Diagnosis and Treatment of Generalized Anxiety Disorder in Japan: Psychiatric Specialist Survey.

Purpose: Generalized anxiety disorder (GAD) is a suboptimally managed chronic recurring psychiatric condition with a lifetime prevalence of 2.6% in Japan. We assessed the current status of GAD management in Japan. Patients and Methods: This was an observational, cross-sectional study conducted through an anonymous web-based survey in Japan from December 12-16, 2022. Psychiatrists and psychosomatic medicine physicians who agreed to participate and saw ≥10 outpatients in the previous month were eligible. Survey questionnaire comprised 37 single/multiple choice, numerical entry, or open-ended questions in Japanese. Results: Among 509 participants (493 psychiatrists and 16 psychosomatic medicine physicians), 96.9% were aware of GAD. On average, 12.4 outpatients and 1.0 inpatient were diagnosed with GAD per physician per month. Of 433 physicians having patients diagnosed with GAD, 46.9% used operational diagnostic tools; among these, DSM-5 diagnostic criteria were used by 81.5% physicians. The majority (54.7%) of participants did not use a self-administered rating scale; depression scales were used more than anxiety scales. Among these 433 physicians, 96.8% used selective serotonin reuptake inhibitors for GAD management, and 79.2% used it as the first choice; of 431 physicians who prescribed drug therapy, 54.3% gave antidepressant monotherapy as first choice. The most frequent symptom in patients diagnosed with GAD was excessive anxiety/worry (96.5%); depression was the most commonly reported comorbidity (84.3%) as per physicians aware of GAD (N=508). Conclusion: This study illustrates that although GAD awareness is high among Japanese psychiatric specialists, GAD is not frequently diagnosed using operational diagnostic approaches. Due to a lack of Japanese guidelines for GAD diagnosis and treatment, diverse international guidelines are followed, with similar treatment paradigms as that of depression. This may not be an optimal approach given cultural/geographical differences. These findings highlight the need for uniform diagnosis and treatment recommendations for GAD management in Japan. Clinical Trial Registration: UMIN-CTR: UMIN000049572.

A lipid index for risk of hyperlipidemia caused by anti-retroviral drugs.

HIV-associated lipodystrophy has been reported in people taking anti-retroviral therapy (ART). Lipodystrophy can cause cardiovascular diseases, affecting the quality of life of HIV-infected individuals. In this study, we propose a pharmacological lipid index to estimate the risk of hyperlipidemia caused by anti-retroviral drugs. Lipid droplets were stained in cells treated with anti-retroviral drugs and cyclosporin A. Signal intensities of lipid droplets were plotted against the drug concentrations to obtain an isodose of 10 µM of cyclosporin A, which we call the Pharmacological Lipid Index (PLI). The PLI was then normalized by EC50. PLI/EC50 values were low in early proteinase inhibitors and the nucleoside reverse transcriptase inhibitor, d4T, indicating high risk of hyperlipidemia, which is consistent with previous findings of hyperlipidemia. In contrast, there are few reports of hyperlipidemia for drugs with high PLI/EC50 scores. Data suggests that PLI/EC50 is a useful index for estimating the risk of hyperlipidemia.

Femtosecond Reduction of Atomic Scattering Factors Triggered by Intense X-Ray Pulse.

X-ray diffraction of silicon irradiated with tightly focused femtosecond x-ray pulses (photon energy, 11.5 keV; pulse duration, 6 fs) was measured at various x-ray intensities up to 4.6×10^{19} W/cm^{2}. The measurement reveals that the diffraction intensity is highly suppressed when the x-ray intensity reaches of the order of 10^{19} W/cm^{2}. With a dedicated simulation, we confirm that the observed reduction of the diffraction intensity can be attributed to the femtosecond change in individual atomic scattering factors due to the ultrafast creation of highly ionized atoms through photoionization, Auger decay, and subsequent collisional ionization. We anticipate that this ultrafast reduction of atomic scattering factor will be a basis for new x-ray nonlinear techniques, such as pulse shortening and contrast variation x-ray scattering.

Propagation-based phase-contrast imaging method for full-field X-ray microscopy using advanced Kirkpatrick-Baez mirrors.

