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Previous cross-sectional studies have reported that adolescent patients with anorexia nervosa (AN) showed global gray matter volume (GMV) reductions at the acute phase which were restored at the weight-recovered phase, compared with healthy controls (HC). However, few studies have investigated white matter volume (WMV) or cortical thickness in the context of AN, and results have been inconsistent. Voxel-based morphometry analyses for GM and WM, and cortical thickness analyses for GM were conducted in 31 adolescent patients with AN (vs. 18 HC) in the acute phase, and 16 patients with AN (vs. 13 HC) in the follow-up weight-recovered phase, over an approximately 1-year follow-up interval. At the acute phase, the AN patients showed significant reductions of GMVs and cortical thickness in widespread brain regions, compared with HC. Significant WMV reductions were identified in the bilateral superior longitudinal fascicle, superior thalamic radiation, corona radiata, and fornix, pons, and medulla in the patients. At the weight-recovered phase, the AN patients showed a significant GMV reduction in the left hippocampus, and a WMV reduction in the pons, compared with the HC. There was no difference in cortical thickness between two groups at the weight-recovered phase. In conclusion, the widespread volumetric reductions in GM and WM, and reduced cortical thickness observed in AN patients in the acute phase were not evident in the follow-up weight-recovered phase. The volume reductions observed in the hippocampus and pons in the weight-recovered phase could potentially reflect delayed neurogenesis or recovery from starvation in the AN patients.

Aims To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). Methods and results The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). Conclusions This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis., Graphical Abstract

Over the past couple of decades, accumulating evidence has shown that structural and functional abnormalities of coronary microvasculature are highly prevalent, associated with adverse clinical outcomes in patients with various cardiovascular diseases. The term coronary microvascular dysfunction (CMD) has been coined to refer to this clinical condition and is increasingly recognized as an important clinical entity in many clinical settings. The potential mechanisms of CMD appear to be heterogenous, including enhanced coronary vasoconstrictive reactivity at microvascular level, impaired endothelium-dependent and independent coronary vasodilator capacities, and increased coronary microvascular resistance secondary to structural factors. Recent experimental and clinical studies have highlighted emerging modulators of vascular functions, vital insight into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will briefly review the current progress on pathophysiology, molecular mechanisms, and clinical management of CMD from bench to bedside.

In vasospastic angina (VSA), coronary vasomotion abnormalities could develop not only in epicardial coronary arteries but also in coronary microvessels, where calcium channel blockers (CCBs) have limited efficacy. However, efficacy of exercise training for VSA remains to be elucidated. We thus aimed to examine whether vasodilator capacity of coronary microvessels is impaired in VSA patients, and if so, whether exercise exerts beneficial effects on the top of CCBs.We performed 2 clinical protocols. In the protocol 1, we measured myocardial blood flow (MBF) using adenosine-stress dynamic computed tomography perfusion (CTP) in 38 consecutive VSA patients and 17 non-VSA controls. In the protocol 2, we conducted randomized controlled trial, where 20 VSA patients were randomly assigned to either 3-month exercise training group (Exercise group) or Non-Exercise group (n= 10 each).In the protocol 1, MBF on CTP was significantly decreased in the VSA group compared with the Non-VSA group (138 ± 6 vs 166 ± 10 ml/100 g/min, P = 0.02). In the protocol 2, exercise capacity was significantly increased in the Exercise group than in the Non-Exercise group (11.5 ± 0.5 to 15.4 ± 1.8 vs 12.6 ± 0.7 to 14.0 ± 0.8 ml/min/kg, P 0.01). MBF was also significantly improved after 3 months only in the Exercise group (Exercise group, 145 ± 12 to 172 ± 8 ml/100 g/min, P 0.04; Non-Exercise group, 143 ± 14 to 167 ± 8 ml/100 g/min, P = 0.11), although there were no significant between-group differences.These results provide the first evidence that, in VSA patients, exercise training on the top of CCBs treatment may be useful to improve physical performance, although its effect on MBF may be minimal.

