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Background Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults. Methods A total of 79,580 individuals aged 35-69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy "sometimes," and "often/very often" (versus "very few" use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated. Results During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs (95% confidence intervals) for "sometimes" were 0.81 (0.67-0.97) for emotional expression, 0.79 (0.66-0.95) for emotional support-seeking, and 0.80 (0.66-0.98) for disengagement. Men who "sometimes" used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15-41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (p for interaction = 0.03). Conclusions In a large Japanese population, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.

Autoimmune pancreatitis (AIP) is a disease concept that originated in Japan. It is characterized by diffuse pancreatic enlargement and irregular narrowing of the main pancreatic duct. Although the usefulness of the histological diagnosis of AIP using endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and EUS-guided fine-needle biopsy (FNB) has been reported, enhanced diagnostic performance is expected with improvements in tissue collection methods and fine-needle techniques. Guidance for establishing the tissue diagnosis of AIP has been developed and is useful for histological evaluation. Histopathological diagnosis by EUS-FNA/FNB is expected to play a central role in AIP diagnosis in the future.

We herein report a patient with giant cell arteritis (GCA) who developed pneumatosis intestinalis (PI) while she was in a clinically sustained remission phase. A 79-year-old woman with GCA involving the thoracic aorta and its first branches to the posterior tibial arteries had been treated with high-dose prednisolone. Nine weeks after initiating treatment and while in clinically sustained remission with a normal CRP level, PI and pneumoperitoneum were incidentally found during scheduled positron emission tomography-computed tomography, which also revealed slight residual inflammation of GCA. This is a very rare case of PI complicated by GCA, and we discuss the possible relationships.

Purpose To compare diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MR imaging (DCE-MRI) for characterization of prostate cancer (PC). Methods 104 PC patients who underwent prostate multiparametric MRI at 3T including DWI and DCE-MRI before MRI-guided biopsy or radical prostatectomy. Apparent diffusion coefficient (ADC) with histogram analysis (mean, 0–25th percentile, skewness, and kurtosis), intravoxel incoherent motion model including D and f; stretched exponential model including distributed diffusion coefficient (DDC) and a; and permeability parameters including Ktrans, Kep, and Ve were obtained from a region of interest placed on the dominant tumor of each patient. Results ADCmean, ADC0–25, D, DDC, and Ve were significantly lower and Kep was significantly higher in GS ≥ 3 + 4 tumors (n = 89) than in GS = 3 + 3 tumors (n = 15), and also in GS ≥ 4 + 3 tumors (n = 57) than in GS ≤ 3 + 4 tumors (n = 47) (P 0.80, there was a significant difference in AUC between ADC0–25 and D, and DDC for separating GS ≤ 3 + 4 tumors from GS ≥ 4 + 3 tumors (P = 0.040 and P = 0.022, respectively). There were no significant differences between metrics with AUC > 0.80 for separating GS = 3 + 3 tumors from GS ≥ 3 + 4 tumors. ADC0–25 had the highest correlation with Gleason grade (ρ = −0.625, P Conclusions DWI and DCE-MRI showed no apparent clinical superiority of non-Gaussian models or permeability MRI over the mono-exponential model for assessment of tumor aggressiveness in PC.

The proximal optimizing technique (POT) -proximal balloon edge dilation (PBED) sequence for side branch (SB) dilatation with cross-over single-stent implantation decreases both strut obstruction at the SB ostium and stent deformation at the main branch (MB).The purpose of this experimental bench test was to assess the impact of stent design on stent deformation, obstruction by stent struts at a jailed SB ostium, and stent strut malapposition in the POT-PBED sequence.Fractal coronary bifurcation bench models (60- and 80-degree angles) were used, and crossover single-stent implantation (3-link stent: XIENCE Sierra, Abbott Vascular, Santa Clara, CA, n = 10; 2-link stent: Synergy, Boston Scientific, Marlborough, MA, n = 10) was performed from the MB using the POT-PBED sequence. Jailing rates at the SB ostium, stent deformation, and stent strut malapposition of the bifurcation segment were assessed using videoscopy and optical coherence tomography.After SB dilatation using the PBED technique, jailing rates at the SB ostium and stent deformation did not differ significantly between the two types of stents. Conversely, the rate of malapposed struts of the bifurcation segment after the PBED procedure was significantly lower with 3-link stents than with 2-link stents for both 60- and 80-degree angles (60-degree angle: 4.3% ± 4.4% versus 22.0% ± 11.1%, P = 0.044; 80-degree angle: 20.8% ± 15.1% versus 57.2% ± 17.0%, P < 0.001, respectively).In the POT-PBED sequence, 3-link stents might be a preferable coronary bifurcation stent, maintaining a jailed SB ostium while significantly reducing stent strut malapposition of the bifurcation segment when compared with 2-link stents.