We demonstrate a propagation-based phase-contrast imaging method for full-field X-ray microscopy based on advanced Kirkpatrick-Baez (AKB) mirrors to achieve high-contrast observations of weak phase objects and correct field curvature aberrations. Through a demonstration performed at SPring-8, the phase contrast of weak phase objects such as polystyrene spheres and chemically fixed cells was successfully observed with high sensitivity (∼0.03 rad). Furthermore, the field of view of the AKB mirrors was expanded to the full area of the obtained images (25 × 30 µm) by correcting the field curvature aberration using reconstructed complex wavefields.

Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model.

Metal homeostasis is tightly regulated in cells and organisms, and its disturbance is frequently observed in some diseases such as neurodegenerative diseases and metabolic disorders. Previous studies suggest that zinc and iron are necessary for the normal functions of pancreatic ß cells. However, the distribution of elements in normal conditions and the pathophysiological significance of dysregulated elements in the islet in diabetic conditions have remained unclear. In this study, to investigate the dynamics of elements in the pancreatic islets of a diabetic mouse model expressing human islet amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis of elements using synchrotron scanning X-ray fluorescence microscopy and quantitative analysis of elements using inductively coupled plasma mass spectrometry. We found that in the islets, zinc significantly decreased in the early stage of diabetes, while iron gradually decreased concurrently with the increase in blood glucose levels of hIAPP-Tg mice. Notably, when zinc and/or iron were decreased in the islets of hIAPP-Tg mice, dysregulation of glucose-stimulated mitochondrial respiration was observed. Our findings may contribute to clarifying the roles of zinc and iron in islet functions under pathophysiological diabetic conditions.

Physician consultation rates and characteristics among workers with chronic pain or headache who participated in a behavioural change program: a retrospective database analysis using real-world healthcare data.

OBJECTIVE: To assess the potential benefit of a behavioural change programme in working individuals with chronic pain or headache, in the form of increased physician consultation. DESIGN: Retrospective observational database study. SETTING: Members of employment-based healthcare insurance in Japan. PARTICIPANTS: Individual-level data of working individuals aged <75 years from November 2019 through March 2020 were extracted from a database managed by MinaCare Co., Ltd. Included individuals had records of programme participation and chronic pain or headache (self-reported), and did not consult physicians for ≥3 months before programme participation. OUTCOME MEASURES: Physician consultation rates after participating in the programme were examined from December 2019 through March 2020, separately for chronic pain and headache. Baseline characteristics included age, pain numeric rating scale (NRS) score (for chronic pain), suspected migraine (for headache), labour productivity including absenteeism and presenteeism, and 4-month indirect costs in Japanese yen (JPY). RESULTS: The baseline mean age (±SD) of 506 individuals with chronic pain was 46.8±10.1 years; that of 352 individuals with headache was 43.6±9.9 years. Of those with chronic pain, 71.4% had an NRS score≥4, and 49.7% of those with headache had suspected migraine. Overall, 11.3% and 5.4% of those with chronic pain or headache consulted physicians, respectively. The mean baseline absenteeism and presenteeism were 1.5% and 19.1% in those with chronic pain, and 1.5% and 23.0% in those with headache. The baseline indirect costs were 586 941.6 JPY and 1 060 281.6 JPY among those with chronic pain or headache, respectively. CONCLUSION: Given that the individuals did not regularly consult physicians before the programme despite reporting substantial symptoms, our results suggest the potential benefit of educational programmes encouraging physician consultation. Further studies are required to evaluate how to effectively implement such educational programmes via healthcare insurers to reduce the burden of pain symptoms and overall medical costs.

The Use of a Network Analysis to Identify Associations and Temporal Patterns Among Non-communicable Diseases in Japan Based on a Large Medical Claims Database.