Objectives Whether there are prognostic links between coronary morphologies and coronary functional abnormalities was examined in ischemia and nonobstructive coronary artery disease (INOCA) patients. Background Although INOCA has attracted much attention, little is known about the prognostic impact of coronary morphologies in this disorder. Methods A total of 329 consecutive INOCA patients were enrolled and underwent spasm provocation testing combined with lactate sampling for diagnosis of epicardial and microvascular spasm (MVS). On the basis of the functional tests, the patients were classified into 4 groups: a control group without epicardial spasm or MVS (n = 32), MVS alone (n = 51), diffuse spasm in ≥2 coronary segments (n = 204), and focal spasm in 1 segment (n = 42). In this population, optical coherence tomography imaging of the left anterior descending coronary artery was performed for evaluation of adventitial vasa vasorum (AVV) and intraplaque neovessels (IPN). Index of microcirculatory resistance was also measured. Results MVS frequently coexisted with diffuse (70%) and focal spasm (68%) with a good correlation between AVV and index of microcirculatory resistance (R = 0.353; p = 0.022). For a median follow-up of 1,043 days, focal spasm showed the worst prognosis (log rank p = 0.005), for which IPN was a significant prognostic factor. By contrast, diffuse spasm showed the greatest AVV with an intermediate prognosis. The prognostic value of INOCA was significantly enhanced by adding AVV and IPN to the physiological indices (area under the curve = 0.88 vs. 0.76; p = 0.048). Conclusions These results provide the first evidence that there are important prognostic links between coronary morphologies (evaluated by optical coherence tomography) and coronary functional abnormalities in patients with INOCA, indicating the importance of both evaluations in this population.

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11 years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.

Fully coherent, soft X-ray attosecond pulses are now available through high-order harmonic generation (HHG); however, the output energy is insufficient for various applications, such as attosecond-scale soft X-ray nonlinear experiments, the seeding of soft X-ray free-electron lasers, attosecond-pump-attosecond-probe spectroscopies, and single-shot imaging. In this paper, we combine a newly developed TW class mid-infrared femtosecond laser and a loose focusing geometry for HHG. A soft X-ray harmonic beam up to the water window region is demonstrated, which is more than 100 times intense compared to previous works. We achieve a high conversion efficiency, low beam divergence and a significantly reduced medium gas pressure. As the first application, we demonstrate near edge X-ray absorption fine structure experiments with clear fine absorption spectra near the K- and L-edges observed. The robust energy scaling method on HHG opens the door for demonstrating single-shot absorption spectrum and live-cell imaging with a femtosecond time resolution. While high harmonic x-ray sources are well established sources for ultrafast spectroscopy, the decrease in efficiency towards higher energies limits their application. Here, a loose-focused, TW mid-IR laser is used to generate high harmonic soft x-rays with pulse energies of a few nJ in the water window and easy energy scaling.

Objective: It remains to be elucidated whether and how endothelial functions are impaired in peripheral circulation of patients with coronary functional disorders, such as vasospastic angina (VSA) and microvascular angina (MVA). We simultaneously examined endothelial functions of peripheral conduit and resistance arteries in patients with coronary functional disorders, with a special reference to NO and endothelium-dependent hyperpolarization factors. Approach and Results: Based on the results of invasive coronary acetylcholine testing and coronary physiological measurements, we divided 43 patients into 3 groups; VSA, MVA, and VSA+MVA. Endothelium-dependent vasodilatations of the brachial artery and fingertip arterioles to intra-arterial infusion of bradykinin were simultaneously evaluated by ultrasonography and peripheral arterial tonometry, respectively. To assess NO and endothelium-dependent hyperpolarization factors, measurements were repeated after oral aspirin and intra-arterial infusion of N G -monomethyl-L-arginine. Additionally, endothelium-independent vasodilatations to sublingual nitroglycerin and plasma levels of biomarkers for endothelial functions were measured. Surprisingly, digital vasodilatations to bradykinin were almost absent in patients with MVA alone and those with VSA+MVA compared with those with VSA alone. Mechanistically, both NO- and endothelium-dependent hyperpolarization–mediated digital vasodilatations were markedly impaired in patients with MVA alone. In contrast, endothelium-independent vasodilatations to nitroglycerin were comparable among the 3 groups. Plasma levels of soluble VCAM (vascular cell adhesion molecule)-1 were significantly higher in patients with MVA alone compared with those with VSA alone. Conclusions: These results provide the first evidence that both NO- and endothelium-dependent hyperpolarization–mediated digital vasodilatations are markedly impaired in MVA patients, suggesting that MVA is a cardiac manifestation of the systemic small artery disease.