The International Convention on the Elimination of All Forms of Racial Discrimination (ICERD) contains the inter-State communication procedure within which the Committee on the Elimination of Racial Discrimination (CERD) received the following three communications in 2018: Qatar v Saudi Arabia, Qatar v the United Arab Emirates, and Palestine v Israel. In these cases, CERD characterized this procedure as relating to collective enforcement, analogous to the inter-State application procedure within the order/regime of the European Court of Human Rights (ECtHR). However, unlike the European Convention on Human Rights (ECHR), ICERD does not refer to ‘collective enforcement’, but merely contains ad hoc conciliation, that is a bilateral means for reaching a mutually agreed solution to a dispute. This article aims, rather critically, to assess whether, and to which extent, it is justified to view the CERD ad hoc conciliation procedure as a means of collective enforcement.

The prevalence of primary axillary hyperhidrosis in Japan is 5.75% (males, 6.60%; females, 4.72%) in the population aged 5–64 years. No study on comprehensively evaluated direct medical costs, hygiene product costs, and productivity loss in axillary hyperhidrosis patients has been published in Japan. The aim of this study was to estimate the cost of illness for axillary hyperhidrosis in Japan by conducting a nationwide insurance claims database analysis and a cross‐sectional Web‐based survey. Among patients diagnosed with primary axillary hyperhidrosis at least once between November 2012 and October 2019, health insurance receipt data of 1447 patients were analyzed. A cross‐sectional Web‐based survey was conducted on 321 patients aged 16–59 years with axillary hyperhidrosis to calculate hygiene product costs and productivity loss using a Work Productivity and Activity Impairment questionnaire. Furthermore, nationwide estimation was performed for the hygiene product costs and productivity loss based on the number of patients estimated from the prevalence. The annual direct medical costs per axillary hyperhidrosis patient were ¥91 491 in 2016, ¥93 155 in 2017, and ¥75 036 in 2018. In all of these years, botulinum toxin type A injection accounted for approximately 90% of the total costs. The annual total cost of hygiene products per axillary hyperhidrosis patient was ¥9325. The overall work impairment (%) of working patients with axillary hyperhidrosis was 30.52%, and its monthly productivity loss was ¥120 593/patient. The activity impairment (%) of full‐time housewives with axillary hyperhidrosis was 49.05% and its monthly productivity loss was ¥176 368/patient. The annual hygiene product cost based on the nationwide estimation was ¥24.5 billion and the monthly productivity loss was ¥312 billion. The significant cost associated with axillary hyperhidrosis was clarified. If out‐of‐pocket expenses for treatments not covered by health insurance are included in the estimation, the cost will further increase.

Multimodal optical microscopy combines different optical and physiological principles working together to obtain rich perspectives from a single biological event. In this paper, the recent advances in multimodal microscopy systems based on off-axis digital holography and transport-of-intensity equation are reviewed. Both methods used the common-path configuration, and realized simultaneous quantitative phase and fluorescence imaging in 3D space. Feasibility checks with fluorescent micro-beads and live plant cells are presented. The results show that both methods are capable of fast acquisition of the quantitative phase and fluorescence information with digital refocusing ability.

