Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Characteristics of goal-setting tools in adult rehabilitation: A scoping review.

OBJECTIVES: This scoping review aims to map the literature on goal-setting tools in adult rehabilitation, exploring their characteristics, target users and supporting evidence to inform practice and future research in this area. METHODS: We completed a comprehensive search of four databases to identify relevant articles on tools for goal setting in rehabilitation. We followed Arkey and O'Malley's scoping review process to guide article selection, data extraction and data analysis. RESULTS: We identified a total of 165 studies that reported on 55 different goal-setting tools, including tools for goal selection and goal documentation (n = 31), goal setting and intervention planning (n = 15), and for measuring the quality of the goal-setting process (n = 9). Over half of the tools were primarily designed for use in rehabilitation of physical disabilities (n = 32). Some tools fell under multiple sub-categories based on their characteristics as follows: 22 framework tools, 12 interview tools, 9 outcome measurement tools for goal achievement, 6 outcome measurement tools for goal quality and 25 documentation tools. The majority of goal-setting instruments targeted goals at the level of activity and participation (n = 51) and aimed to facilitate a client-centred or shared decision-making approach to rehabilitation planning (n = 46). CONCLUSIONS: This study provides a comprehensive overview of existing goal-setting tools, highlighting their characteristics, target users and identified needs. These findings can enhance practitioners' awareness of the range of goal-setting tools available and can enable more effective utilization of these tools in clinical practice. Further research should investigate how clinicians can combine multiple tools to deliver goal setting.

Relationship between coronary high-intensity plaques on T1-weighted imaging by cardiovascular magnetic resonance and vulnerable plaque features by near-infrared spectroscopy and intravascular ultrasound: a prospective cohort study.

BACKGROUND: This study aimed to compare the coronary plaque characterization by cardiovascular magnetic resonance (CMR) and near-infrared spectroscopy (NIRS)-intravascular ultrasound (IVUS) (NIRS-IVUS), and to determine whether pre-percutaneous coronary intervention (PCI) evaluation using CMR identifies high-intensity plaques (HIPs) at risk of peri-procedural myocardial infarction (pMI). Although there is little evidence in comparison with NIRS-IVUS findings, which have recently been shown to identify vulnerable plaques, we inferred that CMR-derived HIPs would be associated with vulnerable plaque features identified on NIRS-IVUS. METHODS: 52 patients with stable coronary artery disease who underwent CMR with non-contrast T1-weighted imaging and PCI using NIRS-IVUS were studied. HIP was defined as a signal intensity of the coronary plaque-to-myocardial signal intensity ratio (PMR) ≥ 1.4, which was measured from the data of CMR images. We evaluated whether HIPs were associated with the NIRS-derived maximum 4-mm lipid-core burden index (maxLCBI4mm) and plaque morphology on IVUS, and assessed the incidence and predictor of pMI defined by the current Universal Definition using high-sensitive cardiac troponin-T. RESULTS: Of 62 lesions, HIPs were observed in 30 lesions (48%). The HIP group had a significantly higher remodeling index, plaque burden, and proportion of echo-lucent plaque and maxLCBI4mm ≥ 400 (known as large lipid-rich plaque [LRP]) than the non-HIP group. The correlation between the maxLCBI4mm and PMR was significantly positive (r = 0.51). In multivariable logistic regression analysis for prediction of HIP, NIRS-derived large LRP (odds ratio [OR] = 5.41; 95% confidence intervals [CIs] 1.65-17.8, p = 0.005) and IVUS-derived echo-lucent plaque (OR = 5.12; 95% CIs 1.11-23.6, p = 0.036) were strong independent predictors. Furthermore, pMI occurred in 14 of 30 lesions (47%) with HIP, compared to only 5 of 32 lesions (16%) without HIP (p = 0.005). In multivariable logistic regression analysis for prediction of incidence of pMI, CMR-derived HIP (OR = 5.68; 95% CIs 1.53-21.1, p = 0.009) was a strong independent predictor, but not NIRS-derived large LRP and IVUS-derived echo-lucent plaque. CONCLUSIONS: There is an important relationship between CMR-derived HIP and NIRS-derived large LRP. We also confirmed that non-contrast T1-weighted CMR imaging is useful for characterization of vulnerable plaque features as well as for pre-PCI risk stratification. Trial registration The ethics committee of Juntendo Clinical Research and Trial Center approved this study on January 26, 2021 (Reference Number 20-313).

