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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are common therapeutic agents for EGFR mutation-positive advanced non-small-cell lung cancer. There has been no report of rhabdomyolysis caused by an overdose of EGFR-TKIs. We herein review the existing literature on the subject and report a rare case of rhabdomyolysis due to an overdose of gefitinib, an EGFR-TKI.

Background Measurement of allergen-specific IgE antibodies to inhaled allergens is important for the diagnosis and risk evaluation of allergic diseases such as asthma and allergic rhinitis. This study aimed to elucidate the prevalence of allergen sensitization among the healthy population in Japan using serum samples stocked in the Japanese Red Cross for blood donation. Methods Age- and gender-stratified serum samples (n = 800) from residents in Tokyo aged 20–59 years were randomly selected from the stocked serum obtained for blood donation in 2005. Total and specific IgE antibodies to 17 inhaled allergens were measured by the ImmunoCAP method. Individuals with positive (≥0.35 UA/mL) specific IgE antibodies to at least one inhaled allergen were defined as atopic. Stocked serums from donors aged 20–29 years in Sapporo, Osaka, Fukuoka, and Okinawa (n = 200 each) were also obtained for the measurement of IgE to six common inhaled allergens, to evaluate regional differences in the rate of positivity. Results Among residents in Tokyo, the prevalence of atopy was 78.0% and highest in men aged 20–29 years (94.0%), which decreased with age. The prevalence of specific IgE antibodies was highest for Japanese cedar pollen (66.8%), followed by cypress pollen (46.8%), Dermatophagoides pteronyssinus (38.3%), and moths (30.1%). Examination of IgE to Japanese cedar pollen, D. pteronyssinus, and moths identified 97.6% of atopic subjects in Tokyo. There were substantial regional differences in the prevalence of pollen IgE positivity. Conclusions This study demonstrated an extremely high prevalence of positivity in inhaled allergen-specific IgE antibodies among healthy adults in Japan.

Achilles tendon xanthoma (ATX) is one of the typical features of familial hypercholesterolemia (FH). The morphological evaluation of ATX by X-ray radiography is widely recognized; however, the utility of other imaging modalities remains unclear. We herein report two cases of FH in which Doppler ultrasound imaging demonstrated a microvascular flow in ATX that only rarely could be observed in normal Achilles tendons. Neoangiogenesis accompanies chronic inflammation and it may play an important role in the deposition of cholesterol crystals leading to ATX. In addition to the morphological evaluation of ATX, the assessment of neoangiogenesis may therefore be essential for the evaluation of ATX.

Objective Patients with Prader-Willi syndrome (PWS) are known to have a high mortality rate. However, little is known about the exact reason for this, particularly in adults, because so few reports have been published. The present study examined cardiovascular abnormalities to determine the cause of death in adults with PWS. Methods From September 2017 to April 2019, a total of 18 adults with PWS, and, no history of cardiovascular diseases, were enrolled. We investigated the levels of the cardiovascular biomarkers: high-sensitivity C-reactive protein (hs-CRP) and troponin T (TnT). To estimate the cardiac function, we measured the left ventricular ejection fraction (LVEF), global longitudinal systolic strain (GLS) of the left ventricle, ratio of peak early mitral filling velocity (E) to early diastolic mitral annular velocity (E/e' ratio), mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) using standard and tissue Doppler echocardiography. Results The mean patient age was 28±9 years old. There were 11 men, and the mean body mass index was 45.1 kg/m2. Dyslipidemia (82%), diabetes mellitus (82%) and hypertension (83%) were commonly found as comorbidities. Most patients had elevated levels of hs-CRP (mean 1.007±0.538 mg/dL). The LVEF (mean 61%±5%) showed normal values, while the GLS (mean 15.0%±3.0%) was decreased. The TAPSE was mildly reduced (mean 16±3 mm). Conclusion These results suggest that subtle cardiovascular abnormalities have already begun in young adults with PWS. We need to manage obesity and the resultant obesity-related disorders in order to prevent heart failure and coronary atherosclerosis in PWS patients.