Field-induced ionic motions in all-inorganic CsPbBr3 perovskite quantum dots (QDs) strongly dictate not only their electro-optical characteristics but also the ultimate optoelectronic device performance. Here, we show that the functionality of a single Ag/CsPbBr3/ITO device can be actively switched on a sub-millisecond scale from a resistive random-access memory (RRAM) to a light-emitting electrochemical cell (LEC), or vice versa, by simply modulating its bias polarity. We then realize for the first time a fast, all-perovskite light-emitting memory (LEM) operating at 5 kHz by pairing such two identical devices in series, in which one functions as an RRAM to electrically read the encoded data while the other simultaneously as an LEC for a parallel, non-contact optical reading. We further show that the digital status of the LEM can be perceived in real time from its emission color. Our work opens up a completely new horizon for more advanced all-inorganic perovskite optoelectronic technologies., Electric field induced ion migration is a well-known phenomenon in perovskite, but the consequences are notorious, and thus needs to be prevented. Here, on the other hand, the authors cleverly manipulate this event for realising resistive random-access memory and light-emitting electrochemical cell in one device based on CsPbBr3 quantum dots.

Islet transplantation is a promising option for the clinical treatment of insulin-dependent diabetes, but a reliable islet cryopreservation/transplantation protocol should be established to overcome the donor shortage. The current study reports that a silk fibroin (SF) sponge disk can be used as a cryodevice for vitrification of large quantity pancreatic islets and the scaffold for subsequent subrenal transplantation in a rat model. The marginal islet mass (550 islet equivalents [IEQs]) on an SF sponge disk was vitrified-warmed and transplanted beneath the kidney capsule of a streptozotocin-induced diabetic rat with or without vascular endothelial growth factor (VEGF). Subrenal transplantation (no scaffold) of 550 IEQ fresh islets and post-warm islets vitrified on a nylon mesh device resulted in achieving euglycemia of recipient rats at 60% and 0%, respectively. Transplantation of 550 IEQ islets vitrified-warmed on an SF sponge disk failed to achieve euglycemia of recipient rats (0%), but the VEGF inclusion in the SF sponge disk contributed to acquiring the euglycemic recipients (33%). All cured recipient rats regained hyperglycemia after nephrectomy, and the histopathologic analysis exhibited a well-developing blood vessel network into the islet engrafts. Thus, an SF sponge disc was successively available as the cryodevice for islet vitrification, the transporter of the angiogenic VEGF, and the scaffold for subrenal transplantation in the rat model.

Background: While laughter is broadly recognized as a good medicine, a potential preventive effect of laughter on disability and death is still being debated. Accordingly, we investigated the association between the frequency of laughter and onset of functional disability and all-cause mortality among the older adults in Japan. Methods: The data for a 3-year follow-up cohort including 14,233 individuals (50.3% men) aged ≥65 years who could independently perform the activities of daily living and participated in the Japan Gerontological Evaluation Study were analyzed. The participants were classified into four categories according to their frequency of laughter (almost every day, 1–5 days/week, 1–3 days/month, and never or almost never). We estimated the risks of functional disability and all-cause mortality in each category using a Cox proportional hazards model. Results: During follow-up, 605 (4.3%) individuals developed functional disability, identified by new certification for the requirement of Long-Term Care Insurance, and 659 (4.6%) deaths were noted. After adjusting for the potential confounders, the multivariate-adjusted hazard ratio of functional disability increased with a decrease in the frequency of laughter (P for trend = 0.04). The risk of functional disability was 1.42 times higher for individuals who laughed never or almost never than for those who laughed almost every day. No such association was observed with the risk of all-cause mortality (P for trend = 0.39). Conclusions: Low frequency of laughter is associated with increased risks of functional disability. Laughter may be an early predictor of functional disability later on in life.

Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of "pathology-specific non-specific therapeutic drugs" and provide benefits to patients with chronic refractory cough.