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Dual-energy CT imaging of atherosclerotic plaque using novel ultrasmall superparamagnetic iron oxide in hyperlipidemic rabbits.

BACKGROUND: A study using magnetic resonance imaging (MRI) revealed that ultra-small superparamagnetic iron oxide is phagocytosed by macrophages. However, MRI has limitations in obtaining clear images due to its poor spatial and temporal resolutions. PURPOSE: To examine whether the use of dual-energy computed tomography (DECT) facilitated the visualization of carboxymethyl-diethylaminoethyl dextran magnetite ultra-small superparamagnetic iron oxide (CMEADM-U) accumulation in arteriosclerotic lesions using hyperlipidemic rabbits. MATERIAL AND METHODS: CMEADM-U at 0.5 mmol Fe/kg was administered to Watanabe hereditary atherosclerotic (WHHL) rabbits (n = 6, 24 sections) and New Zealand white (NZW) rabbits (n = 2, 6 sections). After 72 h, DECT was performed to prepare virtual monochromatic images (35 keV, 70 keV) and an iron-based map. Subsequently, the aorta was collected along with hematoxylin and eosin staining, Berlin blue (BB) staining, and RAM11 immunostaining. RESULTS: In the WHHL rabbits, CMEADM-U accumulation was not observed at 70 keV. However, CMEADM-U accumulation consistent with an arteriosclerotic lesion was observed at 35 keV and the iron-based map. On the other hand, in the NZW rabbits, there was no accumulation of CMEADM-U in any images. Further, there were significant differences in the iron-based map value at the site of accumulation among the grades of expression on BB staining and RAM11 immunostaining. In addition, there was a good correlation at 35 kev and iron-based map value (r = 0.42; P < 0.05). CONCLUSION: DECT imaging for CMEADM-U facilitated the assessment of macrophage accumulation in atherosclerotic lesions in an in vivo study using a rabbit model of induced aortic atherosclerosis.

Clinical significance of 123I-BMIPP washout rate in patients with uncertain chronic heart failure.

BACKGROUND: Recently, triglyceride deposit cardiomyovasculopathy (TGCV) with defective intracellular lipolysis was found to be a disease that causes heart failure. As a diagnostic criterion for TGCV, an Iodaine-123-ß-methyl iodophenyl-pentadecanoic acid washout rate (BMIPP WOR) of < 10% is used, but its clinical significance in patients with heart failure remains to be clarified. METHODS: In 62 hospitalized patients with chronic heart failure, 123I-BMIPP myocardial single-photon emission computed tomography (SPECT) was performed predischarge state. The prevalence of TGCV was investigated. Subsequently, follow-up was conducted for ≥ 90 days (mean: 724.6 ± 392.7 days), and the association between the BMIPP WOR and cardiac events was examined, establishing all-cause mortality and admission due to heart failure as endpoints. RESULTS: Of the 62 patients, the WOR was < 10% in 41 (66.1%). Of these, 26 (41.9%) were diagnosed with definite TGCV. Furthermore, cardiac events were noted in 12 patients (19.4%). Analysis with Cox proportional hazards models showed that the BMIPP WOR < 4.5% was a significant event-predicting factor [HR 4.29, 95% CI: 1.20-16.87; p = 0.0245]. On a Kaplan-Meier curve, the WOR was 4.5%; there was a significant difference in the incidence of events (p = 0.0298). CONCLUSION: In the predischarge state of heart failure, 123I-BMIPP myocardial SPECT was performed. In approximately 40% of the patients, a diagnosis of TGCV was made. The results suggested that the BMIPP WOR is useful for predicting the prognosis of chronic heart failure patients regardless of TGCV.