Epilepsy is known to comorbid with Alzheimer's disease. It can promote cognitive decline, and eventually worsen their prognosis and mortality. It is sometimes difficult to find a suitable drug because of the adverse effects. Perampanel has a unique mechanism of action that antagonizes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptor. Here, we report a case of severe dementia due to Alzheimer's disease with intractable epilepsy, which perampanel effected for controlling seizures with less adverse effects. The subject is an 89-year-old Japanese woman with severe dementia due to Alzheimer's disease and intractable myoclonic epilepsy. She also had psychiatric symptoms, such as circadian rhythm disorder and irritability. Valproic acid, lacosamide, or carbamazepine were prescribed, but none of them was effective. Shortly after perampanel started, however, myoclonus and these psychiatric symptoms improved. Moreover, it did not cause any obvious adverse effects, which made it possible to continue perampanel until the end of her life. Perampanel may be useful for controlling intractable epilepsy accompanied by Alzheimer's disease. It may also improve psychiatric symptoms with less adverse effect. Accumulation of studies is necessary to evaluate the effectiveness of perampanel on the epilepsy of Alzheimer's disease patients and further understand that mechanism.

The aim of this study was to conduct a 5-h training programme on anger-focused emotional management for nurses and verify its effectiveness.The study used a one-group pretest-posttest design.Participants (N = 283) attended a programme comprising lectures and exercises. The Japanese version of the Buss-Perry Aggression Questionnaire was administered pre-, post- and 3-month posttraining. Regression analyses were used to assess the effects of the programme by gender.For the total aggression score, the difference between the pre- and posttraining scores was -2.827 points and remained at -1.602 points 3-month posttraining. Physical aggression scores decreased posttraining, but the scores increased after 3 months. There were statistically significant gender differences in hostility scores; pre-training scores were slightly higher for men than for women and lower for men after 3 months. Total and physical aggression scores were higher for men than for women. The training programme decreased aggression, and the effect persisted after 3 months.

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina attack. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Myocardial lactate production, which could be defined as a negative myocardial lactate extraction ratio (ratio of the coronary arterial-venous difference in lactate concentration to arterial concentration), is considered indicative of objective evidence to support the emerging myocardial ischemia. Thus, monitoring of the myocardial lactate production and the emergence of chest pain and ischemic electrocardiographic changes during acetylcholine (ACh) provocation testing is of significant value for detecting the entity of MVS. Practically, 1 min after incremental doses of ACh (20, 50, and 100 μg) are administered into the left coronary artery (LCA), paired samples of 1 mL of blood are collected from the LCA ostium and coronary sinus for measurement of lactate concentration by a calibrated automatic lactate analyzer. Then, the development of MVS could be confirmed by negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial coronary spasm or before its occurrence throughout ACh provocation testing. In conclusion, assessment of myocardial lactate production is essential and valuable for the diagnosis of MVS.

Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary atherosclerotic stenosis. This clinical condition has recently been described as ischaemia with non-obstructive coronary arteries (INOCA). Coronary functional abnormalities are central to the pathogenesis of INOCA, including epicardial coronary spasm and coronary microvascular dysfunction composed of a variable combination of increased vasoconstrictive reactivity and/or reduced vasodilator function. During the last decade – in INOCA patients in particular – evidence for the prognostic impact of coronary functional abnormalities has accumulated and various non-invasive and invasive diagnostic techniques have enabled the evaluation of coronary vasomotor function in a comprehensive manner. In this review, the authors briefly summarise the recent advances in the understanding of pathophysiology and diagnosis of epicardial coronary artery spasm and coronary microvascular dysfunction.