BACKGROUND. The Vesical Imaging Reporting and Data System (VI-RADS), based on multiparametric MRI (mpMRI), was developed to provide accurate information for the diagnosis of muscle-invasive bladder cancer (MIBC). OBJECTIVE. The purpose of our study was to evaluate the interobserver agreement and diagnostic performance of VI-RADS among readers with different levels of experience. METHODS. This retrospective study included 91 consecutive patients who underwent mpMRI before transurethral resection of bladder tumor (TURBT) from July 2010 through August 2018. After attending a training session, seven radiologists (five radiologists experienced in bladder MRI and two inexperienced radiologists) reviewed and scored all MRI examinations according to VI-RADS. The interobserver agreement was assessed by kappa statistics. ROC analysis was used to evaluate the diagnostic performance for MIBC. AUCs were estimated. RESULTS. Among 91 patients (72 men and 19 women; mean age ± SD, 73.2 ± 10.2 years), 48 (52.7%) had MIBC and 43 (47.3%) had non-muscle-invasive bladder cancer. Sixty-eight patients were treated with TURBT, and 23 were treated with radical cystectomy. Interobserver agreement was moderate to substantial (κ = 0.60-0.80) among the experienced readers, substantial (κ = 0.67) between the two inexperienced readers, and moderate to substantial (κ = 0.55-0.75) between the experienced and inexperienced readers. The pooled AUC was 0.88 (range, 0.82-0.91) for experienced readers and 0.84 (range, 0.83-0.85) for inexperienced readers, and 0.87 for all readers. Using a VI-RADS score of 4 or greater as the cutoff value for MIBC, the pooled sensitivity and specificity were 74.1% (range, 66.0-80.9%) and 94.1% (range, 88.6-97.7%) for experienced readers and 63.9% (range, 59.6-68.1%) and 86.4% (range, 84.1-88.6%) for inexperienced readers. Using a VI-RADS score of 3 or greater as the cutoff value, the pooled sensitivity and specificity were 83.4% (range, 80.9-85.1%) and 77.3% (range, 61.4-88.6%) for experienced readers and 82.0% (range, 80.9-83.0%) and 73.9% (range, 72.7-75.0%) for inexperienced readers. CONCLUSION. We observed moderate to substantial interobserver agreement and a pooled AUC of 0.87 among radiologists of different levels of expertise using VI-RADS. CLINICAL IMPACT. VI-RADS could help determine the depth and range of excision in TURBT, decreasing the risk of complications and enhancing the accuracy of pathologic diagnosis.

Introduction Acute funisitis, a granulocyte-related inflammation of the umbilical cord, is associated with chorioamnionitis and perinatal adverse events. However, there is no efficient procedure for detecting clinically relevant umbilical cord inflammation. The objective of this study was to identify such inflammation, based on immunohistochemical assessment of umbilical cord vasculitis patterns. Methods Accordingly, 261 cases were retrieved from a single medical institute. Using the well-established granulocyte marker CD15, we developed a five-tier umbilical cord inflammation-scoring system. Additionally, previous morphological assessments from pathological reports were compared to the immunohistochemical findings. Results Analysis of results based on our new scoring system revealed that severe umbilical phlebitis (score 3) was significantly associated with maternal inflammatory response and that severe umbilical arteriophlebitis (score 4) was correlated with low umbilical arterial blood pH, a feature linked to fetal mortality and morbidity. These results corresponded with and were validated by the morphology-based assessments. Additionally, immunohistochemical analysis revealed the clinical and pathological relevance of vitelline vasculitis, a recently proposed condition. We found that analyzing three umbilical cord sections enabled superior detection of severe umbilical vasculitis than analyzing two sections. However, whether these sections were sampled from multiple distant sites or a single localized site did not significantly affect the detection of clinically relevant inflammation. Discussion CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation. CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation.

Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors.

Chimeric antigen receptor (CAR)‐T cell therapy has shown salient efficacy in cancer immunotherapy, particularly in the treatment of B cell malignancies. However, the efficacy of CAR‐T for solid tumors remains inadequate. In this study, we displayed that c‐met is an appropriate therapeutic target for papillary renal cell carcinoma (PRCC) using clinical samples, developed an anti‐human c‐met CAR‐T cells, and investigated the anti‐tumor efficacy of the CAR‐T cells using an orthotopic mouse model as pre‐clinical research. Administration of the anti‐c‐met CAR‐T cells induced marked infiltration of the CAR‐T cells into the tumor tissue and unambiguous suppression of tumor growth. Furthermore, in combination with axitinib, the anti‐tumor efficacy of the CAR‐T cells was synergistically augmented. Taken together, our current study demonstrated the potential for clinical application of anti‐c‐met CAR‐T cells in the treatment of patients with PRCC., Administration of the anti‐human c‐met CAR‐T cells induced unambiguous suppression of the tumor growth in an orthotopic model of papillary renal cell carcinoma.

