Development of a novel artificial intelligence algorithm to detect pulmonary nodules on chest radiography.

BACKGROUND: In this study, we aimed to develop a novel artificial intelligence (AI) algorithm to support pulmonary nodule detection, which will enable physicians to efficiently interpret chest radiographs for lung cancer diagnosis. METHODS: We analyzed chest X-ray images obtained from a health examination center in Fukushima and the National Institutes of Health (NIH) Chest X-ray 14 dataset. We categorized these data into two types: type A included both Fukushima and NIH datasets, and type B included only the Fukushima dataset. We also demonstrated pulmonary nodules in the form of a heatmap display on each chest radiograph and calculated the positive probability score as an index value. RESULTS: Our novel AI algorithms had a receiver operating characteristic (ROC) area under the curve (AUC) of 0.74, a sensitivity of 0.75, and a specificity of 0.60 for the type A dataset. For the type B dataset, the respective values were 0.79, 0.72, and 0.74. The algorithms in both the type A and B datasets were superior to the accuracy of radiologists and similar to previous studies. CONCLUSIONS: The proprietary AI algorithms had a similar accuracy for interpreting chest radiographs when compared with previous studies and radiologists. Especially, we could train a high quality AI algorithm, even with our small type B data set. However, further studies are needed to improve and further validate the accuracy of our AI algorithm.

Long-Term Habitual Exercise and Combination of ß-Hydroxy-ß-Methylbutyrate plus Black Ginger Alter the Autophagy and Mitochondria Related Genes in SAMP8 Mice.

Muscle mass and strength decrease with aging; however, habitual exercise can maintain muscle health. ß-Hydroxy-ß-methyl butyrate calcium (HMB) and black ginger (BG) improve muscle protein metabolism and energy production. Combining these two molecules, which have similar effects, may have a synergistic effect. Senescence-accelerated mouse-prone 8 (SAMP8) is a useful model of muscle aging. Therefore, we explored how the combination of habitual exercise, HMB, and BG affected muscle aging. We used 28-wk-old (28w) SAMP8 mice divided into six groups: 28 wk (28w), 44 wk (44w, Con), exercise (Ex), Ex+BG, Ex+HMB, and Ex+BG+HMB (Ex+Comb). Mice were required to run on a treadmill for 16 wk for 5 d per week. In 28w and 44w mice, grip strength tests and dissection were conducted. Muscle weight was measured, and qPCR and immunoblotting were conducted. Muscle mass and strength were declined in the 44w group. Exercise with HMB or BG alone had no effect, whereas muscle mass and strength were augmented in the Ex+Comb group. Similarly, levels of mitochondrial function- and biogenesis-related genes were increased. Autophagy-related protein (Atg3, 7, 16L1 and Beclin1) were altered in the Ex+Comb group. These results suggest that Ex+Comb affects autophagy. Overall, the combination of habitual exercise and HMB+BG may enhance muscle mass and strength by affecting the mitochondrial and autophagy systems in SAMP8.

A MATLAB-based program for three-dimensional quantitative analysis of micronuclei reveals that neuroinflammation induces micronuclei formation in the brain.

The micronucleus is known to be a biomarker for genomic instability, which is a hallmark of tumors and aging. Normally, micronuclei are produced by segregation errors and mechanical stresses arising from dividing or migrating cells, leading to activation of the innate immune response pathway. Although micronuclei often emerge in damaged tissues, the quantitative procedure for analyzing micronuclei accurately has been problematic. Here, we introduce a novel MATLAB-based program for quantifying micronuclei (CAMDi: calculating automatic micronuclei distinction) in vitro and in vivo. CAMDi is adaptable to various experimental imaging techniques and is useful for obtaining reproducible data. CAMDi enables us to measure the accurate size of micronuclei from the three-dimensional images. Using CAMDi, we revealed a novel link between the emergence of micronuclei and neuroinflammation. We found that inflammatory stimulation does not increase the number of micronuclei in primary neurons. On the other hand, the administration of lipopolysaccharide into mice slightly increases micronuclei formation in neurons of the hippocampus region. These findings demonstrate that neuronal micronuclei formations are induced by an inflammatory response in a non-cell-autonomous manner. We provide a novel tool, CAMDi, to quantify micronuclei and demonstrate that neuronal micronuclei are produced not only by the cell-autonomous process but also by the intercellular communication associated with neuroinflammation in vivo.

Cerebral capillary blood flow upsurge during REM sleep is mediated by A2a receptors.

