This study investigated the associations between acute and sub-acute diffusion-weighted imaging hyperintensities and functional outcomes among patients with acute intracerebral hemorrhage.Diffusion-weighted imaging hyperintensities were evaluated within 24 h (acute phase) and at 14 ± 5 days (sub-acute phase). An unfavorable functional outcome was a score of 5-6 on the modified Rankin Scale at 3 months.Among 268 intracerebral hemorrhage patients, diffusion-weighted imaging hyperintensities in the acute phase were observed in 32 (11.9%). Among 227 patients who underwent a second magnetic resonance imaging in the sub-acute phase, diffusion-weighted imaging hyperintensities were observed in 57 (25.1%). Multivariable analysis revealed that the baseline intracerebral hemorrhage volume, history of stroke, and severe white matter lesions were associated with sub-acute diffusion-weighted imaging hyperintensities. The patients with unfavorable outcomes (n = 37) had a higher frequency of sub-acute diffusion-weighted imaging hyperintensities than those without (n = 190) (51.4% vs. 20.0%, P 0.001); the frequencies of acute diffusion-weighted imaging hyperintensities were not significantly different between the groups (13.5% vs. 10.0%, P = 0.559). Sub-acute diffusion-weighted imaging hyperintensities were independently associated with unfavorable outcomes after adjusting for confounding factors (Odds Ratio, 3.35, 95% CI 1.20-9.35, P = 0.021).The rate of sub-acute diffusion-weighted imaging hyperintensities was higher than acute diffusion-weighted imaging hyperintensities among acute intracerebral hemorrhage patients and likely to be associated with unfavorable outcomes.

To investigate the changes in asthma exacerbation, as well as in oral corticosteroid (OCS) use, exacerbation-related healthcare resource utilization (HRU), and healthcare costs before and after mepolizumab treatment initiation in patients with severe asthma who started treatment with mepolizumab in a real-world clinical setting in Japan.A retrospective, observational, self-controlled study was conducted in Japan using a hospital-based administrative claims database. Patients who were diagnosed with asthma and who were new users of mepolizumab were included in the study. The primary outcome was the incidence rate of any asthma exacerbation/patient-year during the 12-month period before (baseline period) and after (follow-up period) the first mepolizumab prescription. Secondary outcome measures included the proportion of patients with ≥1 any asthma exacerbation, patients with exacerbation requiring hospitalization, the incidence rate of exacerbations requiring hospitalization/patient-year, the median daily OCS dose (OCS sparing effect), exacerbation-related HRU (hospitalization length, the proportion of patients with emergency visits, and the number of emergency/outpatient visits), and associated costs.Of the 377 patients included, 56.2% were ≥65 years of age. Following the first mepolizumab prescription, incidence rates for any asthma exacerbation were reduced by 40.6% (4.00/patient-year to 2.38/patient-year; the incidence rate ratio [95% confidence interval]: 0.60 [0.53-0.67]; p lt; 0.0001) from the baseline to follow-up periods. The incidence rate of exacerbations requiring hospitalization was reduced by 55.8% (0.37/patient-year to 0.16/patient-year) from the baseline to follow-up periods. The proportion of patients experiencing any exacerbation decreased from 84.4% to 57.8% and those requiring hospitalization decreased from 23.9% to 10.3% both from the baseline to follow-up periods. The median daily OCS dose decreased by 44.6% (median [interquartile range]: 6.7 [4.7-9.9] mg/day to 3.3 [0.9-5.6] mg/day) from the last baseline quarter to the 4th quarter of the follow-up period. All exacerbation-related HRUs decreased from the baseline to follow-up periods. Inpatient cost reduced bygt;50% (123,279 Japanese Yen [JPY]/patient-year vs. 57,283 JPY/patient-year), reducing the total cost by 80,716 JPY from the baseline to follow-up periods.Mepolizumab was effective in treating patients with severe asthma by reducing the incidence rates of exacerbations and exacerbation requiring hospitalization, OCS dose, exacerbation-related HRU, and cost in routine clinical practice in Japan.

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.

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.

Objective The objective of our study was to examine the direct action of insulin-like growth factor-1(IGF-1) signaling on energy homeostasis in myocytes. Design We studied the IGF-1 stimulation of mitochondrial uncoupling protein 3 (UCP3) expression in the HEK 293 derived cell line TSA201, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal myoblasts. We also investigated the direct effect of IGF-1 on the Insulin/IGF-1 receptor (IGF-1R)/phosphatidylinositol 3 (PI3)-Akt/forkhead box O4 (FOXO4) pathway using a combination of a reporter assay, semi-quantitative polymerase chain reaction, western blotting, and animal experiments. Results We demonstrated that IGF-1 regulates UCP3 expression via phosphorylation of FOXO4, which is a downstream signal transducer of IGF-1. UCP3 expression increased with activated FOXO4 in a dose-dependent manner. We also examined the functional FOXO4 binding site consensus sequences and identified it as the −1922 bp site in the UCP3 promoter region. UCP3 was also found to be concomitantly expressed with IGF-1 during differentiation of C2C12 myoblasts. Our animal experiments showed that high fat diet induced IGF-1 levels which likely influenced UCP3 expression in the skeletal muscle. Conclusion Our findings demonstrate that that IGF-1 directly stimulates UCP3 expression via the IGF-1/IGF-1R/PI3-Akt/FOXO4 pathway.

