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Background: There is limited data on the impact of COVID-19 epidemic on the number of orthopaedic surgeries in Japan., Methods: We conducted a nationwide hospital survey asking for the monthly number of orthopaedic surgeries performed at each facility from January 2019 to June 2021. Those facilities that had performed at least 100 surgeries in 2019 were included for analyses. The facilities were further grouped by prefecture and by hospital characteristics. A brief health economic evaluation was also performed. Risk ratios were compared using univariate analyses with P < 0.05 considered statistically significant., Results: Questionnaire was sent to 1988 hospitals with 1671 hospitals (84%) responding. The survey data indicated a total number of orthopaedic surgeries decreased in 2020 compared to 2019 (1,061,541 vs 1,119,955 P < 0.01), and also for the first six months of 2021 compared to the same period in 2019 (530,388 vs 550,378 P < 0.01). In 2020, over 50% of all facilities in nearly all of the prefectures saw a decline in surgical procedures. The risk of incurring more than a 25% decease in the number of surgeries was significantly higher in 2020 for class I designated medical institutions compared to those that were not designated for any types of infectious diseases among the institutions with a tertiary emergency medical center in 2020 (crude risk ratio 2.9: 95% CI 1.2-7.4, p = 0.02) and in 2021 (crude risk ratio 4.7: 95% CI 1 0.9-12.1, p < 0.01). The estimated total nationwide decrease of revenue were in the range of approximately ¥29.2 to ¥116.8 billion per year for orthopaedic surgeries alone., Conclusion: There was a statistically significant decrease in the number of orthopaedic surgeries in Japan. The magnitude of the decline varied by prefectures and hospital characteristics, with the greater impact imposed on medical institutions with higher classification functions. The estimated immediate health economic impact was sizable., Competing Interests: Declaration of competing interest No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. The first author reports personal speaker fees from Johnson & Johnson K·K., Pfizer Japan, 3 M Japan, Stryker Japan, Taisho Toyama Pharmaceutical, MSD K.K., Hisamitsu Pharmaceutical, Kaken Pharmaceutical, Astellas Pharma, Smith＆Nephew, Daiichi Sankyo Company, outside the submitted work., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to assess the efficacy and safety of a sheathless guiding system in patients who underwent percutaneous coronary intervention (PCI) with distal radial access (DRA)., Background: Hyperion™ Sheathless® guiding catheter (Asahi Intecc, Japan), one of the latest 6-Fr guiding systems for transradial PCI characterized by novel outer dilator, is considered to facilitate smooth insertion of the catheter to the artery and may contribute to further reduction of access site complications in DRA., Methods: Between October 2018 and January 2023, 286 patients underwent PCI with a Hyperion™ Sheathless® guiding catheter with DRA at two Japanese hospitals. Procedural success, bleeding complications, and radial artery occlusion (RAO) detected by Doppler ultrasonography were assessed., Results: Mean age of the patients was 72.7 years, and 236 patients (82.5 %) were male. The target lesions were located in the right coronary artery, left anterior descending artery, left circumflex artery, and left main trunk in 81, 44, 50 patients, and 18 patients respectively. Procedural success rate was 99.7 % with no patients requiring conversion to conventional radial access. Two patients presented with a forearm hematoma equivalent to an Early Discharge After Transradial Stenting of Coronary Arteries Study hematoma classification Grade II and 23 with Grade I. No patient presented minor or major bleeding according to the Thrombolysis in Myocardial Infarction bleeding classification. RAO at 30-day follow-up was observed in 6 out of 277 patients (2.2 %)., Conclusions: 6-Fr sheathless guiding system for PCI via DRA is feasible and associated with a low incidence of access site complications., Competing Interests: Declaration of competing interest The authors report no financial relationships or conflicts of interest regarding the content herein., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Traumatic middle meningeal artery (MMA)-middle meningeal vein (MMV) fistula (MMA-MMV fistula) and MMA pseudoaneurysm are the 2 main MMA-related vascular diseases occurring after blunt head trauma. These are rare but known causes of delayed intracranial hemorrhage. This study investigated predictors that may aid in the diagnosis of these diseases., Methods: In our department, screening digital subtraction angiography (DSA) is performed for patients with blunt head trauma accompanied by intracranial hemorrhage and skull or facial bone fracture. This study included 87 patients who underwent screening DSA without craniotomy from January 2019 to June 2023. The patients' clinical characteristics were retrospectively collected from the database. Statistical analysis was performed to examine the associations of various evaluation items with MMA-related vascular diseases., Results: The first DSA examination revealed 34 MMA-MMV fistulas and 1 MMA pseudoaneurysm. The second follow-up DSA examination