Sleep is generally viewed as a period of recovery, but how the supply of cerebral blood flow (CBF) changes across sleep/wake states has remained unclear. Here, we directly observe red blood cells (RBCs) within capillaries, where the actual substance exchange between the blood and neurons/glia occurs, by two-photon microscopy. Across multiple cortical areas, average capillary CBF is largely increased during rapid eye movement (REM) sleep, whereas it does not differ between periods of active wakefulness and non-REM sleep. Capillary RBC flow during REM sleep is further elevated following REM sleep deprivation, suggesting that capillary CBF reflects REM sleep pressure. At the molecular level, signaling via adenosine A2a receptors is crucial; in A2a-KO mice, capillary CBF upsurge during REM sleep is dampened, and effects of REM sleep pressure are abolished. These results provide evidence regarding the dynamics of capillary CBF across sleep/wake states and insights to the underlying mechanisms.

Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.

BACKGROUND: Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD). OBJECTIVE: To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment. RESULTS: At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (-39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed. CONCLUSION: Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.

Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway.

OBJECTIVE: The Delta-Notch signaling pathway induces fine-grained patterns of differentiation from initially homogeneous progenitor cells in many biological contexts, including Drosophila bristle formation, where mathematical modeling reportedly suggests the importance of production rate of the components of this signaling pathway. In contrast, the epithelial differentiation of bile ducts in the developing liver is unique in that it occurs around the portal vein cells, which express extremely high amounts of Delta ligands and act as a disturbance for the amount of Delta ligands in the field by affecting the expression levels of downstream target genes in the cells nearby. In the present study, we mathematically examined the dynamics of the Delta-Notch signaling pathway components in disturbance-driven biliary differentiation, using the model for fine-grained patterns of differentiation. RESULTS: A portal vein cell induced a high Notch signal in its neighboring cells, which corresponded to epithelial differentiation, depending on the production rates of Delta ligands and Notch receptors. In addition, this epithelial differentiation tended to occur in conditions where fine-grained patterning was reported to be lacking. These results highlighted the potential importance of the stability towards homogeneity determined by the production rates in Delta ligands and Notch receptors, in a disturbance-dependent epithelial differentiation.

Efficacy of combined bland embolization and chemoembolization for huge (≥10 cm) hepatocellular carcinoma.

INTRODUCTION: To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. RESULTS: The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. CONCLUSION: Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

Habitual Aerobic Exercise Diminishes the Effects of Sarcopenia in Senescence-Accelerated Mice Prone8 Model.

Loss of muscle mass and strength are progressing with aging. Exercise is a beneficial method to prevent physical dysfunction, and habitual exercise can improve the muscle quality. Therefore, we evaluated the effects of long-term habitual exercise's impact on sarcopenia utilizing the senescence-accelerated mice prone8 (SAMP8) model. Notably, 27 w SAMP8 were used in this study. Mice were classified into 28 (28 w) and 44 weeks old. The 44-week group was divided into the sedentary group (44 w) and a group exercising for 16 weeks (44 w + Ex). The 44 w + Ex performed habitual exercise from 28 to 44 weeks. Additionally, grip strength tests were performed with mice aged 28 and 44 weeks. Muscles were harvested and measured muscle weight at 44 w. Gastrocnemius decreased in 44 w, but was unchanged in 44 w + Ex. There was a trend for lower muscle grip strength in the 44 w group, but there was no change in 44 w + Ex. The phosphorylation levels of Akt and p70S6K as a protein synthesis marker were decreased in 44 w. Cytochrome c oxidase subunit IV (CoxIV) mRNA and protein levels decreased in 44 w. These results suggested that long-term habitual exercise attenuates muscle mass and strength decline, possibly through maintenance of muscle protein synthesis and mitochondrial maintenance.

Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.

BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD). OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment. METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment. RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD. CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.

Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.