Intra-procedural myocardial ischemia as an iatrogenic complication still remains a critical issue in contemporary interventional cardiology. The aim of this study was to examine the usefulness of fasudil, a selective Rho-kinase inhibitor, for percutaneous coronary intervention (PCI)-related myocardial ischemia.Among 448 PCI sessions performed between October 2015 and December 2017, we retrospectively examined 36 patients (69.0 ± 9.1 [SD] yrs., M/F 26/10) who underwent intracoronary administration of fasudil during a procedure to resolve myocardial ischemia that was resistant to intracoronary nitrate administration.The refractory myocardial ischemia was caused by distal embolization (69%), enhanced vasoconstriction at distal site of chronic total occlusion (11%), coronary spasm (11%), and coronary dissection (8%), most of which occurred immediately after balloon or stent dilatation. Intracoronary fasudil significantly improved corrected TIMI frame count (from 37 [30-56] to 24 [12-36]) and TIMI flow grade (from 2 [1-2.5] to 3 [2-3]) (both P 0.001). Finally, 86% of all subjects successfully obtained TIMI flow grade 3 at the end of the procedure. Intracoronary fasudil tended to be more effective in patients with an attenuated plaque detected by intravascular ultrasound. Importantly, among the 19 elective cases, fasudil successfully prevented 17 patients from developing post-procedure myocardial infarction. Although fasudil-induced transient hypotension requiring a vasopressor was noted in 22% of the subjects, no other adverse effects were noted.These results indicate that fasudil is a useful and safe therapeutic option for PCI-related myocardial ischemia refractory intracoronary nitrate.

Background Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary stenosis, in whom coronary functional abnormalities could be involved. Objectives This study examined the significance of coronary functional abnormalities in a comprehensive manner for both epicardial and microvascular coronary arteries in patients with angina and nonobstructive coronary artery disease (CAD). Methods This study prospectively enrolled 187 consecutive patients (male/female 113/74, 63.2 ± 12.3 years), who underwent acetylcholine provocation test for coronary spasm and measurement of index of microcirculatory resistance (IMR) to evaluate coronary microvascular function, and followed them for a median of 893 days. Results Of all subjects, acetylcholine test identified 128 patients with vasospastic angina (VSA) (68%), and cardiac events occurred in 10 patients (5.3%) during the follow-up. Multivariable analysis revealed that IMR correlated with the incidence of cardiac events (hazard ratio: 1.05; 95% confidence interval: 1.02 to 1.09; p = 0.002) and receiver-operating characteristics (ROC) curve analysis identified IMR of 18.0 as the optimal cut-off value. Among the 4 groups based on the cut-off value of IMR and the presence of VSA, the Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with high IMR (≥18.0) and VSA compared with other groups (log rank, p = 0.002). Importantly, intracoronary administration of fasudil, a Rho-kinase inhibitor, significantly ameliorated IMR in the VSA patients with increased IMR (p Conclusions These results indicate that in patients with angina and nonobstructive CAD, coexistence of epicardial coronary spasm and increased microvascular resistance is associated with worse prognosis, for which Rho-kinase activation may be involved.