revealed 13 MMA-MMV fistulas and four MMA pseudoaneurysms. Temporal/parietal bone fracture (odds ratio, 5.33; P = 0.0005; 95% confidence interval, 1.95-14.60) was significantly associated with MMA-related vascular diseases. Endovascular treatments were performed in 9 patients. All procedures were successfully completed without complications; no delayed bleeding was observed., Conclusions: Temporal/parietal bone fracture in patients with blunt head trauma is a likely predictor of MMA-related vascular diseases. When initial head computed tomography reveals this pathology, we recommend careful imaging follow-up (e.g., DSA) and treatment as needed, while considering the possibility of MMA-related vascular diseases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Individuals who are addicted to one addiction are at an increased risk for developing another new addiction. New-onset addictions among patients with alcohol dependence needs to be considered for more effective treatment of alcohol dependence., Methods: In this cross-sectional study, Japanese outpatients with alcohol dependence were assessed using a comprehensive, originally designed questionnaire to determine whether they were addicted to substances or behaviors other than alcohol. The prevalence rates of new-onset addictions were compared between alcohol-dependent patients who had abstained from alcohol for a year or more and those who had not. Multiple regression analysis was performed to examine the association between the number of new-onset addictions and the demographic and clinical characteristics., Results: One hundred and nine outpatients with alcohol dependence (54.6±11.0 years; 97 men) participated in the study. The prevalence of new-onset addictions was 41.3%. No significant differences were found in the prevalence of new-onset addictions between the patients who had abstained for a year or more and those who had not. Multiple regression analysis revealed that the number of new-onset addictions was positively associated with the presence of psychiatric comorbidity (β = 0.24; p = 0.02) and use of benzodiazepines (β = 0.20; p = 0.04) with a R 2 of 0.153., Conclusion: Alcohol dependent patients with characteristics such as psychiatric comorbidity and use of benzodiazepines should be given more attention to the development of new-onset addictive behaviors. On the other hand, those behaviors could be acceptable for harm-reduction unless excessive and loss of control., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The effectiveness of the presence of a prehospital physician for patients with out-of-hospital cardiac arrest (OHCA) undergoing extracorporeal cardiopulmonary resuscitation (ECPR) remains unknown. In this multicenter, retrospective, observational study, we enrolled patients aged ≥18 years who developed OHCA and received ECPR. The primary outcome was the 1-month favorable neurological outcome. We estimated the impact of the presence of a prehospital physician on outcomes using a propensity score analysis with inverse probability weighting. We enrolled 1269 patients. Favorable neurological outcomes occurred in 25 of 316 (7.9%) patients with prehospital physicians and 94 of 953 (9.9%) patients without prehospital physicians. In the propensity score analysis, favorable neurological outcomes did not differ between 2 groups (odds ratio = 0.72; 95% confidence interval: 0.44-1.17). The 1-month favorable neurological outcome was not associated with the presence of a prehospital physician for patients with OHCA who underwent EPCR., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate., Objective: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition., Methods: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ 2 test, and Fisher's exact test., Results: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate., Conclusion: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate., Competing Interests: Conflict of Declaration The authors have no conflict of interest to declare., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan., Methods: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region., Results: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0-9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0-19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20-24 years. We also evaluated differences in prescription rates by geographic region., Conclusions: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Focusing on compression fractures of bone by finite elements, we evaluated bone strength based on the computed tomography-based finite element method. However, the exposure dose is an issue. We aimed to investigate the quantity of reduction of the radiation dose with respect to the reference dose by comparing the calculation results of compression fractures of the vertebral body using experimental data obtained from the spine of a pig., Methods: Computed tomography images of a self-made phantom that enclosed the lower lumbar vertebra of edible wild pigs were obtained under baseline-dose conditions using various lower tube currents. Images obtained under reference-dose conditions were reconstructed using the filtered back-projection method, whereas images obtained under low-dose conditions were reconstructed using both the filtered back-projection method and the iterative