Increased left ventricular (LV) afterload in patients with aortic stenosis consists of valvular and vascular loads; however, the effects of vascular load induced by arterial stiffness on clinical outcomes after transcatheter aortic valve replacement (TAVR) remain unclear. This study evaluated the prognostic value of brachial-ankle pulse wave velocity (baPWV) after TAVR.A retrospective study including 161 consecutive patients who underwent TAVR with a pre-procedural baPWV assessment was conducted. We investigated the association between baPWV and the 1-year composite outcome comprising all-cause death and rehospitalization related to heart failure. Echocardiographic measurements including the LV mass index (LVMi) and LV diastolic function at 1, 6, and 12 months after TAVR were assessed.Of the 161 patients, 31 patients experienced composite outcome within 1 year after TAVR. The receiver operating characteristic curve analysis revealed that the discriminating baPWV level to discern 1-year composite outcome was 1,639 cm/s, and all subjects were allocated to two groups based on the result. Baseline characteristics were comparable between the high baPWV (n = 72) and low baPWV groups (n = 89). The Kaplan-Meier curve revealed a significantly higher cumulative 1-year composite outcome in the high baPWV group than in the low baPWV group (31% vs. 10%; log-rank test, p0.001). High baPWV was an independent predictor of the 1-year composite outcome (adjusted hazard ratio, 3.42; 95% confidence interval, 1.62-7.85; p = 0.002). Furthermore, post-procedural echocardiography revealed that the high baPWV group had less LVMi regression and higher E/e' after TAVR compared to the low baPWV group. The delayed reversal in LVMi and diastolic function attributable to arterial stiffness might be linked to impaired clinical outcomes after TAVR.Higher baPWV could be associated with adverse clinical outcomes and delayed reverse LV remodeling after TAVR.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Background Left ventricular hypertrophy (LVH) develops with both structural and electrical remodeling in response to elevated afterload due to aortic stenosis (AS). This study evaluated the prognostic value of electrocardiographic LVH (ECG LVH) after transcatheter aortic valve replacement (TAVR). Methods A retrospective study including 157 consecutive patients who underwent TAVR was conducted. ECG LVH was defined as Sokolow–Lyon voltage (S in V1 + R in V5/6) before TAVR was ≥3.5mV. We investigated the association between ECG LVH and the 1-year composite outcome comprising all-cause death and rehospitalization related to heart failure. ECG and echocardiographic measurements at 1, 6, and 12 months after TAVR were assessed. Results The baseline characteristics were comparable between the ECG LVH (n = 74) and non-ECG LVH groups (n = 83). The ECG LVH was associated with a significantly greater reduction of Sokolow–Lyon voltage and LV mass index than the non-ECG LVH after TAVR. The absence of ECG LVH was an independent predictor of the 1-year composite outcome [adjusted hazard ratio (HR), 2.27; 95% confidence interval (CI), 1.01 – 5.60; p = 0.04]. Furthermore, a reduction of Sokolow–Lyon voltage from baseline to 1-month follow-up, but not a reduction of LV mass index, was associated with a lower cumulative composite outcome from 1 month to 1 year (adjusted HR, 0.36; 95% CI, 0.15 – 0.86; p = 0.02). Conclusions ECG LVH was associated with a low incidence of adverse clinical outcomes and greater reverse LV remodeling after TAVR. Preprocedural and serial LVH assessment by ECG might be useful in AS patients undergoing TAVR.

A 72-year-old man was treated with prednisolone and cyclosporine A for idiopathic pulmonary fibrosis. A nodule with a diameter of 19 mm was found in the right lung and diagnosed as lung squamous cell carcinoma. Anti-cancer treatments were not performed because of the presence of advanced interstitial pneumonia and chronic respiratory failure. Cyclosporine A was tapered to avoid suppression of anti-tumor immunity, and pirfenidone was initiated. Within 2 months, the tumor had shrunk to 10 mm in diameter and remained regressed for 9 months. This is the first report of a non-hematologic solid organ tumor responding to the discontinuation of immunosuppressants.

In this brief, we discuss top-gate InGaZnO thin-film transistors (InGaZnO TFTs) fabricated with boron (B) implantation into the source–drain regions, focusing on channel shortening. B was implanted through the gate insulator into the InGaZnO layer. From scanning capacitance microscopy (SCM) analysis, we found that boron implantation in the S/D regions of InGaZnO TFTs induces channel shortening. We also found that such channel shortening is suppressed by optimizing acceleration voltage in the boron implantation process, leading to good operation in short-channel ( $1.5~\mu \text{m}$ ) InGaZnO TFT.

Objective nutritional indexes have been shown to predict prognoses in some clinical settings. We aimed to investigate the prognostic values of these indexes in patients undergoing transcatheter aortic valve implantation (TAVI).We retrospectively analyzed 95 consecutive patients who underwent TAVI at our institution from December 2013 to February 2017. As objective nutritional indexes, a controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were calculated at baseline. The optimal cut-off values were determined using receiver operating characteristic curve analysis. According to the cut-off values, we investigated the association of these indexes with 1-year clinical outcomes including all-cause mortality and re-hospitalization due to heart failure.In the Kaplan-Meier analysis, patients with a higher CONUT score and lower PNI had significantly higher incidence rates of 1-year mortality (26.9% vs. 2.9%; p0.001, 17.4% vs. 2.0%; p=0.011, respectively) and composite outcome of mortality and re-hospitalization due to heart failure (38.5% vs. 13.0%; p=0.006, 39.3% vs. 11.9%; p=0.002, respectively). On Cox hazard analysis, CONUT score and PNI were significantly associated with 1-year mortality [hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.27-2.88; p=0.002, HR: 0.86; 95% CI: 0.75-0.99; p=0.031, respectively] and the composite outcome (HR: 1.49; 95% CI: 1.11-2.00; p=0.007, HR: 0.88; 95% CI: 0.80-0.97; p=0.011, respectively).The CONUT score and PNI are associated with 1-year clinical outcomes especially with 1-year all-cause mortality in patients undergoing TAVI. Moreover, the CONUT score and PNI might have better predictive values than GNRI.