BACKGROUND: Reducing the considerable non-communicable disease (NCD) burden in the aging Japanese population depends on better understanding of the comorbid and temporal relationships between different NCDs. OBJECTIVE: We aimed to identify associations between NCDs and temporal patterns of NCDs in Japan using data from a large medical claims database. METHODS: The study used three-digit International Classification of Diseases, Tenth Revision codes for NCDs for employees and their dependents included in the MinaCare database, which covers the period since 2010. Associations between pairs of NCDs were assessed by calculating risk ratios. The calculated risk ratios were used to create a network of closely associated NCDs (risk ratio > 15, statistically significant) and to assess temporal patterns of NCD diagnoses (risk ratio ≥ 5). The Infomap algorithm was used to identify clusters of diseases for different sex and age strata. RESULTS: The analysis included 4,200,254 individuals (age < 65 years: 98%). Many of the temporal associations and patterns of the diseases of interest identified in this study were previously known. Regarding the diseases of interest, these associations can be classified as comorbidities, early manifestations initially diagnosed as something else, diseases attributable to or that cause the disease of interest, or caused by pharmacological treatment. International Classification of Diseases, Tenth Revision chapters that were most associated with other chapters included L Diseases of the skin and subcutaneous tissue. In the age-stratified and gender-stratified networks, clusters with the highest numbers of International Classification of Diseases, Tenth Revision codes included I Diseases of the circulatory system and F Mental and behavioral disorders. CONCLUSIONS: Our findings reinforce established associations between NCDs and underline the importance of comprehensive NCD care.

The new X-ray/visible microscopy MAXWELL technique for fast three-dimensional nanoimaging with isotropic resolution.

Microscopy by Achromatic X-rays With Emission of Laminar Light (MAXWELL) is a new X-ray/visible technique with attractive characteristics including isotropic resolution in all directions, large-volume imaging and high throughput. An ultrathin, laminar X-ray beam produced by a Wolter type I mirror irradiates the sample stimulating the emission of visible light by scintillating nanoparticles, captured by an optical system. Three-dimensional (3D) images are obtained by scanning the specimen with respect to the laminar beam. We implemented and tested the technique with a high-brightness undulator at SPring-8, demonstrating its validity for a variety of specimens. This work was performed under the Synchrotrons for Neuroscience-an Asia-Pacific Strategic Enterprise (SYNAPSE) collaboration.

Wide field-of-view x-ray imaging optical system using grazing-incidence mirrors.

A field-curvature-corrected imaging optical system for x-ray microscopy using only grazing-incidence mirrors is proposed. It combines a Wolter type I (WO1) mirror pair, which forms a real image, with field curvature correction (FCC) optics-a convex hyperbolic mirror pair-that form a virtual image; compensation of the field curvatures realizes a wide field-of-view (FOV) and high magnification. Ray-tracing and wave-optics simulations verified the efficacy of the design, for which a FOV width was 111 µm-4.7 times larger than that for the uncorrected WO1 design. The addition of FCC optics also produced a 2.3-fold increase in magnification.

Formation Mechanism and Toxicological Significance of Biogenic Mercury Selenide Nanoparticles in Human Hepatoma HepG2 Cells.

It is widely recognized that the toxicity of mercury (Hg) is attenuated by the simultaneous administration of selenium (Se) compounds in various organisms. In this study, we revealed the mechanisms underlying the antagonistic effect of sodium selenite (Na2SeO3) on inorganic Hg (Hg2+) toxicity in human hepatoma HepG2 cells. Observations by transmission electron microscopy indicated that HgSe (tiemannite) granules of up to 100 nm in diameter were accumulated in lysosomal-like structures in the cells. The HgSe granules were composed of a number of HgSe nanoparticles, each measuring less than 10 nm in diameter. No accumulation of HgSe nanoparticles in lysosomes was observed in the cells exposed to chemically synthesized HgSe nanoparticles. This suggests that intracellular HgSe nanoparticles were biologically generated from Na2SeO3 and Hg2+ ions transported into the cells and were not derived from HgSe nanoparticles formed in the extracellular fluid. Approximately 85% of biogenic HgSe remained in the cells at 72 h post culturing, indicating that biogenic HgSe was hardly excreted from the cells. Moreover, the cytotoxicity of Hg2+ was ameliorated by the simultaneous exposure to Na2SeO3 even before the formation of insoluble HgSe nanoparticles. Our data confirmed for the first time that HepG2 cells can circumvent the toxicity of Hg2+ through the direct interaction of Hg2+ with a reduced form of Se (selenide) to form HgSe nanoparticles via a Hg-Se soluble complex in the cells. Biogenic HgSe nanoparticles are considered the ultimate metabolite in the Hg detoxification process.