The complex molecular formats of recent therapeutic antibodies, including bispecific antibodies, antibody fragments, and other fusion proteins, makes the task of purifying the desired molecules in a limited number of purification steps more and more challenging. Manufacturing these complicated biologics can be substantially improved in the affinity capture stage if the simple bind-and-elute mode is accompanied by targeted removal of the impurities, such as mis-paired antibodies and oligomers or aggregates. Here, we report a method, based on the binding valency to Protein L resin, of separating proteins during the elution step by simply controlling the conductivity at low pH. We show that the method efficiently separated targeted antibodies from mis-paired and aggregated species. Notably, the number of Protein L binding sites can be built into the molecule by design to facilitate the purification. This method may be useful for purifying various antibody formats at laboratory and manufacturing scales.

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.

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.

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.

The mitochondrial unfolded protein response (UPRmt) is a stress response mediated by the expression of genes such as chaperones, proteases, and mitokines to maintain mitochondrial proteostasis. Certain genetically modified mice, which defect mitochondrial proteins specifically in adipocytes, developed atrophy of the white adipose tissue, resisted diet-induced obesity, and had altered whole-body metabolism. UPRmt, which has beneficial functions for living organisms, is termed “mitohormesis”, but its specific characteristics and detailed regulatory mechanism have not been elucidated to date. In this review, we discuss the function of UPRmt in adipose atrophy (lipoatrophy), whole-body metabolism, and lifespan based on the concept of mitohormesis.

An 80-year-old man visited our hospital because of abdominal distension and epigastralgia. He was diagnosed esophageal cancer(Mt, SCC, T3N0M0, Stage Ⅱ). Because he was elderly, he received chemoradiotherapy(CRT)with S-1. At 54 Gy/27 Fr, he was admitted to the hospital because of cough exacerbation, fever, and food intake loss. A chest and abdominal CT showed a pneumonia pattern. First, antibiotics were started for suspected bacterial pneumonia. Nevertheless, elevation of inflammatory reactions and continuous fever were observed. As interstitial pneumonia was suspected, we started to administer an injection of prednisolone 60 mg. His respiratory symptoms were improved. However, we observed that disseminated erythema of the trunk spread throughout the body and liver enzymes further increased. As blood examination revealed elevated CMV-IgG antibody and C7-HRP positive, we diagnosed cytomegalovirus(CMV)reactivation. Administration of ganciclovir improved liver damage and disseminated erythema. He discharged our hospital while the steroid dose was reduced and valganciclovir continued administrating. The therapeutic effect of esophageal cancer was partial response(PR). We are following his symptoms and CT scan while adjusting the steroid dose. This is a rare case of CMV reactivation due to immunosuppression caused by steroids therapy during CRT against esophageal cancer. We should be aware of CMV infection during CRT and steroid therapy.

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.

Purpose To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers. Methods We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromatography time-of-flight mass spectrometry. The altered metabolomic profiles were visualized by heat map and principal component analysis. Metabolic pathway analysis was performed by Metabo Analyst 4.0 using differentially expressed metabolites. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. Machine learning algorithms were implemented by random forest using the R environment. Finally, an independent set of 18 IgG4-ROD and 17 orbital MALT lymphoma specimens were used to validate the identified biomarkers. Results The principal component analysis showed a significant difference of both IgG4-ROD and orbital MALT lymphoma for biopsy specimens and controls. Interestingly, lesions in IgG4-ROD were uniquely enriched in arachidonic metabolism, whereas those in orbital MALT lymphoma were enriched in tricarboxylic acid cycle metabolism. We identified spermine as the best discriminator between IgG4-ROD and orbital MALT lymphoma, and the area under the receiver operating characteristic curve of the spermine to discriminate between the two diseases was 0.89 (95% confidence interval, 0.803-0.984). A random forest model incorporating a panel of five metabolites showed a high area under the receiver operating characteristic curve value of 0.983 (95% confidence interval, 0.981-0.984). The results of validation revealed that four tissue metabolites: N1,N12-diacetylspermine, spermine, malate, and glycolate, had statistically significant differences between IgG4-ROD and orbital MALT lymphoma with receiver operating characteristic values from 0.708 to 0.863. Conclusions These data revealed the characteristic differences in metabolomic profiles between IgG4-ROD and orbital MALT lymphoma, which may be useful for developing new diagnostic biomarkers and elucidating the pathogenic mechanisms of these common orbital lymphoproliferative disorders.