Background Possible ethnic differences in clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina (VSA) remain to be elucidated. Methods and results The Japanese Coronary Spasm Association (JCSA) conducted an international, prospective, and multicenter registry study for VSA patients. A total of 1457 VSA patients (Japanese/Caucasians, 1339/118) were enrolled based on the same diagnostic criteria. Compared with Caucasian patients, Japanese patients were characterized by higher proportions of males (68 vs. 51%) and smoking history (60 vs. 49%). Japanese patients more often had angina especially during the night and early morning hours, compared with Caucasians. Ninety-five percent of Japanese and 84% of Caucasian patients underwent pharmacological provocation test. Importantly, no significant differences in the patterns of coronary spasm were apparent, with diffuse spasm most frequently noted in both ethnicities. The prescription rate of calcium-channel blockers was higher in Japanese (96 vs. 86%), whereas the uses of nitrates (46 vs. 59%), statins (43 vs. 65%), renin-angiotensin-system inhibitors (27 vs. 51%), and β-blockers (10 vs. 24%) were more common in Caucasian patients. Survival rate free from major adverse cardiac events (MACE) was slightly but significantly higher in Japanese than in Caucasians (86.7 vs. 76.6% at 5 years, P Conclusion These results indicate that there are ethnic differences in clinical profiles and long-term prognosis of contemporary VSA patients.

Background Suicide remains one of the leading causes of death among adolescents. Although recent studies have suggested a strong association between auditory hallucinations and suicidal behaviors, little is known regarding the association between suicidal behaviors and visual hallucinations, which are also common among adolescent psychiatric patients. Method A cross-sectional study of all first-time patients aged 10-15 years was conducted at three child and adolescent psychiatric outpatient facilities in Kanagawa Prefecture, Japan, from April 2015 to March 2018. Self-reported questionnaires were administered to evaluate auditory and visual hallucinations, suicide planning, and suicide attempts within the two weeks prior to the first visit. Our logistic regression model included three covariates (sex, age, and presence of major depressive episode) for adjustments. Among the 1285 respondents, 37 who had moderate or severe intellectual disability were excluded, leaving 1248 for analysis. Results Among the 1069 patients who completed questionnaire items on hallucinations, 230 (21.5%) experienced auditory or visual hallucinations. After controlling for all confounders, visual hallucinations, but not auditory hallucinations, were significantly associated with increased odds of suicide planning (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.5-4.1). In contrast, auditory hallucinations, but not visual hallucinations, were significantly associated with increased odds of suicide attempts (OR 2.8, 95% CI 1.3-6.1). No interaction effects were observed between suicidal behaviors and auditory or visual hallucinations. Conclusions Clinicians should consider the prevalence of both auditory and visual hallucinations among young adolescent patients, with emphasis on auditory hallucinations, given their association with suicide attempts.

IntroductionThe COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date.MethodsThe targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a “telepsychiatry group” (at least 50% of visits to be conducted using telemedicine, with at least one face-to-face treatment [FTF] every six months) or an “FTF group” (all visits to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group.DiscussionThis study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry.Trial RegistrationjRCT1030210037, Japan Registry of Clinical Trials (jRCT)

To generate an intense femtosecond pulse with an energy of several mJ or more, the pulse must be sufficiently stretched and compressed using grating-based optics in a chirped pulse amplification system. However, the stability of the carrier–envelope phase (CEP) is readily degraded by movement of the diffraction gratings due to vibration caused by pump lasers and other equipment. By suppressing the vibration and acoustic waves, we reduced the CEP noise to much less than 100 mrad (rms). With feedback control using a wedge pair with a single shot f - 2 f interferometer (1 ms integration time), we were able to stabilize the CEP, achieving a CEP noise of 58 mrad (rms) at a pulse energy of 0.5 mJ and 99 mrad (rms) at a pulse energy of 7 mJ and a repetition rate of 1 kHz. We also analyzed the effects of vibration on the pulse stretcher and compressor using a geometrical optics approach and found that roof mirrors were the most influential.