Guidelines recommend shorter duration (1–12 months) for dual antiplatelet therapy (DAPT) in the second-generation drug-eluting stent (DES) era. However, whether shorter DAPT duration affects stent strut conditions and neointimal characteristics at mid-term follow-up remains uncertain. Therefore, we studied the relation between DAPT duration and vascular healing response as assessed by optical coherence tomography (OCT). This study was retrospective observational study. Participants comprised 64 patients who underwent serial OCT at both 9 and 18 months after DES implantation. All patients received DAPT until the 9-month follow-up then were divided into two groups: 49 patients who continued DAPT (longer DAPT group); and 15 patients who stopped taking the P2Y12 inhibitor and were treated with aspirin alone (shorter DAPT group) at the 18-month follow-up. Using OCT, we evaluated and compared stent strut conditions and neointimal characteristics between groups at both 9 and 18 months after stent implantation. Baseline clinical and procedural parameters were mostly similar between groups. At the 18-month follow-up, no in-stent thrombus assessed by OCT was observed in either group. No significant differences in OCT characteristics or measurements of neointima were seen between groups at 9- or 18-month follow-ups. Neointimal volume increased from 9 to 18 months in both groups, with a similar degree of neointimal proliferation in both groups (shorter DAPT group, 0.23 ± 0.29 mm3/mm; longer DAPT group, 0.19 ± 0.27 mm3/mm; P = 0.56). In conclusion, interrupting DAPT 9 months after second-generation DES implantation did not affect the development of in-stent thrombus, neointimal proliferation or stent strut coverage at 18-month follow-up compared with continuing DAPT.

High-density colloidal quantum dot (QD) thin films are promising materials for optoelectronic devices. Our experimental data revealed a unique layer number-dependent photoluminescence (PL) from mul...

OBJECTIVEThe basal encephalocele (BEC) is the rarest form of encephalocele, with an incidence of about 1/35,000 live births. The incidence of its subtype, sphenoidal BEC, is even lower at about 1/700,000 live births. The aim of this study was to propose the optimal surgical approach to repairing BEC, with special attention to the reconstruction of the skull base bone defect.METHODSFourteen consecutive pediatric patients with BEC who underwent surgical repair between March 2004 and March 2020 (10 boys and 4 girls, age 25 days to 7 years, median age 4 months) were enrolled. The follow-up period of the surviving patients ranged from 53 to192 months (mean 119.8 months). The patient demographics, BEC subtypes, preoperative clinical condition, radiographic findings, surgical procedures, and postoperative course were retrospectively analyzed.RESULTSThere were 4, 8, and 2 cases of sphenoidal BEC, sphenoethmoidal BEC, and ethmoidal BEC, respectively. The size of the bone defect was small in 3 patients, medium in 7, and large in 4 patients. All the patients with sphenoethmoidal and ethmoidal BEC showed associated congenital anomalies other than cleft palate. In total, 25 operations were performed. Two patients underwent multiple operations, whereas the remaining 9 patients received only 1 operation. The transoral transpalatal approach was the initial procedure used in all 14 patients. The transfrontobasal approach was applied as an additional procedure in 2 patients and as part of a 1-stage combined operation in 2 patients. Autograft bone alone was used for skull base reconstruction in 17 early operations. A titanium mesh/plate was used in the remaining 8 operations without any perioperative complications. All BECs were successfully repaired. Three patients died during the clinical course due to causes unrelated to their surgery. All but one of the surviving patients started growth hormone replacement therapy before school age.CONCLUSIONSBased on the authors’ limited experience, the key to successful BEC repair involves circumferential dissection of the BEC and a firm reconstruction of the skull base bone defect with a titanium plate/mesh. The transoral transpalatal approach is a promising, reliable procedure that may be used in the initial operation. When a cleft palate is absent, transnasal endoscopic repair is recommended. The transfrontobasal approach should be reserved for cases with a huge BEC and other anomalies. Long-term prognosis is apparently favorable in survivors.

We demonstrate a flexible transmissive color filter based on a hybrid metallic–optical Tamm state device composed of a thin metallic film on top of dual dielectric distributed Bragg reflectors (DBR...