reconstruction method. Computer simulations involving the creation of finite element models using all images were implemented for the compression load calculation for vertebral body parts. Based on the calculated results, images of the low-dose and reference-dose conditions were compared., Results: Using pigs' lower lumbar vertebrae, finite element model analysis of low-dose X-ray computed tomography images showed that equivalent results can be obtained with a dose of approximately 40% of the standard radiographic reference doses. As for the compression stress intensity, the same results as those under reference-dose conditions were obtained using the iterative reconstruction method in combination with computed tomography-based finite element method., Conclusions: The combination of the iterative reconstruction method with the computed tomography-based finite element method is an effective image reconstruction method for achieving dose reduction., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p<.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed., Competing Interests: Declaration of Competing Interest The authors declare no financial conflicts of interest related to the study., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1b in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1β in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2‒CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1β expression for neutrophil accumulation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest None.

Background: Difficulties in fine and gross motor skills are often overlooked as developmental problems, although approximately 6-13% of all school-age children have poor motor coordination. Understanding motor coordination is important from the perspective of school adaptation. This longitudinal cohort study aimed to determine whether fine and gross motor skills in preschool children predict later academic achievement and psychosocial maladaptation., Methods & Procedures: Participants were 2,501 children from nursery and elementary schools (5-13 years old). The motor skills of preschool children were assessed by their nursery teacher immediately before entering elementary school. The Strengths and Difficulties Questionnaire and a standardized Japanese test were administered annually throughout elementary school., Results: Early motor difficulties in preschool children had significant effects on their academic achievement and psychosocial maladaptation up until the sixth grade. Gross motor difficulties in preschool were associated with the later peer problems and worsened emotional symptoms., Conclusions: Motor skills in preschool children are useful as a predictor of later psychosocial maladaptation and academic achievement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Among adult and pediatric patients, concern is growing in regard to toxic shock syndrome (TSS) resulting from methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection. We investigated the incidence and characteristics of this form of TSS in patients with burn injury who were admitted to our burn care units from January 2008 to December 2011. Of the 244 patients with nosocomial MRSA infection admitted during the study period, TSS occurred in 20 (8.2%) patients whose average age was 42.9 years, average total burn surface area (TBSA) was 31.7%, and average day of TSS appearance was 9.5 days after injury. There were no particular characteristics associated with age, TBSA or day of TSS appearance in these patients. All but 1 patient recovered from TSS within an average of 9.4 days. The incidence of TSS due to nosocomial MRSA infection in these burn patients was higher than expected. TSS due to nosocomial MRSA infection should be considered in burn care., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

Background: One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine., Methods: Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa., Results: Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015)., Conclusion: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey., Objective: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey)., Methods: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information., Results: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52)., Conclusion: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the association between living alone at home and the care and outcomes of patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (pPCI)., Methods: In total, 557 patients with STEMI underwent pPCI between January 2008 and September 2017. Among them, we included 208 patients who were transferred directly by emergency medical services from their home to the hospital., Results: Patients were classified into two groups, namely living alone (n = 45) and living with others (n = 163). There were no significant differences in age, sex, and cardiovascular risk factors between the two groups. The onset-to-door (OTD) and onset-to-balloon times were significantly shorter in patients living with others than in those living alone (106.4 vs. 190.8 min, p < 0.01 and 152.3 vs. 236.9 min; p < 0.01, respectively). The left ventricular ejection fraction after pPCI was significantly lower in patients living alone than in those living with others (48.7 % vs. 54.9 %, p < 0.01). Multivariate logistic regression analysis indicated that living alone and the incidence of congestive heart failure were independent predictors of a longer OTD time., Conclusions: Patients living alone were less likely to arrive early at the hospital than those living with others. A greater understanding of the inter-relationships among living alone, access to acute cardiac care, and outcomes is essential., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