Hard X-ray nanoprobe scanner.

X-ray scientists are continually striving to improve the quality of X-ray microscopy, due to the fact that the information obtained from X-ray microscopy of materials can be complementary to that obtained from optical and electron microscopes. In contrast to the ease with which one can deflect electron beams, the relative difficulty to deflect X-ray has constrained the development of scanning X-ray microscopes (SXMs) based on a scan of an X-ray small probe. This restriction has caused severe complications that hinder progress toward achieving ultimate resolution. Here, a simple and innovative method for constructing an SXM equipped with a nanoprobe scanner is proposed. The nanoprobe scanner combines X-ray prisms and advanced Kirkpatrick-Baez focusing mirrors. By rotating the prisms on the order of degrees, X-ray probe scanning with single-nanometre accuracy can be easily achieved. The validity of the concept was verified by acquiring an SXM image of a test pattern at a photon energy of 10 keV, where 50 nm line-and-space structures were resolved. This method is readily applicable to an SXM with a single-nanometre resolution and will assist effective utilization of increasing brightness of fourth-generation synchrotron radiation sources.

Properties of macrophages and lymphocytes appearing in rat renal fibrosis followed by repeated injection of cisplatin.

Properties of macrophages and lymphocytes appearing in renal fibrosis remains to be investigated. F344 rats were injected once a week with cisplatin (2 mg/kg body weight) for 8 weeks and examined at post-final injection weeks 1, 3, 6, 9, and 12. Rats developed progressive renal fibrosis at weeks 1 to 6 as fibrosis-progress phase, and subsequent amelioration at weeks 9 and 12. CD68+ M1-macrophages and major histocompatibility complex (MHC) class II+ macrophages remarkably increased persistently, whereas CD163+ M2-macrophages slightly increased. MHC class II+/CD68+ and MHC class II+/CD163+ macrophages were present, indicating that MHC class II+ macrophages might have both functions of M1- and M2-macrophages. In the fibrosis-progress phase, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ for M1-factors, and transforming growth factor (TGF)-ß1 and IL-10 for M2-factors tended to increase; tissue injury by M1 and fibrosis by M2 might have occurred simultaneously. Lots of CD4+ and CD8+ T cells appeared in close relation with MHC class II+ macrophages, and mainly CD4+ T cells formed aggregations. In the lymphocyte aggregates collected by laser microdissection, expression of IL-17A (for Th17 cells) and forkhead box P3 (FoxP3) (for Treg) significantly increased at weeks 1 and 6, respectively; presumably, Th17 cells might be involved in tissue injury, whereas Treg might be related to fibrosis amelioration. These results suggested that macrophages and T cells may contribute interrelatedly to renal fibrosis.

[Studies on Monoamine Transporter Occupancy of Antidepressants using PET: Focusing on SERT and NET].

Monoamine transporter occupancy of antidepressants in the brain can be measured by positron emission tomography. For antidepressive effects to appear, serotonin transporter (SERT) occupancy should rise to 80% or higher. Despite a recent increase in the number of reports on norepinephrine transporter (NET) occupancy, estimating the threshold level of NET occupancy required for antidepressive effects is difficult based on the analysis of NET alone. Therefore, studies should be conducted on NET occupancy required for a valid treatment, including an ideal balance between SERT and NET occupancy. (Received 24 September 2020; Accepted December 18, 2020; Published June 1, 2021).

X-ray adaptive zoom condenser utilizing an intermediate virtual focus.

We propose an extended X-ray adaptive zoom condenser that can form an intermediate virtual focus. The system comprises two deformable mirrors for focusing within a single dimension and can vary its numerical aperture (NA) without changing the positions of the light source, mirrors, or final focus. The desired system NA is achieved simply by controlling the mirror surfaces, which enables conversion between convex and concave forms, by varying the position of the intermediate virtual focus. A feasibility test at SPring-8 under a photon energy of 10 keV demonstrated that the beam size can be varied between 134 and 1010 nm.