The total cerebral small vessel disease (SVD) score is a proposed comprehensive index of SVD severity in the brain. However, data on lifestyle-related risk factors affecting SVD scores are limited. We conducted a cross-sectional study with 858 neurologically healthy adults who underwent brain magnetic resonance imaging (MRI). Information on clinical and lifestyle-related risk factors was obtained from health screenings. The SVD score (0-4) was calculated from the presence of lacunes, cerebral microbleeds, moderate to severe white matter lesions, and basal ganglia perivascular spaces on MRI. Subjects were divided into two groups by SVD score; potential risk factors and their joint effects in the two groups were assessed by logistic regression. Biologic interactions were estimated using the synergy index. After adjustment for possible confounders, the adjusted odds ratio for moderate to severe SVD scores (SVD score ≥ 2) was 1.12 (95% confidence interval (CI) 1.08-1.16) for age per year, 1.33 (95% CI 1.02-1.74) for body mass index per standard deviation, 3.39 (95% CI 1.90-6.03) for hypertension, 2.31 (95% CI 1.14-4.69) for diabetes, and 2.35 (95% CI 1.10-5.02) for smoking. Hypertension and current smoking had a synergistic effect on the risk of moderate to severe SVD (OR 10.59, 95% CI 3.97-28.3; synergy index 4.03, 95% CI 1.17-28.30), and the combination of hypertension and diabetes had an additive effect on the risk of moderate to severe SVD (OR 9.48, 95% CI 3.80-23.66; synergy index 2.12, 95% CI 0.68-6.67). Therefore, combined strategies for managing hypertension, smoking, and diabetes may be effective for preventing SVD.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a serious adverse effect that leads to treatment discontinuation by patients receiving anticancer therapy. Treatment discontinuation is a serious and life-threatening problem for patients with cancer; hence, there is a need for drugs that suppress the induction of CIPN by anticancer drugs. Intravenous immunoglobulin (IVIg) reportedly suppresses bortezomib-induced CIPN in a rat model. Here, using rodent models, we showed that IVIg can also suppress peripheral neurotoxicity induced by anticancer drugs other than bortezomib. Furthermore, the suppressive effect of IVIg disappeared when macrophages were depleted. These findings indicate two novel independent possibilities of alleviating CIPN using IVIg. First, CIPN can be controlled by macrophage modulation. Second, IVIg directly combined with anti-cancer drugs can avoid restrictions on the use of anti-cancer drugs due to CIPN inductions. However, further research is necessary for the bench-to-bedside translation of these novel applications of IVIg. Our findings lay a strong foundation for research on IVIg therapeutics.

Objective To evaluate the improvement of drop foot following lumbar decompression surgery and determine the prognostic factors that might influence the recovery of drop foot. Summary and background date Drop foot is a common but serious problem that can lead to deteriorate patient’s daily activities. There are numerous studied regarding the prognostic factors for the recovery of drop foot. However a few reports have been described the pathophysiological etiology of not only drop foot but also Trendelenburg’s sign due to the L5 nerve root palsy. Therefore, there is a possibility drop foot caused by peroneal nerve palsy is included. In addition, none have evaluated the presence or absence of radicular leg pain with drop foot patients. The purpose of this study was to evaluate the improvement of paretic leg muscles and determine the prognostic factors that might influence the recovery of drop foot. Methods Fifty-five drop foot patients were included in the study. Prognostic factors were retrospectively studied.Patients were assessed in terms of 10 items: 1) age, 2) sex, 3) diagnosis (LDH or LSS), 4) muscle strength of tibialis anterior, 5) muscle strength of extensor halluces longus, 6) muscle strength of gluteus medius, 7) presence or absence of radicular leg pain, 8) duration before surgery, 9) surgical treatment (spinal fusion or not), 10) anamnesis of diabetes mellitus. Results Thirty-two (58.2%) of 55 patients recovered from their drop foot (manual muscle test of tibialis anterior ≥ 4 at final follow-up), while 23 (41.8%) did not (manual muscle test of tibialis anterior ≤ 3 at final follow-up). The strength of all muscles that were innervated and controlled by the L5 nerve root had recovered at the final follow-up when evaluated as averages. Multivariate logistic regression analysis revealed significant differences in terms of 2 items: “duration before surgery” and “presence or absence of radicular leg pain”. Conclusions “Duration before surgery” and “presence or absence of radicular leg pain” are important to predict the recovery of drop foot. Painless drop foot patients with lumbar degenerative disease are difficult to recover their paralysis.