It is challenging to investigate neutrophil extracellular traps (NETs) and bacterial colonization in vivo. Bitschar et al. (2020) oppose an existing paradigm regarding neutrophils in host defense and propose that neutrophils increase Staphylococcus aureus skin colonization through NETs, not by trapping microbes but via indirect mechanisms. These results are open to interpretation and should stimulate productive discussions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic β-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy., Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups., Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F 3,96  = 2.93, p = .038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p = .038). There were no group differences in the caudate or dorsolateral prefrontal cortex., Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Because of aggressive immunosuppression, heart transplant recipients have a high risk of de novo malignancy, which is a major cause of death and worse prognosis, regardless of the type. However, the impact of de novo malignancy on Japanese heart transplant recipients is unknown., Methods: We analyzed 103 Japanese heart transplant recipients over 18-years-old at the time of transplantation between April 1999 and April 2017. Patient characteristics and prognosis were compared between heart transplant recipients with or without de novo malignancy after heart transplantation (HTx). Additionally, univariate and multivariate analyses for the risk factors of de novo malignancy after HTx were performed., Results: De novo malignancy developed in 7 patients (6.8%; post-transplant lymphoproliferative disorders, n=3; Bowen's disease, n=1; colon cancer, n=2; bladder cancer, n=1). Follow-up time and previous antibody mediated rejection (AMR)≥grade 1 were risk factors of de novo malignancy after HTx in multivariate analysis (OR: 1.19, 95% CI: 1.00-1.42, p=0.043; and OR: 10.7, 95% CI: 1.37-83.68, p=0.038, respectively). History of malignancy was a potential risk factor, albeit not significant (OR: 23.05, 95% CI: 0.99-534.53, p=0.071). The survival rates in patients with de novo malignancy was significantly lower than in those without de novo malignancy (3-year survival rate: 100% versus 67%, p=0.0025)., Conclusions: Long follow-up time and previous AMR≥grade 1 were risk factors of de novo malignancy after HTx. Japanese heart transplant recipients with de novo malignancy have worse prognosis; therefore, screening examinations are important for early diagnosis., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

During percutaneous coronary intervention performed for a stenotic lesion with heavy calcification in the left coronary artery, the microcatheter tip became transected in the vessel. The fragment was successfully retrieved using the twin guidewire method after negotiating to cross a chronic total occlusion-dedicated guidewire outside the retained tip., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Evidence on the toxicity of hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) for thyroid hormones (TH) is limited, and the underlying mechanism remains unknown., Objectives: We aimed to investigate the effects of environmental prenatal exposure to OH-PCBs and maternal and neonatal TH levels, taking the maternal-fetal TH transfer into account., Methods: In this prospective birth cohort (the "Hokkaido study") we included 222 mother-neonate pairs. We measured five OH-PCB isomers in maternal serum samples either during pregnancy or within 5 days of delivery. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from maternal blood samples at an early gestational stage (median; 11.1 weeks) and from heel prick samples of neonates between 4 and 7 days after birth. Multiple linear regression analysis and structural equation modeling (SEM) were performed to investigate the associations between maternal OH-PCB and maternal and neonatal TH levels., Results: Median concentration of ∑OH-PCBs was 25.37 pg/g wet weight. The predominant isomer was 4-OH-CB187, followed by 4-OH-CB146+3-OH-CB153. In the fully adjusted linear regression analysis, maternal ∑OH-PCBs was positively associated with maternal FT4, and 4-OH-CB187 was positively associated with both maternal and neonatal FT4 levels. Maternal OH-PCBs showed no significant association with TSH among mothers and neonates. Path analysis indicated the indirect pathway from 4-OH-CB187 exposure to increased neonatal FT4, via maternal THs and neonatal TSH., Conclusions: These findings suggest that maternal exposure to OH-PCBs during pregnancy may increase both maternal and neonatal FT4 levels. Neonatal FT4 is presumed to be increased by prenatal 4-OH-CB187 indirectly, and this process may be mediated by maternal THs and neonatal TSH., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cyclic phosphatidic acid (cPA) is a simple