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.Merck SharpDohme Corp, a subsidiary of MerckCo, Inc.

Objectives To investigate neuroendocrine carcinoma (NEC) of the uterine cervix cases for MRI features and staging, as well as pathological correlations and survival. Results FIGO was I in 42, II in 14, III in 1, and IV in 5 patients. T2-weighted MRI showed homogeneous slightly high signal intensity and obvious restricted diffusion (ADC map, low intensity; DWI, high intensity) throughout the tumor in most cases, and mild enhancement in two-thirds. In 50 patients who underwent a radical hysterectomy and lymphadenectomy without neoadjuvant chemotherapy (NAC), intrapelvic T staging by MRI overall accuracy was 88.0% with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for metastatic pelvic lymph node detection was 38.5%, 100%, and 83.3%, respectively. During a mean follow-up period of 45.6 months (range 4.3-151.0 months), 28 patients (45.2%) experienced recurrence and 24 (38.7%) died. Three-year progression-free and overall survival rates for FIGO I, II, III, and IV were 64.3% and 80.9%, 50% and 64.3%, 0% and 0%, and 0% and 0%, respectively. Materials and methods Sixty-two patients with histologically surgery-proven uterine cervical NEC were enrolled. Twelve received NAC. Clinical data, pathological findings, and pretreatment pelvic MRI findings were retrospectively reviewed. Thirty-two tumors were pure NEC and 30 mixed with other histotypes. The NECs were small cell type (41), large cell type (18), or a mixture of both (3). Conclusions Homogeneous lesion texture with obvious restricted diffusion throughout the tumor are features suggestive of cervical NEC. Our findings show that MRI is reliable for T staging of cervical NEC.

The motion of a football in air is influenced by the combination of various aerodynamic effects caused by the parameters such as velocity, surface roughness, panel orientation and shape. This paper analyzes the individual and combined effects of these parameters on the flight characteristics of various footballs using CFD Analysis. Four balls, a smooth sphere, a 32-panel conventional football, 14-panel Teamgeist and 6-panel Brazuca ball are subjected to different velocities of air flow over them, both in the laminar and turbulent regime, different surface roughness values and the influence of these parameters on the aerodynamics of the balls is evaluated by the drag force, drag coefficient and hydrodynamic boundary layer separation angle. The effect of the seam length, number of panels and panel orientation are also compared. The results of these effects are discussed later in the paper and are used to explain the knuckling effects and unpredictable trajectory of the Jabulani ball.

Aims/Introduction Continuous glucose monitoring (CGM) metrics, such as times in range (TIR) and time below range, have been shown to be useful as clinical targets that complement glycated hemoglobin (HbA1c) for patients with type 2 diabetes mellitus. We investigated the relationships between TIR, glycemic variability and patient characteristics in patients with type 2 diabetes mellitus. Materials and Methods We carried out continuous glucose monitoring in 281 outpatients with type 2 diabetes mellitus who participated in a multicenter cohort (Hyogo Diabetes Hypoglycemia Cognition Complications) study. Results The results are shown as the median (interquartile range). The age, disease duration and HbA1c were 68 years (62–71 years), 13 years (7–23 years) and 6.9% (6.5–7.5%), respectively. TIR and standard deviation obtained by continuous glucose monitoring worsened significantly with increasing disease duration. Multiple regression analyses showed that disease duration (standard partial regression coefficient, β = −0.160, P = 0.003), diabetic peripheral neuropathy (β = −0.106, P = 0.033) and urinary albumin excretion (β = −0.100, P = 0.043) were useful explanatory factors for TIR. In contrast, HbA1c (β = −0.398, P, In type 2 diabetes mellitus, the longer the duration of the disease, the number of patients treated with multiple medications or insulin increases and the glycemic fluctuation index measured by CGM worsens. CGM evaluations demonstrated that in elderly patients with type 2 diabetes mellitus, there is a high risk of hypoglycemia for insulin users and those with low HbA1c levels.