Structured Abstract Objective Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are recommended for high stroke-risk patients with carotid artery stenosis to reduce ischemic events. However, we often face difficulty in determining the best treatment method. Therefore, it is necessary to develop a useful decision support tool to identify an appropriate patient-specific treatment for carotid artery stenosis. Our objective is to develop an accurate post-CEA/CAS outcome prediction model using machine learning (ML) algorithms that will serve as a basis for a new decision support tool for patient-specific treatment planning. Methods Retrospectively collected data from 165 consecutive patients with carotid artery stenosis underwent CEA or CAS at a single institution were divided into training and test samples. The following six ML algorithms were tuned, and their predictive performance evaluated by comparison with surgeon predictions: an artificial neural network, logistic regression, support vector machine, Gaussian naive Bayes, random forest, and extreme gradient boosting (XGBoost). A total of 17 clinical parameters were used for the ML model development. These parameters consisted of age, pretreatment modified Rankin scale, hypertension, diabetes mellitus, medical history of arteriosclerotic disease, serum low-density lipoprotein cholesterol value, internal carotid artery peak systolic velocity, symptomatic, crescendo transient ischemic attack or stroke in evolution, previous neck irradiation, type III aorta, contralateral carotid occlusion, stenosis at a high position, mobile plaque, plaque ulceration, vulnerable plaque, and procedure (CEA or CAS). Outcome was defined as any ischemic stroke within 30 days after treatment. Results The XGBoost model performed the best in the evaluation; its sensitivity, specificity, positive predictive value, and accuracy were 66.7%, 89.5%, 50.0%, and 86.4%, respectively. The average of the outcome predictions made by four surgeons had a sensitivity of 41.7%, specificity of 75.0%, positive predictive value of 20.1%, and accuracy of 70.5%. Internal carotid artery peak systolic velocity, serum low density lipoprotein cholesterol, and procedure (CEA or CAS) were the most contributing factors according to the XGBoost algorithm. Conclusions We were able to develop a post-CEA/CAS outcome prediction model comparable to surgeons in performance. The accurate outcome prediction model will make it possible to make a more appropriate patient-specific selection of CEA or CAS for the treatment of carotid artery stenosis.

Background Renal impairment is a common phenomenon that portends a poor prognosis of heart failure (HF). The renal arterial resistance index (RRI) can be useful for defining renal function and predicting outcomes in patients with HF. This study aimed to investigate the determining factors of the RRI in HF patients with preserved ejection fraction (HFpEF) and with reduced EF (HFrEF). Methods This retrospective study included 330 patients with HF. We investigated the determining factors for the RRI and the association between the RRI and 1-year composite outcome, comprising all-cause mortality and re-hospitalization for HF. Results The independent predictors of the RRI were tricuspid regurgitation peak gradient and estimated glomerular filtration rate in HFpEF, and pulse pressure and blood urea nitrogen in HFrEF. During the follow-up, 30 (9.1%) patients presented the composite outcome. Cox proportional hazard analysis revealed the association of the RRI with the composite outcome in both HFrEF (HR 1.08; 95% CI 1.03–1.14) and HFpEF (HR 1.07; 95% CI 1.03–1.12) without an interaction (p for interaction = 0.770). Conclusions The RRI was a consistent prognosticator in patients with HFpEF and those with HFrEF, while factors defining RRI were different between these groups.

Background The emergency medical system, one of the essential elements of public health, has been around for more than 50 years. Although many studies have assessed the factors associated with overcrowding and prolonged length of stay in emergency departments, whether the clinical characteristics and background of a patient are associated with prolonged hospitalization among patients transported by ambulance is unknown. The purpose of this study was to reveal factors associated with the continuation of hospitalization at 21 days after hospital admission among patients transported by ambulance using a population-based patient registry in Osaka, Japan. Method: This was a retrospective observational study whose study period was the three years from January 2016 to December 2018. In this study, we included patients who were hospitalized after transportation by ambulance as determined using cleaned data that was recorded in the ORION system. The main outcome was continuation of hospitalization at 21 days after hospital admission. We calculated the adjusted odds ratios (AOR) and 95% confidence interval (CI) with a multivariable logistic regression model to assess factors associated with the outcome. Results We included 481,886 patients in this study, of whom 158,551 remained hospitalized at 21 days after hospital admission and 323,335 had been discharged home by 21 days after hospital admission. Factors associated with prolonged hospitalization were elderly (AOR: 1.767 [95% CI: 1.730–1.805]), traffic accident (AOR: 1.231 [95% CI: 1.183–1.282]), no fixed address (AOR: 4.494 [95% CI: 3.632–5.314]), need for nursing care (AOR: 1.420 [95% CI: 1.397–1.443]) and solitary person (AOR: 1.085 [95% CI: 1.050–1.120]). Conclusion In this study, the elderly, traffic accidents, no fixed address, need for nursing care, and solitary person were the factors associated with prolonged hospitalization of patients transported by ambulance in Japan.