The bottleneck for an attosecond science experiment is concluded to be the lack of a high-peak-power isolated attosecond pulse source. Therefore, currently, generating an intense attosecond pulse would be one of the highest priority goals. In this paper, we review a TW-class parallel three-channel waveform synthesizer for generating a gigawatt-scale soft-x-ray isolated attosecond pulse (IAP) using high-order harmonics generation (HHG). Simultaneously, using several stabilization methods, namely, the low-repetition-rate laser carrier-envelope phase stabilization, Mach-Zehnder interferometer, balanced optical cross-correlator, and beam-pointing stabilizer, we demonstrate a stable 50-mJ three-channel optical-waveform synthesizer with a peak power at the multi-TW level. This optical-waveform synthesizer is capable of creating a stable intense optical field for generating an intense continuum harmonic beam thanks to the successful stabilization of all the parameters. Furthermore, the precision control of shot-to-shot reproducible synthesized waveforms is achieved. Through the HHG process employing a loose-focusing geometry, an intense shot-to-shot stable supercontinuum (50-70 eV) is generated in an argon gas cell. This continuum spectrum supports an IAP with a transform-limited duration of 170 as and a submicrojoule pulse energy, which allows the generation of a GW-scale IAP. Another supercontinuum in the soft-x-ray region with higher photon energy of approximately 100-130 eV is also generated in neon gas from the synthesizer. The transform-limited pulse duration is 106 as. According to this work, the enhancement of HHG output through optimized waveform synthesis is experimentally proved. The high-energy multicycle pulse with 10-Hz repetition rate is proved to have the same controllability for optimized waveform synthesis for HHG as few- or subcycle pulses from a 1-kHz laser., Comment: 21 pages, 10 figures

BACKGROUND Stable coronary artery disease is caused by a variable combination of organic coronary stenosis and functional coronary abnormalities, such as coronary artery spasm. Thus, we examined the clinical importance of comorbid significant coronary stenosis and coronary spasm. METHODS AND RESULTS We enrolled 236 consecutive patients with suspected angina who underwent acetylcholine provocation testing for coronary spasm and fractional flow reserve (FFR) measurement. Among them, 175 patients were diagnosed as having vasospastic angina (VSA), whereas the remaining 61 had no VSA (non‐VSA group). The patients with VSA were further divided into the following 3 groups based on angiography and FFR: no organic stenosis (≤50% luminal stenosis; VSA‐alone group, n=110), insignificant stenosis of FFR>0.80 (high‐FFR group, n=36), and significant stenosis of FFR≤0.80 (low‐FFR group, n=29). The incidence of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, urgent percutaneous coronary intervention, and hospitalization attributed to unstable angina was evaluated. All patients with VSA received calcium channel blockers, and 28 patients (95%) in the low‐FFR group underwent a planned percutaneous coronary intervention. During a median follow‐up period of 656 days, although the incidence of major adverse cardiovascular events was low and comparable among non‐VSA, VSA‐alone, and high‐FFR groups, the low‐FFR group had an extremely poor prognosis (non‐VSA group, 1.6%; VSA‐alone group, 3.6%; high‐FFR group, 5.6%; low‐FFR group, 27.6%) ( P CONCLUSIONS These results indicate that patients with VSA with significant coronary stenosis represent a high‐risk population despite current guideline‐recommended therapies, suggesting the importance of routine coronary functional testing in this population.