Coronary flow disturbance assessed by vorticity as a cause of functionally significant stenosis.

OBJECTIVES: Vorticity calculated using computational fluid dynamics (CFD) could assess the flow disturbance generated by coronary stenosis. The purpose of this study was to investigate whether vorticity would be an underlying cause of functionally significant stenosis assessed by invasive fractional flow reserve (FFR). METHODS: This retrospective study included 113 patients who underwent coronary CT angiography showing intermediate stenosis and subsequent invasive FFR between December 2015 and March 2020. Vorticity at the stenosis site was calculated using a mesh-free CFD method. We also evaluated the minimum lumen area (MLA) and diameter stenosis (DS) of the lesion. Invasive FFR of ≤ 0.80 was considered functionally significant. Data were compared using Student's t-test and logistic regression analysis was performed. RESULTS: Of the evaluated 144 vessels, 53 vessels (37%) showed FFR ≤ 0.80. Vorticity of significant stenosis was significantly higher than non-significant stenosis (569 ± 78 vs. 328 ± 34 s-1, p < 0.001). A significant negative relationship was present between vorticity and invasive FFR (R2 = 0.31, p < 0.001). Multivariate logistic regression analysis including MLA and DS showed that vorticity (per 100 s-1, odds ratio: 1.36, 95% confidence interval: 1.21-1.57, p < 0.001) was a statistically significant factor to detect functional significance. The area under the receiver operating characteristic curve statistically significantly increased when vorticity was combined with DS and MLA (0.76 vs. 0.87, p = 0.001). CONCLUSIONS: Vorticity had a statistically significant negative relationship with invasive FFR independent of geometric stenosis. KEY POINTS: • Flow disturbance caused by coronary stenosis could be evaluated by calculating vorticity which is defined as the norm of the rotation of the velocity vector. • Vorticity was statistically significantly higher in stenosis with functional significance than stenosis without. • Vorticity has an additive value to detect functionally significant stenosis over geometrical stenosis.

Plaque characteristics on coronary CT angiography associated with the positive findings of fractional flow reserve and instantaneous wave-free ratio.

BACKGROUND: Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are useful in determining indications for revascularization of coronary artery disease (CAD). Although the discordance of FFR and iFR was noted in approximately 20%, this cause has not been well established. We investigated patient background and features on coronary CT angiography (CCTA) showing not only FFR- and iFR-positive findings but also discordance between FFR ≤ 0.8 and iFR ≤ 0.89. METHODS: Subjects were consecutively treated in 83 cases with 105 vessels in which stenosis of 30-90% was detected at one vessel of at least 2 mm or more in the major epicardial vessels and FFR and iFR was performed within subsequent 90 days, among suspected CAD which underwent CCTA. The factors affecting not only FFR- and iFR-positive findings, respectively, but also discordance between FFR and iFR was evaluated using logistic regression analysis on per-patient and per-vessel basis. RESULTS: FFR- and iFR-positive findings were observed in 42 vessels (40.0%) and 34 vessels (32.3%), respectively. Discordance between FFR ≤ 0.8 and iFR ≤ 0.89 was observed in 22 vessels (21.0%) of 21 patients. In multivariate logistic analysis, LAD (OR 3.55; 95%CI 1.20-11.71; p = 0.0217) and lumen volume/myocardial weight (L/M) ratio (OR 0.93; 0.86-0.99, p = 0.0290) were significant predictors for FFR-positive findings. For iFR-positive findings, LAD (OR 3.86; 95%CI 1.12-13.31; p = 0.0236) was only significant predictor. In FFR ≤ 0.8 and iFR > 0.89 group (15 vessels, 14.3%), positive remodeling (PR) (OR 5.03, 95%CI 1.23-20.48, p = 0.0205) was significant predictor. In FFR > 0.8 and iFR ≤ 0.89 group (7 vessels, 6.7%), there were no significant predictors. CONCLUSION: On CCTA characteristics, a relevant predictor for FFR-positive findings included low L/M ratio. PR was significant predictor in FFR-positive, iFR-negative patients among those with discordance between the FFR and iFR.