Aims A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. Methods and results In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642–1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213–1.434). The safety profile for eplerenone was as expected. Conclusion The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Background Natural history of coronary plaque progression (PP) in patients with diabetes mellitus (DM) remains unclear. This study aimed to investigate the clinical predictors of coronary PP in patients with DM. Methods In this prospective observational study, we analyzed 70 asymptomatic patients (age, 64.4 years; male, 67%) with type 2 DM without prior history of coronary artery disease who underwent serial 320-row computed tomography coronary angiography with an interscan interval of more than 24 months (median 37.7 months). Study endpoint was PP, which was defined if coronary plaque volumes (PVs) at follow-up minus PVs at baseline was >0. We evaluated plaque composition using the Hounsfield Unit thresholds and insulin resistance estimated by the homeostasis model assessment of insulin resistance (HOMA-IR). Results Thirty-nine patients who showed PP had a higher increase in hemoglobin A1c (⊿HbA1c) from baseline to follow-up than those without PP (0.3% ± 0.8% vs −0.4% ± 1.1%; p = 0.01), although there was no statistical difference in HbA1c at baseline (7.1 ± 0.5% vs. 7.3 ± 1.4%; p = 0.24). In multivariable analysis, ⊿HbA1c [odds ratio (OR): 3.05; 95% confidence interval (CI): 1.39–6.67; p = 0.001] was an independent predictor for PP. Increase in low-density lipoprotein cholesterol (⊿LDL-C), not ⊿HbA1c, was significantly correlated to percent change in necrotic core (NC) volume (β-coefficients: 0.04; 95% CI: 0.004 - 0.08; p = 0.03). Among 48 patients without insulin therapy, patients with PP (n = 28) had a higher increase in HOMA-IR than those without PP (n = 20) (0.95 ± 2.00 vs. −0.63 ± 1.31; p = 0.003). Conclusions Increase in HbA1c and HOMA-IR was associated with PP in asymptomatic patients with type 2 DM, whereas increase in LDL-C was correlated to increase in NC.

Aims The association of vascular dysfunction and amyloid beta deposition attracted attentions for its relationship with cognitive decline. Previous studies show the correlation between the declined cardiac function and the cognitive impairment. In the present study, we analysed the association between cognitive functions and cardiac parameters in community-dwelling people with preserved ejection fraction without heart failure. Methods and results Subjects were 108 Japanese community-dwelling middle-aged and older adults with preserved ejection fraction (25 men and 83 women; mean age 74.7 years). Cardiac functional parameters at rest were assessed with B-type natriuretic peptide and echocardiography. The cardiopulmonary exercise test was used to test these parameters during exercise. Cognitive function was assessed with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Other indices were assessed biochemically, physiologically, and physically. There were significant correlations between MoCA-J score and age (r = -0.388), peak oxygen uptake (VO2 , r = 0.201), peak VO2 /heart rate (HR, r = 0.243), peak VO2 /weight (r = 0.244), peak metabolic equivalents (r = 0.244), usual walking speed (r = -0.200), and the Timed Up and Go test (r = -0.230). Multiple linear regression analysis showed peak VO2 /HR was an independent determinant of MoCA-J score after adjusting for potential confounders (B = 0.424). After 6 months of exercise training with 64 subjects, we found that the per cent change of peak VO2 /HR was related to the per cent change of MoCA-J score (r = 0.296). Conclusions These results suggested that peak VO2 /HR (an index of stroke volume at peak exercise) might be associated with cognitive impairment based on the vascular cascade hypothesis.

Objective Abducens nerve palsy (ANP) after transvenous embolization (TVE) for cavernous sinus (CS) dural arteriovenous fistulas (DAVFs) sometimes persists. The aim of this study was to assess the correlation between the coil mass and the long-term outcome of ANP after TVE. Methods Between January 2008 and July 2016, 33 patients with a CS DAVF underwent TVE at our institute. On the basis of the relationship to the internal carotid artery (ICA), we divided the lateral part of the CS into the following 3 portions: anterolateral, anterolateral to the anterior bend of the ICA; middle-lateral (ML), lateral to the horizontal segment of the ICA; and posterolateral, posterolateral to the posterior bend of the ICA. Results ANP persisted in 4 patients. The number of coils (35.3 vs. 21.9 coils; P = 0.04), coil volume (198.4 vs. 103.6 mm3; P = 0.03), and coil volume in the ML (54.9 vs. 20.3 mm3; P = 0.01) were significantly greater in the ANP group than in the non-ANP group. In the logistic regression analysis, only the ML coil volume was significantly associated with the persistence of ANP (P = 0.04). Based on the receiver operating characteristic curve, the optimal cutoff value of the ML coil volume was 27.9 mm3 (sensitivity, 100%; specificity, 72.4%). Conclusions Overpacking in the ML of the CS should be avoided to prevent persistent ANP. The cutoff value of the ML coil volume may provide a good guide for the practical use of TVE for CS DAVFs.

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.

A 51-year-old woman with cardiac sarcoidosis presented with 2:1 atrial flutter (AFL) ([Figure 1Ai][1]) and was referred for catheter ablation. During sinus rhythm, a 12-lead electrocardiogram revealed trifascicular block ([Figure 1Aii][1]). Echocardiography revealed basal thinning of the

We report an autopsy case of an 80-year-old woman who underwent left atrial appendage closure with a WATCHMAN (Boston Scientific, St. Paul, MN, USA) device. This is the first report of histologic assessment following left atrial appendage closure with a WATCHMAN device at 3 months. Gross and histopathological examinations revealed neoendocardial coverage of the WATCHMAN device. Partial endothelialization was verified by CD34 staining; however, it remains unclear when complete endothelialization is likely to occur.