Introduction Hashimoto's thyroiditis, which is characterized by anti-thyroid antibodies such as the anti-thyroglobulin (Tg) antibody and anti-thyroid peroxidase (TPO) antibody, is one of the autoimmune diseases associated with psychiatric illnesses. We previously reported a high prevalence of antibodies to N-terminals of N-methyl-D-aspartate (NMDA) type glutamate receptor (GluR) subunits (GluN1-NT and GluN2B-NT2) among psychiatric patients with anti-thyroid antibodies. However, it remains unclear whether the presence of anti-thyroid antibodies influences antibodies to GluN1-NT or GluN2B-NT2 among psychiatric patients. The present study aims to examine antibodies to GluN1-NT and GluN2B-NT2 in psychiatric patients with anti-thyroid antibodies (PPATs) and in those without (non-PPATs). Material and methods We recruited psychiatric inpatients aged 20–60 years. Patients were excluded if they had a history of neurological diseases, dementia, developmental disorders, tumors, or autoimmune diseases except autoimmune thyroiditis. The rest of the participants were divided into two groups according to the presence of serum anti-Tg and anti-TPO antibodies. We investigated serum and cerebrospinal fluid (CSF) antibodies to GluN1-NT and GluN2B-NT2 using an enzyme-linked immunosorbent assay (ELISA). Results We initially recruited seventy-three psychiatric inpatients. Forty-six patients were excluded because of the exclusion criteria. Eighteen PPATs and nine non-PPATs were ultimately enrolled. We also collected stored sera of eighteen healthy controls (HCs) who were age- and sex-matched with PPATs. The optical densities (ODs) of serum antibodies to GluN1-NT (p = 0.0020) and GluN2B-NT2 (p = 0.039) were significantly higher in PPATs than in HCs. The ODs of CSF antibodies to GluN1-NT (p = 0.030) and GluN2B-NT2 (p = 0.017) as well as the positive ratios of those antibodies were significantly higher in PPATs than in non-PPATs. Conclusion Our finding indicates that detecting anti-thyroid antibodies in psychiatric patients would be a clue to consider psychiatric conditions related to antibodies to GluN1-NT/GluN2B-NT2. Further studies focusing on the relationship between PPATs and antibodies to GluN1-NT/GluN2B-NT2 are needed., Behavioral medicine; Biological psychiatry; Depression; Nervous system; Psychiatry; Glutamate receptor; Anti-thyroid antibody; Hashimoto's encephalopathy; Hashimoto's thyroiditis.

Introduction Ischemia and non-obstructive coronary artery disease (INOCA), including microvascular spasm (MVS) and epicardial spasm, has recently attracted much attention, for which in vivo imaging evaluation for coronary artery morphology is warranted for better understanding of this disorder. Besides the improved diagnostic accuracy of optical coherence tomography (OCT) for coronary plaques, we have recently demonstrated its capability for in vivo visualization of coronary adventitial vasa vasorum (VV) and the enhanced VV formation in patients with epicardial spasm. Purpose We aimed to examine OCT-delineated morphological characteristics in patients with INOCA in vivo. Methods A total of 335 consecutive INOCA patients, who underwent pharmacological spasm provocation tests, lactate sampling, and OCT imaging over the entire length of the left anterior descending (LAD) coronary arteries, were enrolled at our institute over 68 months from April 2013. They were classified into 4 groups; control with non-cardiac chest pain, MVS, diffuse spasm (DS), or focal spasm (FS) (Fig. 1A). MVS was diagnosed when negative lactate extraction ratio (coronary orifice < coronary sinus) was detected despite the absence of epicardial spasm during the spasm provocation test. DS was defined as epicardial spasm induced in more than 2 coronary segments in LAD, and FS as epicardial spasm in one segment. Quantitative analyses for adventitial inflammation and atherosclerotic changes were performed by calculating VV density and %area stenosis (AS) on OCT (Fig. 1B, E). Furthermore, index of microcirculatory resistance (IMR), a marker of microvascular disorder with a cut-off value of ≥25, was measured during intravenous infusion of adenosine, which was then correlated with VV densities in the MVS and DS groups. Coronary plaque with a necrotic core was classified as fibroatheroma (FA), and the number of OCT frames with internal VV (IVV) in the atheroma was counted. Results VV density was significantly higher in MVS as compared with the controls (Fig. 1B). DS was most prevalent in INOCA (Fig. 1A) with highest VV density (Fig. 1B). Patients with IMR≥25 were predominantly distributed with a gradual increase in the MVS, DS, and FS groups, but none in the controls (Fig. 1C). Importantly, there was a significant positive correlation between VV densities and IMR in the MVS and DS groups (Fig. 1D). In addition, FS had the largest plaque size and showed the highest prevalence of FA and IVV (Fig. 1E–G). Conclusions These results indicate that MVS and DS are characterized by vasomotion abnormalities associated with adventitial inflammation and microvascular disorder, while FS by vulnerable atherosclerotic phenotype, suggesting that OCT may be useful for screening high-risk populations in INOCA. Figure 1 Funding Acknowledgement Type of funding source: None