lipid containing a fatty acid attached at the sn-1 position and a cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. The pharmacological effects of cPA have been demonstrated in several diseases such as cancer and neuropathic pain; however, the composition of the molecular species of cPA in relative to other lipid species in biological samples is still unclear. Recently, hydrophilic interaction liquid chromatography (HILIC) has demonstrated the ability to perform lipidomic analyses of biological samples. In the present study, we developed the quantitative measurement of cPA and its related lipid species, such as lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), in rat serum using HILIC equipped with tandem-mass spectrometry (MS/MS). The lipid analysis using HILIC-MS/MS system demonstrated high linearity and reproducibility. The modified Bligh and Dyer method using citric acid was showed high efficiency on the extraction of cPA and LPA without contamination of artificial products. In rat serum, cPA and LPC contained more saturated fatty acids such as palmitic acid and stearic acid than unsaturated fatty acids, whereas LPA and phosphatidylcholine more contained unsaturated fatty acids than saturated fatty acids. The analytical methods for measuring cPA and its related lipid species in the present study will aid the analysis of their metabolism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Previous proton magnetic resonance spectroscopy ( 1 H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1 H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1 H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1 H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Prenatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs) or polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dioxin-like compounds [DLCs]) through environmental chemicals may affect the neurodevelopment of children. In our previous study, an inverse association was observed between prenatal DLCs and neurodevelopment of infants aged 6months in both sexes. However, studies are yet to determine how long these adverse effects last., Objective: To examine whether the effects of DLCs on cognitive development remains at 42months., Methods: In this prospective cohort study conducted in Sapporo, Japan, pregnant mothers' blood was analyzed for the congener level of DLCs. The Kaufman Assessment of Battery for Children (K-ABC) was used to test their children's cognitive development at 42months. A total of 141 mother-child pairs were included in the final analysis. The multiple linear regression analysis was used to examine the association between the K-ABC scores and DLC levels in the maternal blood., Results: Seven isomers (1,2,3,6,7,8-HxCDD, 2,3,4,7,8-PeCDF, 33'44'55'-HxCB(#169), 2344'5- PenCB(#114), 233'44'5-HexCB(#156), 233'44'5'-HexCB(#157), 23'44'55'-HexCB(#167), total PCDF, and TEQ-PCDD, PCDF, PCDD/DFs levels were positively associated with the achievement score (AS) of K-ABC. However, total non-ortho PCBs were negatively associated with the Mental Processing Composite Score (MPCS) of K-ABC in males. In females, increased TEQ-dl PCB and TEQ-PCDD/F/dl-PCB were also associated with increasing AS score., Conclusions: This study suggests that the negative effects of prenatal DLC exposure on children's cognitive development at 6months were not observed in children aged 42months. Regarding the sex-specific effects, AS and DLCs were positively correlated in females, whereas those of MPCS and DLCs were significantly negative in males., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The various guidelines clearly mention the treatment strategies for in patient of acute myocardial infarction (MI) presenting more than 24h from symptom onset (recent myocardial infarction, RMI). However, the appropriate timing of reperfusion for RMI is unclear., Methods: We retrospectively evaluated 525 consecutive MI patients who underwent percutaneous coronary intervention (PCI) in our hospital between January 2008 and December 2012., Results: Sixty RMI patients were more frequently associated with cardiac complications such as myocardial rupture (3.3% vs. 0%; p<0.01), ventricular septal rupture (3.3% vs. 0.4%; p<0.05), and congestive heart failure (15% vs. 2.6%; p<0.001) than 272 consecutive ST-elevation myocardial infarction (STEMI) patients. Of the 60 RMI patients, 33 (55.0%) underwent PCI within 7days (early-PCI group) and 27 (45.0%) underwent PCI after 7days (late-PCI group). Left ventricular ejection fraction measured by echocardiography at second hospital day was similar between the groups. The early-PCI group was more significantly associated with cardiogenic shock and heart failure and more frequently required intra-aortic balloon pumping (24.2% vs. 3.7%; p<0.05) than the late-PCI group. There were no significant differences in 30-day mortality, cardiac complications, and major cardiac events during long-term follow-up (12-36 months) between the groups., Conclusion: RMI patients had a higher incidence of cardiac complications than AMI patients. Clinical outcomes were similar between patients undergoing early revascularization and those undergoing late revascularization, although the former group included a higher proportion of patients with severe cardiac failure., (Copyright © 2017. Published by Elsevier B.V.)