Objective: We report a case of a spinal dural arteriovenous fistula (s-dAVF) involving feeders from multiple intervertebral levels. Transarterial glue embolization was performed with controlling the blood flow from a feeder other than the one through which n-butyl-2-cyanoacrylate (NBCA) was injected using a balloon placed at a different level of a segmental artery. With this technique, complete occlusion was achieved with satisfactory penetration of NBCA. Case Presentation: A 57-year-old male presented with progressive gait disturbance and bladder bowel dysfunction. DSA revealed an s-dAVF fed by the right 6th, 7th, and 8th intercostal arteries (ICAs). During injection of NBCA from the radicular artery of the 6th ICA, the blood flow was controlled by occluding the feeder from the right 7th ICA with NBCA and a balloon placed at the orifice of the feeder from the right 8th ICA. Complete occlusion of the fistula was achieved by the balloon-assisted injection of NBCA. Conclusion: NBCA injection with flow control using a balloon placed in a feeder from a different segmental artery was useful for the treatment of an s-dAVF fed by multiple segmental arteries.

Background: Hand grip strength and peak oxygen uptake (VO2) are important components of frailty. However, the relationship between these two variables among community-dwelling elderly people is still unclear. The present study aimed to investigate this relationship. Methods: Participants were 190 Japanese community-dwelling elderly outpatients (61 men and 129 women, mean age 78.0 years). Hand grip strength of participants’ dominant hand was measured using a Smedley-type hand dynamometer. Peak VO2 levels were assessed with a cardiopulmonary exercise test. Skeletal muscle mass index (SMI) and usual walking speed were assessed physiologically and physically. Sample size was calculated using G*Power 3.1.9.2. Results: There were significant correlations between hand grip strength and age (r = −0.22), peak VO2 (r = 0.40), SMI (r = 0.51), and usual walking speed (r = 0.29). There were significant differences in age, peak VO2 and SMI after participants were divided into normal and low hand grip strength groups according to the Asian Working Group for Sarcopenia threshold, whether both sexes were combined or considered separately. Multiple logistic regression analysis showed that peak VO2, SMI and age were independent determinants of hand grip strength after adjusting for potential confounders (Exp(B) = 0.871; 0.475; 1.065). Longitudinal analysis after 6 months of exercise training showed the percentage of change in hand grip strength and peak VO2 were correlated positively (r = 0.22) for 92 participants. Conclusion: Peak VO2 is independently associated with hand grip strength among community-dwelling elderly outpatients.

Background Allergic bronchopulmonary aspergillosis (ABPA) is an allergic pulmonary disease characterized by a hypersensitivity reaction to Aspergillus species colonizing the airways. The clinical characteristics of ABPA may differ depending on genetic and environmental background. We performed a nationwide survey to determine the clinical characteristics of ABPA in Japan. Methods In 2013, a questionnaire on physician-diagnosed ABPA/allergic bronchopulmonary mycosis was sent to 903 medical centers specializing in respiratory or allergic diseases. Cases fulfilling the following criteria were categorized as possible ABPA-central bronchiectasis (ABPA-CB): 1) presence of specific serum immunoglobulin E (IgE) antibodies or a positive skin reaction to Aspergillus , and 2) bronchiectasis or mucoid impaction in the central bronchi. Results Of 499 physician-diagnosed cases reported by 132 clinical centers, 358 cases met the criteria for possible ABPA-CB. Median age of ABPA-CB onset was 57 (interquartile range, 44–68) years; later-onset disease, developing ≥50 years of age, accounted for 66% of the cases and was associated with female sex, delayed onset of asthma, and lower levels of serum IgE. A third of the patients (120 patients, 34%) exhibited low levels of serum total IgE ( Aspergillus species were isolated from sputum in 126/213 cases (59%), and Schizophyllum commune was identified in 12 (6%) patients. During the course of the treatment, ABPA recurred in 169 (48%) cases. Conclusions This nationwide survey identified several unique clinical characteristics of ABPA in Japan, such as late-onset, relatively lower serum IgE levels, and frequent recurrences/flares.

Aspergillus udagawae has morphological similarities to Aspergillusfumigatus; however, it shows a low susceptibility to common antifungal drugs and poor in vitro sporulation. We present the first reported case of infectious endocarditis caused by A. udagawae. An awareness of this newly described Aspergillus species is vital for further clarification.