The aim of the present study was to investigate the psychological effects of the COVID-19 outbreak and associated factors on hospital workers at the beginning of the outbreak with a large disease cluster on the Diamond Princess cruise ship. This cross-sectional, survey-based study collected demographic data, mental health measurements, and stress-related questionnaires from workers in 2 hospitals in Yokohama, Japan, from March 23, 2020, to April 6, 2020. The prevalence rates of general psychological distress and event-related distress were assessed using the 12-item General Health Questionnaire (GHQ-12) and the 22-item Impact of Event Scale-Revised (IES-R), respectively. Exploratory factor analysis was conducted on the 26-item stress-related questionnaires. Multivariable logistic regression analysis was performed to identify factors associated with mental health outcomes for workers both at high- and low-risk for infection of COVID-19. A questionnaire was distributed to 4133 hospital workers, and 2697 (65.3%) valid questionnaires were used for analyses. Overall, 536 (20.0%) were high-risk workers, 944 (35.0%) of all hospital workers showed general distress, and 189 (7.0%) demonstrated event-related distress. Multivariable logistic regression analyses revealed that ‘Feeling of being isolated and discriminated’ was associated with both the general and event-related distress for both the high- and low-risk workers. In this survey, not only high-risk workers but also low-risk workers in the hospitals admitting COVID-19 patients reported experiencing psychological distress at the beginning of the outbreak.

Background Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction. Methods A total of 91 schizophrenia patients treated with olanzapine monotherapy participated in this study. A power spectral analysis of heart rate variability was used to assess ANS activity. The TaqMan system was used to genotype seven single nucleotide polymorphisms (SNPs) in CYP1A2 (rs2069514 and rs762551), UGT1A4 (rs2011425), and ABCB1 (rs1045642, rs1128503, rs2032582, rs2235048). Results Sympathetic nervous activity was significantly higher in individuals with the UGT1A4 rs2011425 G allele than in those with the UGT1A4 rs2011425 non-G allele (sympathetic activity, p = .001). Furthermore, sympathetic nervous activity was also significantly associated with UGT1A4 rs2011425 genotype as revealed by multiple regression analysis (sympathetic activity, p = .008). Conclusions We suggest that the UGT1A4 rs2011425 polymorphism affects olanzapine tolerability because it is associated with the observed side effects of olanzapine in schizophrenia patients, namely sympathetic dysfunction.

Background Patients with schizophrenia have a higher mortality risk than the general population. Additionally, the autonomic nervous system (ANS) activity of patients with schizophrenia is lower and more dysfunctional than that of the general population. Nonetheless, the association between ANS dysfunction and mortality in schizophrenia is unclear. The aim of this study was to investigate the association between ANS activity and mortality in schizophrenia and to evaluate the predictive values of heart rate variability for long-term survival. Methods This study involves the 10-year follow-up of a sample population consisting of 59 Japanese inpatients with schizophrenia between 60 and 70 years of age from 2007 to 2016. The ANS activity of all patients was evaluated using heart rate variability in 2007. Results Fifty-three participants could be followed up because they stayed in the hospital during the follow-up period. Of these patients, 11 died during follow-up. Their mean age at death was 70.55 ± 3.45 years. The parasympathetic activity of nonsurvivors was significantly lower than that of survivors, and multiple logistic regression analysis showed a significant association between death and parasympathetic activity. Conclusion We suggest that decreased parasympathetic activity could be associated with 10-year all-cause mortality in older schizophrenic patients.

Background There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. Methods In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. Results For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier–rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). Conclusion We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined-risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity.

INTRODUCTION: The COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date. METHODS: The targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a "telepsychiatry group" (at least 50% of treatments to be conducted using telemedicine, with at least one face-to-face treatment [FTF] within six months) or an "FTF group" (all treatments to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group. DISCUSSION: This study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry. TRIAL REGISTRATION: jRCT1030210037, Japan Registry of Clinical Trials (jRCT). ispartof: CONTEMPORARY CLINICAL TRIALS vol:111 ispartof: location:United States status: published