Adjustment of CT-fractional flow reserve based on fluid-structure interaction underestimation to minimize 1-year cardiac events.

The purpose of the study was to evaluate the optimal cut-off value of CT-Fractional Flow Reserve (CT-FFR) using fluid-structure interaction and how to adjust the CT-FFR's underestimation from a standpoint of minimize 1-year cardiac events. Subjects were 38 cases with 44 vessels in which stenosis of 30-90% was detected using one-rotation scanning by 320-row coronary CT angiography (CCTA) and invasive FFR (i-FFR) was performed within subsequent 90 days. CT-FFR was calculated using on-site from the multiple cardiac phases. A hypothetical 1-year cardiac event incidence was estimated using previous evidences when revascularization was decided based on CT-FFR. We assessed the optimal cut-off value of CT-FFR and how to correct the CT-FFR to minimize hypothetical cardiac events under four different disease prevalence (20%, 25%, 30%, 35%, and 40%). A total of 16 vessels had i-FFR ≤ 0.8. On per-patient basis, the sensitivity, specificity, positive predict value, negative predict value, and diagnostic accuracy of CT-FFR â‰¦ 0.8 vs CCTA > 50% to detect functional stenosis defined as invasive FFR â‰¦ 0.80 were 93.3% vs 73.3%, 73.9% vs 26.1%, 70.0% vs 39.3%, 94.4% vs 60.0%, and 81.6% vs 44.7%, respectively. For minimize 1-year cardiac events, the optimal cut-off value for more than 30% of disease prevalence was 0.80. However, the optimal cut-off value for 20, 25, and 30% was 0.54 in any cases. After the adjustment of CT-FFR using a formula of 0.3X + 0.634 for CT-FFR < 0.7 to counteract its underestimation, the % reduction of the events for 20, 25, 30, 35, and 40% at a 0.80 cut-off were 19.0%, 15.6%, 12.6%, 10.0%, and 7.7% respectively. It was reasonable to support that the optimal cut-off value was 0.80 in disease prevalence of more than 30% for minimize 1-year cardiac events. However, underestimation should be adjusted to reduce cardiac events, especially when disease prevalence is low.

Understanding the Molecular Mechanism Underlying the High Catalytic Activity of p-Hydroxybenzoate Hydroxylase Mutants for Producing Gallic Acid.

p-Hydroxybenzoate hydroxylase (PHBH) is a flavoprotein monooxygenase that catalyzes the hydroxylation of p-hydroxybenzoate (p-OHB) to 3,4-dihydroxybenzoate (3,4-DOHB). PHBH can bind to other benzoate derivatives in addition to p-OHB; however, hydroxylation does not occur on 3,4-DOHB. Replacement of Tyr385 with Phe forms a mutant, which enables the production of 3,4,5-trihydroxybenzonate (gallic acid) from 3,4-DOHB, although the catalytic activity of the mutant is quite low. In this study, we report how the L199V/Y385F double mutant exhibits activity for producing gallic acid 4.3-fold higher than that of the Y385F single mutant. This improvement in catalytic activity is primarily due to the suppression of a shunt reaction that wastes reduced nicotinamide adenine dinucleotide phosphate by producing H2O2. To further elucidate the molecular mechanism underlying this higher catalytic activity, we performed molecular dynamics simulations and quantum mechanics/molecular mechanics calculations, in addition to determining the crystal structure of the Y385F·3,4-DOHB complex. The simulations showed that the Y385F mutation facilitates the deprotonation of the 4-hydroxy group of 3,4-DOHB, which is necessary for initiating hydroxylation. Moreover, the L199V mutation in addition to the Y385F mutation allows the OH moiety in the peroxide group of C-(4a)-flavin hydroperoxide to come into the proximity of the C5 atom of 3,4-DOHB. Overall, this study provides a consistent explanation for the change in the catalytic activity of PHBH caused by mutations, which will enable us to better design an enzyme with different activities.