Aims This study aimed to investigate the relationship between skeletal muscle mass and cardiac functional parameters in older adults during cardiopulmonary exercise testing (CPET). Methods and results Sixty-three Japanese community-dwelling older adults were enrolled (20 men and 43 women; mean age 80 years, range 65–97 years). Cardiac functional parameters during exercise were assessed using CPET. Skeletal muscle mass index (SMI) was calculated by dividing the appendicular lean mass (measured using dual-energy X-ray absorptiometry) by height in metres squared. Subjects were divided into two groups: men with SMI ≥ 7.0 kg/m2 and women with SMI ≥ 5.4 kg/m2 (non-sarcopenic group); or men with SMI

We describe here a case of nivolumab‐induced type 1 diabetes, which developed within 9 days of treatment. The case highlights the importance of frequent monitoring of glucose after initiation of nivolumab treatment.

Purpose We investigated whether the proportion of intracerebral haemorrhage (ICH) due to cerebral amyloid angiopathy (CAA) differs between patients admitted to hospitals in the East and the West. Methods This international cross-sectional study included consecutive spontaneous ICH patients admitted to one stroke centre in the United Kingdom (Western centre origin) and one in Japan (Eastern centre origin) during the same period. We classified spontaneous ICH into “CAA-related” or “other” using the Edinburgh CT-based diagnostic criteria. We used multivariable logistic regression analyses to assess the relationship between CAA-related ICH and geographical location or ethnicity (White vs. East Asian or other ethnicities). Sensitivity analyses were performed using the modified Boston MRI-based diagnostic criteria for CAA-related ICH. Results Of 433 patients (median age, 72 years; Western centre origin, 55%), 15% were classified as CAA-related ICH. In the multivariable logistic regression model, Eastern centre and ethnicity had a lower proportion of CAA-related ICH (odds ratio [OR] vs Western centre origin 0.55, 95%CI 0.31–0.98; OR [vs. White] 0.47, 95%CI 0.25–0.87); these findings remained robust in sensitivity analyses. The estimated incidence of “other” (non-CAA) ICH (attributed to hypertensive arteriopathy) was 2.5-fold higher in East Asian populations. Conclusions The proportion CAA-related ICH is lower in an Eastern compared to a Western hospital ICH population; this might be explained by a higher incidence of ICH related to hypertensive arteriopathy in East Asian populations, suggesting that optimal ICH prevention strategies might differ between the East and West.

Objectives: We investigated whether the proportion of intracerebral haemorrhage (ICH) due to cerebral amyloid angiopathy (CAA) differs between patients of Eastern and Western origin. Methods: This is a retrospective international cross-sectional study of consecutive first-ever spontaneous ICH patients (including patients with surgical intervention) admitted to one stroke centre in the United Kingdom (Western centre origin) and one in Japan (Eastern centre origin) during the same period. We classified spontaneous ICH into “CAA-related ICH” defined by the Edinburgh CT diagnostic criteria, and “other ICH”. We used multivariable logistic regression analyses to assess the relationship between CAA-ICH and geographical location (Western or Eastern centre origin) or ethnicity (Western [reference], East Asian, or other) with adjustment for confounders. Results: Of 334 patients (median age, 71 years; male, 54%; Western centre origin, 58%), 15% were classified as CAA-ICH, and 85% were defined as other ICH. In multivariable logistic regression analysis, Eastern centre and ethnicity had a lower proportion of CAA-ICH (odds ratio [OR] vs Western centre origin 0.47, 95%CI 0.23-0.98; OR [vs. white] 0.41, 95%CI 0.20-0.97, respectively).The estimated incidence of CAA-related ICH in East Asian was similar to that in White populations, but the rate of other ICH was 2.5-fold higher in East Asian populations. Sensitivity analyses using the modified Boston criteria for diagnosis of CAA-related ICH showed similar results. Conclusions: The proportion CAA-ICH is lower in an Eastern compared to a Western population; this appears to be explained by a higher incidence of ICH due to hypertensive (deep perforator) arteriopathy in East Asian populations.

BackgroundAlthough development of immune checkpoint inhibitors and various molecular target agents has extended overall survival time (OS) in advanced non-small cell lung cancer (NSCLC), a complete cure remains rare. We aimed to identify features and treatment modalities of complete remission (CR) cases in stages III and IV NSCLC by analyzing long-term survivors whose OS exceeded 3 years.MethodsFrom our hospital database, 1,699 patients, registered as lung cancer between 1stMar 2004 and 30thApr 2011, were retrospectively examined. Stage III or IV histologically or cytologically confirmed NSCLC patients with chemotherapy initiated during this period were enrolled. A Cox proportion hazards regression model was used. Data collection was closed on 13thFeb 2017.ResultsThere were 164 stage III and 279 stage IV patients, including 37 (22.6%) and 51 (18.3%) long-term survivors and 12 (7.3%) and 5 (1.8%) CR patients, respectively. The long-term survivors were divided into three groups: 3 ≤ OS < 5 years, 5 years ≤ OS with tumor, and 5 years ≤ OS without tumor (CR). The median OS of these groups were 1,405, 2,238, and 2,876 days in stage III and 1,368, 2,503, and 2,643 days in stage IV, respectively. The mean chemotherapy cycle numbers were 16, 20, and 10 in stage III and 24, 25, and 5 in stage IV, respectively. In the stage III CR group, all patients received chemoradiation, all oligometastases were controlled by radiation, and none had brain metastases. Compared with non-CR patients, the stage IV CR patients had smaller primary tumors and fewer metastases, which were independent prognostic factors for OS among long-term survivors. The 80% stage IV CR patients received radiation or surgery for controlling primary tumors, and the surgery rate for oligometastases was high. Pathological findings in the stage IV CR patients revealed that numerous inflammatory cells existed around and inside resected lung and brain tumors, indicating strong immune response.ConclusionsMultiple line chemotherapies with primary and oligometastatic controls by surgery and/or radiation might achieve cure in certain advanced NSCLC. Cure strategies must be changed according to stage III or IV.This study was retrospectively registered on 16thJun 2019 in UMIN Clinical Trials Registry (number UMIN000037078).