Background: Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known., Objectives: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects., Methods: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121)., Results: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index., Conclusions: These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Interleukin-17-producing CD4 + T helper (Th17) cells are a key immune lineage that protects against bacterial and fungal infections at mucosal surfaces. At steady state, Th17 cells are abundant in the small intestinal mucosa of mice. There are several mechanisms for regulating the population of Th17 cells in the small intestine, reflecting the importance of maintaining their numbers in the correct balance. Here we demonstrate the existence of a time-of-day-dependent variation in the frequency of Th17 cells in the lamina propria of the small intestine in wild-type mice, which was not observed in mice with a loss-of-function mutation of the core circadian gene Clock or in mice housed under aberrant light/dark conditions. Consistent with this, expression of CCL20, a chemokine that regulates homeostatic trafficking of Th17 cells to the small intestine, exhibited circadian rhythms in the small intestine of wild-type, but not Clock-mutated, mice. In support of these observations, the magnitude of ovalbumin (OVA)-specific antibody and T-cell responses in mice sensitized with OVA plus cholera toxin, a mucosal Th17 cell-dependent adjuvant, was correlated with daily variations in the proportion of Th17 cells in the small intestine. These results suggest that the proportion of Th17 cells in the small intestine exhibits a day-night variation in association with CCL20 expression, which depends on circadian clock activity. The findings provide novel insight into the regulation of the Th17 cell population in the small intestine at steady state, which may have translational potential for mucosal vaccination strategies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The relationship between hospital volume and outcome after traumatic brain injury (TBI) is not completely understood in a real clinical setting. We investigated whether patients admitted with TBI achieved better outcomes in high-volume hospitals than in low-volume hospitals using a national inpatient database in Japan., Methods: This retrospective cohort study used the Diagnosis Combination Procedure database in Japan. We included patients with TBI admitted to hospitals with a Japan Coma Scale (JCS) score ≥2 between April 1, 2013 and March 31, 2014. Hospital volume was defined as the annual number of all admissions with TBI in individual hospitals. The hospital volume was categorized into four volume groups: low (≤60 admissions per hospital), medium-low (61-120 admissions per hospital), medium-high (121-180 admissions per hospital) and high (≥181 admissions per hospital). The outcomes of interest included 28-day mortality and survival discharge with complete dependency defined as a Barthel Index score of 0 at discharge. We used multivariate logistic regression models fitted with generalized estimating equations to evaluate relationships between the hospital volume and the outcomes. The hospital volume was evaluated both as categorical variables defined above and as continuous variables., Results: The analysis dataset consisted of 20,146 eligible patients. Of these, 2,784 died within 28days (13.8%) and 3,409 were completely dependent among 16,996 patients discharged alive (20.1%). Multivariate analyses found that there was no significant difference between the high-volume and low-volume groups for 28-day mortality (adjusted odds ratio [OR] 0.79, 95% confidence interval [CI] 0.58-1.06 for the high-volume group) or complete dependency at discharge (adjusted OR 0.94, 95% CI 0.71-1.23 for the high-volume group). The results were the same when the hospital volume was evaluated as a continuous variable., Conclusions: Hospital volume did not appear to influence outcomes in patients with TBI. High-volume hospitals may not be necessarily beneficial for patients with TBI exhibiting