Previous studies demonstrated that delgocitinib ointment, a novel topical Janus kinase inhibitor, rapidly improved clinical signs and symptoms of atopic dermatitis (AD) in Japanese adult patients. We sought to evaluate the long-term safety and efficacy of delgocitinib 0.5% ointment in a 52-week study (QBA4-2). Japanese patients aged 16 years or older with AD received delgocitinib 0.5% ointment b.i.d. for up to 52 weeks. Topical corticosteroids for the treatment of worsening of AD could be used at the investigators' discretion during the treatment period. Safety end-points included the incidence and severity of adverse events (AEs). Pooled safety analyses included the data from the other long-term study (QBA4-1). Efficacy end-points included the percentage change from baseline in the modified Eczema Area and Severity Index (mEASI). A total of 506 patients were included in the pooled safety population. Overall, AEs were reported in 69.0% of patients; most AEs were mild and unrelated to delgocitinib ointment. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. No skin atrophy or telangiectasia was found at the application sites of delgocitinib ointment. Application site irritation symptoms were infrequent (<2%) and mild. The incidence of AEs did not increase over time, except for seasonal diseases. The improvement effects on AD as assessed by mEASI were maintained throughout the treatment period. Delgocitinib 0.5% ointment was well tolerated and effective when administrated to Japanese adult patients with AD for up to 52 weeks.

Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.

BACKGROUND: Topical delgocitinib (JTE-052), a novel Janus kinase inhibitor, had been shown to be clinically effective in adults with atopic dermatitis (AD). However, the efficacy of topical delgocitinib in pediatric patients with AD remained unclear. OBJECTIVE: We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: In this phase 2 clinical study (JapicCTI-173553) Japanese patients aged 2 through 15 years with AD were randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or vehicle ointment twice daily for 4 weeks. The primary efficacy end point was the percentage change from baseline in the modified Eczema Area and Severity Index score at the end of treatment (EOT). RESULTS: At EOT, modified Eczema Area and Severity Index scores in both delgocitinib groups were significantly reduced compared with that in the vehicle group. The least-squares mean percentage change from baseline was -54.2% in the 0.25% group and -61.8% in the 0.5% group versus -4.8% in the vehicle group (P < .001 for both comparisons). Similarly, all other efficacy parameters, including Investigator's Global Assessment and pruritus scores, in both delgocitinib groups were significantly improved compared with those in the vehicle group at EOT. Adverse events in both delgocitinib groups were mild in severity, and no serious adverse events were reported. CONCLUSIONS: Delgocitinib ointment improved clinical signs and symptoms in pediatric patients with AD and was well tolerated. These study results indicate that delgocitinib ointment can be a promising therapeutic option for pediatric patients with AD.

Three-dimensional shape variation and sexual dimorphism of the face, nose, and mouth of Japanese individuals.

Three-dimensional (3D) shape variations of the face and facial parts in Japanese adults were examined to collect basic data to be used for facial comparison in forensics. In total, 1000 3D facial scans (500 males, 500 females) of Japanese individuals were re-meshed into anatomically homologous shape models and analyzed by principal component analysis (PCA) after Procrustes superimposition. Facial parts (the nose and the mouth) were segmented from homologous face models and analyzed by PCA, too. Among all kinds of objects (the face, the nose, and the mouth), the most predominant shape variation represented by the first principal component (PC1) was the height-width proportion. The second largest variation (PC2) in the face and the nose was depth; for the mouth, it was the relative protrusion of the upper and lower lips. We interpreted predominant shape variations represented by the first five principal components (PCs) in each object. Asymmetric shape variations were observed within these PCs for the nose and the mouth. Sexual dimorphism of the face and the facial parts was also examined by testing the significance of sex-linked differences in PC scores. A significant difference was found between males and females for many PCs. Sexual dimorphism was examined also by emphasizing the shape difference between average male and female faces. Our results revealed predominant 3D shape variations and sexual dimorphism of the face and facial parts. The results may be informative for performing facial comparison in police investigations, an increasingly used technique.

Comparison between Negative-Pressure Fixation and Film Dressing in Wound Management after Tissue Expansion: A Randomized Controlled Trial.

Wound compression and fixation are important to reduce scarring. Numerous postoperative treatments have been developed to reduce scar formation; however, a simple and effective device that improves the appearance and histochemical properties of incisional scars is needed. Therefore, the authors have devised a novel method, negative-pressure fixation, that applies negative pressure inside polyurethane foam covered with film. In the present study, negative-pressure fixation was applied to incisional wounds resulting from the insertion of a tissue expander in patients undergoing two-stage breast reconstruction. The authors aimed to evaluate the effects of negative-pressure fixation on scar appearance and histochemical properties in comparison to those for film dressing without negative pressure. A prospective, open-label, randomized, single-center study was performed. A half-side test was conducted on the incisional scar resulting from tissue expander insertion during breast reconstruction after mastectomy in 13 female patients. The dressings on both sides of the scar were replaced once per week until the tissue expander was adequately inflated. The outcomes were assessed 6 months later. Scars were photographed before the second operation and were evaluated using a visual analogue scale. All scars were removed and resutured during the final operation, allowing a histochemical analysis. The mean visual analogue scale score for the negative-pressure fixation side was significantly lower compared with that for the film dressing side (p = 0.0025). In addition, the scar on the negative-pressure fixation side was significantly narrower (p = 0.0015). Thus, negative-pressure fixation is a simple and effective device for improving the appearance and histochemical properties of incisional scars.

Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis.

The purpose of the present two phase 1 studies was to assess the safety, tolerability and pharmacokinetics for topical application of a novel Janus kinase (JAK) inhibitor, JTE-052, in Japanese healthy adult male volunteers and Japanese adult patients with atopic dermatitis (AD). Additionally, exploratory investigation was performed on the efficacy for disease severity and pruritus score in AD patients. In the QBX1-1 study, the cutaneous safety of JTE-052 ointment by a patch test and a photo patch test was assessed in an intra-individual comparative study using placebo ointment, white petrolatum and non-application as comparators. The study demonstrated that JTE-052 ointment would be associated with a low potential for phototoxicity but had no potential for skin irritation or photoallergy. In the QBX1-2 study, it was revealed that the systemic exposure to JTE-052 in both healthy volunteers with normal skin and AD patients with inflamed skin was low in application of not only 1% but also 3% JTE-052 ointment. JTE-052 ointments of 1% and 3% were generally safe and well tolerated in both populations. In a repeated twice-daily application for 7 days, the efficacy of JTE-052 ointment to AD patients was observed with both 1% and 3% ointments in the exploratory investigations evaluated by Eczema Area and Severity Index, Investigator's Global Assessment and Numeric Rating Scale assessments. The mean scores for each assessment declined from the baseline throughout the study. These results suggest that the treatment of JTE-052 ointment is generally safe and effective in AD patients, although further large confirmatory studies are needed.

Unusual underlying disorder for pulmonary embolism: Cold agglutinin disease.

Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia caused by cold-reacting autoantibodies. The manifestations of CAD are commonly anemia, acrocyanosis, and fatigue caused by hemolysis and agglutination of red blood cells (RBCs) at a temperature lower than normal body temperature. We report a case of CAD presenting with pulmonary embolisms in an 86-year-old man. The patient visited our emergency department complaining of acute chest pain and respiratory distress. Laboratory data showed decreased RBC and hematocrit and markedly elevated mean corpuscular hemoglobin (MCH) and MCH concentration (MCHC). A contrast-enhanced computed tomographic scan demonstrated bilateral massive pulmonary embolisms. After admission, diagnosis of CAD was made on the basis of a high cold agglutinin titer without other factors of coagulation. CAD can contribute to the onset of pulmonary embolisms. It is necessary to incubate blood samples at 37 °C when laboratory data show markedly elevated MCH and MCHC and to consider the presence of cold agglutinins as an underlying disorder for the formation of venous thrombosis. .

Importance of Three-Body Interactions in Molecular Dynamics Simulations of Water Demonstrated with the Fragment Molecular Orbital Method.

The analytic first derivative with respect to nuclear coordinates is formulated and implemented in the framework of the three-body fragment molecular orbital (FMO) method. The gradient has been derived and implemented for restricted second-order Møller-Plesset perturbation theory, as well as for both restricted and unrestricted Hartree-Fock and density functional theory. The importance of the three-body fully analytic gradient is illustrated through the failure of the two-body FMO method during molecular dynamics simulations of a small water cluster. The parallel implementation of the fragment molecular orbital method, its parallel efficiency, and its scalability on the Blue Gene/Q architecture up to 262,144 CPU cores are also discussed.

Spontaneous isolated left gastric artery dissection: unusual visceral artery dissection.

Case: A 51-year-old woman visited our emergency department complaining of acute onset of upper abdominal pain and nausea. Abdominal contrast-enhanced computed tomography showed an isolated left gastric artery dissection and pseudoaneurysm. After conservative management for 6 days, endovascular embolization was carried out for treatment of the pseudoaneurysm. Spontaneous dissection of a visceral artery rarely occurs in the case of a left gastric artery. Outcome: Contrast-enhanced computed tomography is essential to make an accurate diagnosis and establish a therapeutic strategy. Conclusion: We should consider the occurrence of minor visceral artery dissection if a patient has acute abdominal pain without other obvious causes.