Background: The extracellular volume (ECV) calculated by T1 mapping, and tissue-tracking strain using cardiac magnetic resonance (CMR) are useful for assessing the left ventricular (LV) function. However, those parameters are controversial for assessing left atrial (LA) function. This study aimed to investigate the usefulness of CMR to evaluate the LA function using those parameters. Furthermore, those LA function parameters were compared in each LV function. Methods: A total of 65 consecutive patients who underwent contrast CMR were prospectively enrolled (age 55.7 ± 14. 6 years, males 67.7%). Among the 65 patients, there were 15 without hypertension, diabetes, or atrial fibrillation (Healthy group). The remaining 50 patients were divided into two groups according to a left ventricular ejection fraction (LVEF) of 50%. We assessed the correlations between the LV- and LA-CMR parameters among the three groups (LVEF

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Background: There has been no effective method to predict ischemic intolerance to temporary internal carotid artery (ICA) occlusion during carotid artery reconstruction. Pencil beam presaturation (BeamSAT) pulse suppresses the flow signal of the target vessel in magnetic resonance angiography (MRA). Applying this method, we constructed ICA-selective MRA images. The aim of this study was to identify patients at risk for ischemic intolerance by ICA-selective MRA. Methods: By evaluating flow of anterior communicating artery (Acom) and A1 portion of anterior cerebral artery with ICA-selective MRA and posterior communicating artery (Pcom) with conventional MRA, we investigated associations of these collateral flow patterns with ischemic intolerance and decrease of regional cerebral oxygen saturation. Results: The study included 58 patients who underwent carotid endarterectomy or carotid artery stenting. Six of 7 patients without Acom flow and Pcom flow demonstrated ischemic intolerance, whereas all patients (n = 51) with Acom and/or Pcom flow demonstrated tolerance. The accuracy of this prediction model according to Acom and Pcom flow patterns for ischemic intolerance was 0.98 (P = 0.01, binomial test). Regional cerebral oxygen saturation decrease after ICA occlusion was significantly larger in patients without Acom flow and Pcom flow (12.0% ± 6.0%) than in patients with Acom flow and Pcom flow (3.0% ± 3.1%, P < 0.01) and in patients with Acom flow but no Pcom flow (2.4% ± 5.2%, P < 0.01). Conclusions: These findings support the importance of Acom flow as a collateral route. ICA-selective MRA enables prediction of ischemic intolerance to temporary ICA occlusion during carotid endarterectomy or carotid artery stenting. This method provides valuable information regarding probability of an ischemic complication.

Background There are several clinical diagnostic criteria for allergic bronchopulmonary aspergillosis (ABPA). However, these criteria have not been validated in detail, and no criteria for allergic bronchopulmonary mycosis (ABPM) are currently available. Objective This study proposes new diagnostic criteria for ABPA/ABPM, consisting of 10 components, and compares its sensitivity and specificity to existing methods. Methods Rosenberg-Patterson criteria proposed in 1977, the International Society for Human and Animal Mycology (ISHAM) criteria proposed in 2013, and this new criteria were applied to 79 cases with pathological ABPM and the control population with allergic mucin in the absence of fungal hyphae (n = 37), chronic eosinophilic pneumonia (n = 64), Aspergillus-sensitized severe asthma (n = 26), or chronic pulmonary aspergillosis (n = 24). These criteria were also applied to the 179 cases with physician-diagnosed ABPA/ABPM in a nationwide Japanese survey. Results The sensitivity for pathological ABPM with Rosenberg-Patterson criteria, ISHAM criteria, and this new criteria were 25.3%, 77.2%, and 96.2%, respectively. The sensitivity for physician-diagnosed ABPA/ABPM were 49.2%, 82.7%, and 94.4%, respectively. The areas under the curve for the receiver-operating characteristic curves were 0.85, 0.90, and 0.98, respectively. The sensitivity for ABPM cases that were culture-positive for non-Aspergillus fungi were 13.0%, 47.8%, and 91.3%, respectively. Conclusions The new diagnostic criteria, compared with existing criteria, showed better sensitivity and specificity for diagnosing ABPA/ABPM.