Chest X-Ray Revealed a Slowly Progressive Giant Right Coronary Artery Aneurysm in an Asymptomatic Patient.

A giant right coronary artery aneurysm (60 × 70 mm in size) was incidentally found by chest X-ray as an abnormal right atrial enlargement, and it needed surgical resection. Although the majority of giant coronary artery aneurysms present with symptoms of coronary ischemia, this case presented without any specific symptom. This study indicates that when chest X-ray shows abnormal atrial enlargement, a differential diagnosis of giant coronary artery aneurysm may need to be considered.

Noninvasive Computed Tomography-Derived Fractional Flow Reserve Based on Structural and Fluid Analysis: Reproducibility of On-site Determination by Unexperienced Observers.

OBJECTIVE: The aim of this study was to evaluate the reproducibility of computed tomography (CT)-derived fractional flow reserve (FFR) determined on site by inexperienced observers using a postprocessing software based on structural and fluid analysis. METHODS: Using 21 coronary vessels in 7 patients who underwent 320-row coronary CT angiography and catheter-FFR, 2 independent inexperienced observers (A: a student radiation technologist; B: a nonmedical staff) determined the CT-FFR using a postprocessing software. After a 20-minute training session, both observers postprocessed all vessels and readjusted their settings after another training/feedback. These CT-FFRs were compared with values determined by an expert analyst. RESULTS: The mean processing times were 23 ± 4 minutes (automatic), 71 ± 5 minutes (observer A), and 57 ± 7 minutes (observer B) per patient. The initial correlations with expert data were r = 0.92 (observer A) and 0.73 (observer B) and increased to 0.83 for observer B after additional training. The final absolute difference with the expert data was 0.000 to 0.020. The correlation between catheter-FFR and expert CT-FFR was r = 0.76. CONCLUSIONS: The CT-derived FFR on-site postprocessing software showed good reproducibility for measurements by inexperienced observers.

Clinical significance of transluminal attenuation gradient in 320-row area detector coronary CT angiography.

The clinical significance of the transluminal attenuation gradient (TAG) has not been established. We evaluated the incremental diagnostic value of TAG by 320-row area detector computed tomography (320-ADCT). Subjects were 65 patients who underwent one-rotation scanning by 320-ADCT and invasive coronary angiography (ICA) within 3 months. TAG values were obtained for the major epicardial vessels 2 mm or more each in RCA, LAD and LCX using automatic analysis software. Moreover, TAG values that excluded calcified lesions in calculation of the regression line were also evaluated (excluded-TAG). In LAD, 21 intermediate lesions underwent functional flow reserve (FFR), and the incremental diagnostic value for functional stenosis was evaluated. The TAG values in the normal vessels were - 8.3 ± 5.0 (HU/cm) for the RCA (n = 32), - 23.3 ± 4.3 for the LAD (n = 9) and - 20.6 ± 10.0 for the LCX (n = 32). The RCA value was significantly higher (p < 0.001). The TAG values with stenosis degrees of ≤ 25%, 26-75%, ≥ 76% on ICA were - 8.3 ± 5.0 (n = 32) vs - 10.3 ± 7.2 (n = 25) vs - 10.0 ± 5.4 (n = 4) in the RCA, - 23.3 ± 4.3 (n = 9) vs - 21.0 ± 11.5 (n = 35) vs - 23.5 ± 15.3 (n = 10) in the LAD and - 21.1 ± 15.1 (n = 32) vs - 21.1 ± 15.1 (n = 16) vs - 17.7 ± 15.7 (n = 6) in the LCX, with no significant difference among the three groups. The excluded-TAG values also showed no significant difference. The area under the curve in the diagnosis of FFR < 0.8 in 21 LAD cases was 0.542 for CT only, 0.694 for CT + TAG, and 0.694 for CT + excluded-TAG. In single time-phase scanning by 320-ADCT, TAG does not offer an incremental diagnostic value.