Objectives To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy. Methods This phase II, open-label, single-arm study (ClinicalTrials.gov registration number: NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60 mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8-week stable disease), progression-free survival, overall survival and safety. Results Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively. The median duration of cabozantinib exposure was 27.0 weeks (range 5.1-43.0 weeks). The objective response rate was 20.0% (90% confidence interval 9.8-34.3%), and the clinical benefit rate was 85.7% (95% confidence interval 69.7-95.2%). The 6-month estimated progression-free survival was 72.3% (95% confidence interval 53.3-84.6%); the median progression-free survival and overall survival were not reached. All patients reported adverse events, which were manageable by supportive treatment or dose modification; two patients (5.7%) discontinued therapy due to adverse events. Conclusions The results showed that findings from METEOR can be extrapolated, and that cabozantinib 60 mg/day is a viable treatment option in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.

We propose a unique random metal nanohemisphere on mirror (NHoM) structure to tune the surface plasmon (SP) resonance in a flexible manner. The SP resonance peak was split into two peaks owing to the strong coupling between the SP mode in the metal nanohemisphere and the mirror image mode generated in the metal substrate. This phenomenon is based on the fact that the strong coupling and the induced electromagnetic effects are similar to those pertaining to the Rabi splitting, Fano resonance, and electromagnetically induced transparency, thus providing quantum effect analogies. These phenomena have recently attracted increased attention and have been studied with nanocavities fabricated with top-down nanotechnologies. Compared with previous reports, NHoM structures can be fabricated in a much easier manner and are tunable in rather wider wavelength regions without nanofabrication technologies. The SP resonance peaks were enhanced, sharpened dramatically, and tuned flexibly, based on the optimization of the thickness of the spacer layer between the metal hemisphere and metal substrate. Experimental results were reproduced and were explained based on finite difference time domain (FDTD) simulations. These phenomena have never been observed previously on similar nanosphere on mirror (NSoM) because nanohemispherical structures were required. The NHoM nanocavity structure has a quality factor >200 that is surprisingly high for the localized SP mode of nanoparticles. Flexible tuning of the SP resonance with the use of NHoM is envisaged to lead to the development of new applications and technologies in the field of plasmonics and nanophotonics.

The present report aimed to document the clinical features of a case of Marshall-Smith syndrome (MSS), an extremely rare embryonic developmental disorder with associated craniosynostosis. We presented herein a case of a 2-year-old female patient with MSS who underwent fronto-orbital advancement for multisuture craniosynostosis. The patient’s proptosis improved after surgery, and no further surgical intervention was required for corneal exposure. A second FOA followed by revision tarsorrhaphy further improved eye closure. Surgical procedures to correct dysplastic features and limit neurological impairment are a worthwhile supportive treatment for improving the quality of life and general condition of patients with MSS.

Social coding platforms (SCPs) have realized spontaneous software evolution, where new source code and ideas are spontaneously proposed by altruistic developers. Although there are many projects operated by active communities performing spontaneous evolution, it is yet unclear that how such successful projects and communities have been formed and governed. This article proposes a method that can investigate the history of every project in the SCP. Introducing the concept of project as a city, the authors consider every project in the SCP as a city, where a government and citizens develop a city through collaborative activities. This research then identifies essential attributes that characterize a state of a city. For each attribute, the authors develop metrics that quantify the state S(p; t) of a project p at time t. An experimental evaluation investigating GitHub projects of famous code editors shows that the proposed metrics well visualize the history of the projects from essential perspectives of a city.

Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers.

The authors acknowledge the facilities, as well as the scientific and technical assistance, from the NSW Node of the Australian National Fabrication Facility (ANFF) and the Research & Prototype Foundry Core Research Facility at the University of Sydney, part of the ANFF. The authors also thank the Electron Microscope Unit within the Mark Wainwright Analytical Centre at UNSW Sydney for the use of facilities. N.S. is grateful to the advanced graduate course on molecular systems for devices, a program for leading graduate schools, Kyushu University, Japan.