Optimal deformation procedure for hybrid adaptive x-ray mirror based on mechanical and piezo-driven bending system.

A hybrid deformable x-ray mirror consisting of a mechanical bender and a bimorph deformable mirror has been developed to realize adaptive optical systems, such as zoom condenser optics, for synchrotron-radiation-based x-ray microscopy. In the developed system, both bending mechanisms comprehensively contribute to the formation of the target mirror shape and can narrow the role of piezoelectric actuators, thereby enabling a more stable operation. In this study, the behavior of the bimorph mirror under the clamped condition was investigated, and the sharing of the deformation amount for each bending mechanism was optimized to minimize the amplitude of the voltage distribution of the bimorph mirror.

High-throughput deterministic plasma etching using array-type plasma generator system.

A deterministic processing method is a high-precision finishing method, where the to-be-removed amount of material at each point of the work surface is calculated based on an accurately measured present surface shape and is removed precisely using a numerically controlled (NC) processing system. Although this method has achieved nanometer-scale accuracy, the method requires considerable time to scan the work surface, leading to low productivity. Therefore, using an individual on-off controllable array-type plasma generator covering the entire work surface, enabling simultaneous NC plasma processing is proposed herein. A novel intermittent gas flow system was constructed using cyclic on-off control of the gas supply and exhaust valves instead of the commonly used continuous gas flow to achieve uniform in-plane plasma etching. It was found that uniform removal could be achieved by combining it with a pulse-modulated high-frequency power supply and setting the plasma generation time in one cycle to be sufficiently short. Furthermore, a power control approach was developed for maintaining a constant plasma state, even while varying the plasma-generating array elements, which resulted in a demonstration experiment of NC plasma etching that successfully reduced the thickness variation of a silicon substrate.

X-Ray Single-Grating Interferometry for Wavefront Measurement and Correction of Hard X-Ray Nanofocusing Mirrors.

X-ray single-grating interferometry was applied to conduct accurate wavefront corrections for hard X-ray nanofocusing mirrors. Systematic errors in the interferometer, originating from a grating, a detector, and alignment errors of the components, were carefully examined. Based on the measured wavefront errors, the mirror shapes were directly corrected using a differential deposition technique. The corrected X-ray focusing mirrors with a numerical aperture of 0.01 attained two-dimensionally diffraction-limited performance. The results of the correction indicate that the uncertainty of the wavefront measurement was less than λ/72 in root-mean-square value.

High-resolution micro channel-cut crystal monochromator processed by plasma chemical vaporization machining for a reflection self-seeded X-ray free-electron laser.

A high-resolution micro channel-cut crystal monochromator (µCCM) composed of an Si(220) crystal is developed for the purpose of narrowing the bandwidth of a reflection self-seeded X-ray free-electron laser. Subsurface damage on the monochromator, which distorts the wavefront and broadens the bandwidth of the monochromatic seed beam, was removed by using a plasma etching technique. High diffraction performance of the monochromator was confirmed through evaluation with coherent X-rays. Reflection self-seeding operation was tested with the Si(220) µCCM at SPring-8 Angstrom Compact free-electron laser. A narrow average bandwidth of 0.6 eV, which is five times narrower than the value previously reported [I. Inoue et al., Nat. Photonics13, 319 (2019)10.1038/s41566-019-0365-y], was successfully obtained at 9 keV. The narrow-band X-ray beams with high intensity realized in this study will further expand the capabilities of X-ray free-electron lasers.

hv2-concept breaks the photon-count limit of RIXS instrumentation.

Upon progressive refinement of energy resolution, the conventional resonant inelastic X-ray scattering (RIXS) instrumentation reaches the limit where the bandwidth of incident photons becomes insufficient to deliver an acceptable photon-count rate. Here it is shown that RIXS spectra as a function of energy loss are essentially invariant to their integration over incident energies within the core-hole lifetime. This fact permits RIXS instrumentation based on the hv2-concept to utilize incident synchrotron radiation over the whole core-hole lifetime window without any compromise on the much finer energy-loss resolution, thereby breaking the photon-count limit.