[The Effect of Reconstruction Method on the Ability to Analyze of FFR Using CT].

BACKGROUND: Invasive-fractional flow reserve (FFR) is the reference standard to evaluate functional ischemia of coronary arteries, and is used to decide if percutaneous transluminal coronary angioplasty is necessary. Recently, computed tomography-derived FFR (CT-FFR) is emerged as an alternative non-invasive method. OBJECTIVES: To evaluate the effect of reconstruction methods and image parameters on the accuracy of CT-FFR calculation. METHODS: A total of 26 segments in the consecutive 10 coronary CT angiography (CCTA) studies were evaluated. All studies were reconstructed using three different techniques: 1) filtered back projection (FBP), 2) adaptive iterative dose reduction 3D (AIDR 3D), and 3) forward projected model-based iterative reconstruction solution (FIRST). Vessel segmentation was performed automatically by CT-FFR software, with manual adjustment if necessary. Calculated CT-FFR was compared with the invasive FFR data. RESULTS: Compared to FBP, AIDR 3D and FIRST resulted in more successful automatic segmentation. When using FIRST, 7 segments (27%) were completed without manual adjustment. These segments had relatively larger vessel diameter, higher CT number, and lower noise. The difference between the calculated CT-FFR and invasive-FFR was 0.02±0.01. Among the remaining, 10 segments (38%) required manual adjustments of centerline, 7 segments (27%) required manual adjustments of contour, and 2 segments (8%) did not reach to the CT-FFR calculation. CONCLUSION: AIDR 3D and FIRST were useful for reliable automatic segmentation and analysis of CT-FFR.

Silica aerogel for capturing intact interplanetary dust particles for the Tanpopo experiment.

In this paper, we report the progress in developing a silica-aerogel-based cosmic dust capture panel for use in the Tanpopo experiment on the International Space Station (ISS). Previous studies revealed that ultralow-density silica aerogel tiles, comprising two layers with densities of 0.01 and 0.03 g/cm(3) developed using our production technique, were suitable for achieving the scientific objectives of the astrobiological mission. A special density configuration (i.e., box framing) aerogel with a holder was designed to construct the capture panels. Qualification tests for an engineering model of the capture panel as an instrument aboard the ISS were successful. Sixty box-framing aerogel tiles were manufactured in a contamination-controlled environment.

Fluorescence imaging of microbe-containing particles shot from a two-stage Light-gas gun into an aerogel.

We have proposed an experiment (the Tanpopo mission) to capture microbes on the Japan Experimental Module of the International Space Station. An ultra low-density silica aerogel will be exposed to space for more than 1 year. After retrieving the aerogel, particle tracks and particles found in it will be visualized by fluorescence microscopy after staining it with a DNA-specific fluorescence dye. In preparation for this study, we simulated particle trapping in an aerogel so that methods could be developed to visualize the particles and their tracks. During the Tanpopo mission, particles that have an orbital velocity of ~8 km/s are expected to collide with the aerogel. To simulate these collisions, we shot Deinococcus radiodurans-containing Lucentite particles into the aerogel from a two-stage light-gas gun (acceleration 4.2 km/s). The shapes of the captured particles, and their tracks and entrance holes were recorded with a microscope/camera system for further analysis. The size distribution of the captured particles was smaller than the original distribution, suggesting that the particles had fragmented. We were able to distinguish between microbial DNA and inorganic compounds after staining the aerogel with the DNA-specific fluorescence dye SYBR green I as the fluorescence of the stained DNA and the autofluorescence of the inorganic particles decay at different rates. The developed methods are suitable to determine if microbes exist at the International Space Station altitude.