impaired consciousness as a whole., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Aims: Coronary computed tomography (CT) angiography allows non-invasive classification of non-calcified coronary plaques (NCCPs) based on Hounsfield unit (HU) values. This methodology, however, is somewhat limited for reliable classification of NCCPs. Therefore, we evaluated the effective atomic number (EAN) for classifying NCCPs by single-source dual-energy CT with fast tube voltage switching (SSDECT)., Methods: We prospectively enrolled 18 patients undergoing both SSDECT and intravascular ultrasonography (IVUS). Monochromatic images at 70 keV and EAN images were reconstructed from SSDECT data sets. Regions of interest (ROIs) within NCCPs were placed on IVUS-matched SSDECT images, and mean HU values and EANs for soft and fibrous plaques, classified using IVUS, were compared with an unpaired t-test., Results: We placed 96 ROIs in 29 soft plaques and 37 ROIs in 15 fibrous plaques in 12 coronary arteries of 11 patients. The mean HU value in soft plaques (58.2 ± 32.8 HU) was significantly lower than that in fibrous plaques (103.9 ± 48.3 HU) (p < 0.001). The mean EAN in soft plaques (8.7 ± 0.5) was also significantly lower than that in fibrous plaques (9.6 ± 0.5) (p < 0.0001). Area under the curve for EAN (0.91) was significantly higher than that for HU value (0.79) in receiver operating characteristic curve analysis (p = 0.046). With a cutoff EAN of 9.3, sensitivity was 90% and specificity, 87%; whereas with a cutoff HU value of 55.0 HU, sensitivity was 62% and specificity, 93%., Conclusions: EAN measurement by SSDECT can be clinically useful for accurately classifying soft and fibrous coronary plaques., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although chronic total occlusion of the left main coronary artery (LMCA) is considered very rare, this condition could be fatal if it becomes complicated with an acute coronary syndrome lesion in the right coronary artery (RCA) which is usually the only remaining coronary artery for the myocardium. We reported a successfully treated case of a nonagenarian patient with ST-segment elevation myocardial infarction, who had subtotal occlusion of the RCA and total occlusion of the LMCA with Rentrop grade 2 collateral coronary artery supply from the RCA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: This study aimed to clarify the prognostic impact of partial pressure of end-tidal carbon dioxide (PETCO 2 ) in patients with advanced chronic heart failure (HF)., Methods: Forty-eight patients (mean age 43.1±11.9years, 32 males) with chronic HF (44 with non-ischemic and 4 with ischemic cardiomyopathy) were prospectively enrolled. Echocardiography, blood tests, pulmonary function testing, and PETCO 2 measurements were performed as noninvasive tests, whereas right heart catheterization and arterial blood gas analysis were conducted as invasive tests. The primary end point of this study was left ventricular assist device (LVAD) implantation or cardiac death., Results: Eighteen patients underwent LVAD implantation at the Interagency Registry for Mechanically Circulatory Support (INTERMACS) profile 3 during the follow-up period, and no patient died. PETCO 2 was significantly lower in a stepwise manner with New York Heart Association functional class (class I or II, 34.2±9.3mmHg vs. class III or IV, 27.7±2.5mmHg; p<0.001). Univariate and multivariate Cox proportional hazard models and time-dependent receiver operating characteristic curve analysis revealed that PETCO 2 ≤31mmHg is an independent noninvasive predictor of LVAD implantation. Univariable and multivariable linear regression analyses showed that pulmonary arterial pressure was independently and highly correlated with PETCO 2 (r 2 =-0.512, p<0.001)., Conclusions: Among various noninvasive clinical parameters investigated, PETCO 2 was the independent predictor of LVAD implantation at the INTERMACS profile 3 in patients with chronic HF. Pulmonary congestion may significantly contribute to decreases in PETCO 2 in patients with HF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)