Additional prognostic impact of plaque characterization with on-site CT-derived fractional flow reserve in coronary CT angiography.

BACKGROUND: On-site computed tomography-derived fractional flow reserve (CT-FFR) is a feasible method for examining lesion-specific ischemia, and plaque analysis of coronary CT angiography (CCTA) is useful for predicting future cardiac events. However, their utility and association on a per-vessel level remain unclear. METHODS: We analyzed vessels showing 50-90 % stenosis on CCTA where planned revascularization was not performed after CCTA within 90 days. Relevant features, including CT-FFR and the plaque burden [necrotic core to the total plaque volume (% necrotic core), and non-calcified plaque (NCP) to vessel volume (% NCP)] using a novel algorithm for analyzing plaque to predict vessel-oriented composite outcomes (VOCO), including cardiac death, non-fatal myocardial infarction, and unplanned vessel-related revascularization, were assessed. RESULTS: In 256 patients (68.7 ±â€¯9.4 years; 73.8 % male) with 354 vessels (10.5 % CT-FFR ≤ 0.80), VOCO occurred in 24 vessels (6.8 %) during a median follow-up of 3.6 years. Multivariable Cox analysis revealed CT-FFR ≤ 0.80 had the pronounced impact on VOCO, and moreover, higher % necrotic core and % NCP were independently associated with VOCO [adjusted hazard ratio 3.43 (95 % confidence interval 1.42-8.29) and 4.05 (1.19-13.71), respectively], especially for vessels with CT-FFR > 0.80. CONCLUSIONS: In vessels without planned revascularization, per-vessel CT-FFR ≤ 0.80 was the notable predictor of future cardiac events. Additionally, necrotic core volume and NCP were identified as independent predictors along with CT-FFR.

The possible interplanetary transfer of microbes: assessing the viability of Deinococcus spp. under the ISS Environmental conditions for performing exposure experiments of microbes in the Tanpopo mission.

To investigate the possible interplanetary transfer of life, numerous exposure experiments have been carried out on various microbes in space since the 1960s. In the Tanpopo mission, we have proposed to carry out experiments on capture and space exposure of microbes at the Exposure Facility of the Japanese Experimental Module of the International Space Station (ISS). Microbial candidates for the exposure experiments in space include Deinococcus spp.: Deinococcus radiodurans, D. aerius and D. aetherius. In this paper, we have examined the survivability of Deinococcus spp. under the environmental conditions in ISS in orbit (i.e., long exposure to heavy-ion beams, temperature cycles, vacuum and UV irradiation). A One-year dose of heavy-ion beam irradiation did not affect the viability of Deinococcus spp. within the detection limit. Vacuum (10(-1) Pa) also had little effect on the cell viability. Experiments to test the effects of changes in temperature from 80 °C to -80 °C in 90 min (± 80 °C/90 min cycle) or from 60 °C to -60 °C in 90 min (± 60 °C/90 min cycle) on cell viability revealed that the survival rate decreased severely by the ± 80 °C/90 min temperature cycle. Exposure of various thicknesses of deinococcal cell aggregates to UV radiation (172 nm and 254 nm, respectively) revealed that a few hundred micrometer thick aggregate of deinococcal cells would be able to withstand the solar UV radiation on ISS for 1 year. We concluded that aggregated deinococcal cells will survive the yearlong exposure experiments. We propose that microbial cells can aggregate as an ark for the interplanetary transfer of microbes, and we named it 'massapanspermia'.

Fully automated coronary artery calcium quantification on electrocardiogram-gated non-contrast cardiac computed tomography using deep-learning with novel Heart-labelling method.

Aims: To develop an artificial intelligence (AI)-model which enables fully automated accurate quantification of coronary artery calcium (CAC), using deep learning (DL) on electrocardiogram (ECG)-gated non-contrast cardiac computed tomography (gated CCT) images. Methods and results: Retrospectively, 560 gated CCT images (including 60 synthetic images) performed at our institution were used to train AI-model, which can automatically divide heart region into five areas belonging to left main (LM), left anterior descending (LAD), circumflex (LCX), right coronary artery (RCA), and another. Total and vessel-specific CAC score (CACS) in each scan were manually evaluated. AI-model was trained with novel Heart-labelling method via DL according to the manual-derived results. Then, another 409 gated CCT images obtained in our institution were used for model validation. The performance of present AI-model was tested using another external cohort of 400 gated CCT images of Stanford Center for Artificial Intelligence of Medical Imaging by comparing with the ground truth. The overall accuracy of the AI-model for total CACS classification was excellent with Cohen's kappa of k = 0.89 and 0.95 (validation and test, respectively), which surpasses previous research of k = 0.89. Bland-Altman analysis showed little difference in individual total and vessel-specific CACS between AI-derived CACS and ground truth in test cohort (mean difference [95% confidence interval] were 1.5 [-42.6, 45.6], -1.5 [-100.5, 97.5], 6.6 [-60.2, 73.5], 0.96 [-59.2, 61.1], and 7.6 [-134.1, 149.2] for LM, LAD, LCX, RCA, and total CACS, respectively). Conclusion: Present Heart-labelling method provides a further improvement in fully automated, total, and vessel-specific CAC quantification on gated CCT.

Validation and clinical impact of novel pericoronary adipose tissue measurement on ECG-gated non-contrast chest CT.

BACKGROUND AND AIMS: We aimed to develop a method for quantifying pericoronary adipose tissue (PCAT) on electrocardiogram (ECG)-gated non-contrast CT (NC-PCAT) and validate its efficacy and prognostic value. METHODS: We retrospectively studied two independent cohorts. PCAT was quantified conventionally. NC-PCAT was defined as the mean CT value of epicardial fat tissue adjacent to right coronary artery ostium on ECG-gated non-contrast CT. In cohort 1 (n = 300), we evaluated the correlation of two methods and the association between NC-PCAT and CT-verified high-risk plaque (HRP). We dichotomized cohort 2 (n = 333) by the median of NC-PCAT, and assessed the prognostic value of NC-PCAT for primary endpoint (all-cause death and non-fatal myocardial infarction) by Cox regression analysis. The median duration of follow-up was 2.9 years. RESULTS: NC-PCAT was correlated with PCAT (r = 0.68, p<0.0001). In multivariable logistic regression analysis, high NC-PCAT (OR:1.06; 95%CI:1.03-1.10; p = 0.0001), coronary artery calcium score (CACS) (OR:1.01 per 10 CACS increase, 95%CI:1.00-1.02; p = 0.013), and current smoking (OR:2.58; 95%CI:1.03-6.49; p = 0.044) were independent predictors of HRP. Among patients with CACS>0 (n = 193), NC-PCAT (OR:1.06; 95%CI:1.03-1.10; p = 0.0002), current smoking (OR:3.02; 95%CI:1.17-7.82; p = 0.027), and male sex (OR:2.81; 95%CI:1.06-7.48; p = 0.028) were independent predictors of HRP, whereas CACS was not (p = 0.15). Multivariable Cox regression analysis revealed high NC-PCAT as an independent predictor of the primary endpoint, even after adjustment for sex and age (HR:4.3; 95%CI:1.2-15.2; p = 0.012). CONCLUSIONS: There was a positive correlation between NC-PCAT and PCAT, with high NC-PCAT significantly associated with worse clinical outcome (independent of CACS) as well as presence of HRP.