Objective The purpose of this experimental bench test was to compare stent deformation, obstruction of stent struts at a jailed side branch (SB) ostium, and stent strut malapposition between SB inflation using proximal balloon edge dilation (PBED) technique and SB inflation using conventional balloon dilation in repetitive-proximal optimizing technique (re-POT) sequence. Background The second proximal optimizing technique (POT) procedure in the re-POT sequence might increase obstruction of stent struts at a jailed SB ostium, because deformation of stent cells at the main branch (MB) occurred during SB inflation for opening the SB ostium. Methods A fractal coronary bifurcation bench model made of flexible urethane was used, and crossover single-stent implantation (Xience Sierra, Abbott Vascular, Santa Clara, CA, n = 12) was performed from the MB with the re-POT sequence. During the re-POT sequence, the jailing rate at the SB ostium assessed by videoscopy was compared between SB inflation using PBED technique (PBED group, n = 6) and SB inflation using conventional balloon dilation (conventional group, n = 6). Results The jailing rate after the second POT procedure tended to be lower in the PBED group than in the conventional group (26 ± 12% vs. 34 ± 8%, p = .211), and the change in the jailing rate during the second POT procedure was significantly smaller in the PBED group than in the conventional group (4.8 ± 5.3% vs. 11.6 ± 3.5%, p = .026). Conclusions In the re-POT sequence, the PBED technique with a short balloon for SB inflation might minimize worsening of the jailing rate at the SB ostium during the second POT procedure.

For assessing a cancer treatment, and for detecting and characterizing cancer, Diffusion-weighted imaging (DWI) is commonly used. The key in DWI’s use extracranially has been due to the emergence of of high-gradient amplitude and multichannel coils, parallelimaging, and echo-planar imaging. The benefit has been fewer motion artefacts and high-quality prostate images.Recently, new techniques have been developed to improve the signal-to-noise ratio of DWI with fewer artefacts, allowing an increase in spatial resolution. For apparent diffusion coefficient quantification, non-Gaussian diffusion models have been proposed as additional tools for prostate cancer detection and evaluation of its aggressiveness. More recently, radiomics and machine learning for prostate magnetic resonance imaging have emerged as novel techniques for the non-invasive characterisation of prostate cancer. This review presents recent developments in prostate DWI and discusses its potential use in clinical practice.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

Objective: To evaluate time-dependent changes in hepatic extracellular volume (ECV) fraction using contrast-enhanced CT (CECT) and serological liver fibrosis markers, the fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), before and after direct-acting antiviral therapy (DAA) for hepatitis C virus (HCV) infection. Methods: 41 HCV-infected patients who achieved sustained virological response (SVR) after DAA (SVR group) and 10 control patients (untreated or unresponsive to treatment) who underwent CECT and serum biochemical tests before or after the first examination/DAA (T1) and at intervals thereafter (T2:24 months) were evaluated. Results: In the control group, ECV fractions remained relatively unchanged through the study, and significant differences in FIB-4 index comparisons and APRI comparisons were only seen between the T2 and T4 values (p = 0.046 and p = 0.028, respectively). In the SVR group, ECV fractions were significantly different between T1 and T4 and T1 and T5 (p = 0.046 and 0.022, respectively), and both FIB-4 index and APRI were significantly different between T1 and all other time points (p = 0.017 to p < 0.001 and p = 0.001 to p < 0.001, respectively). Conclusion: After DAA, ECV fraction decreased slowly, suggesting an improvement in hepatic fibrosis, while serological liver fibrosis markers decreased immediately, probably due to improvement in hepatic inflammation. Advances in knowledge: ECV fraction has the potential to be a non-invasive biomarker for the assessment of liver fibrosis after direct-acting antiviral therapy.

Objective: To evaluate the diagnostic performance and image quality of the low-tube voltage and low-contrast medium dose protocol for hepatic dynamic CT. Methods: This retrospective study was conducted between January and May 2018. All patients underwent hepatic dynamic CT using one of the two protocols: tube voltage, 80 kVp and contrast dose, 370 mgI/kg with hybrid iterative reconstruction or tube voltage, 120 kVp and contrast dose, 600 mgI/kg with filtered back projection. Two radiologists independently scored lesion conspicuity and image quality. Another radiologist measured the CT numbers of abdominal organs, muscles, and hepatocellular carcinoma (HCC) in each phase. Lesion detectability, HCC diagnostic ability, and image quality of the arterial phase were compared between the two protocols using the non-inferiority test. CT numbers and HCC-to-liver contrast were compared between the protocols using the Mann–Whitney U test. Results: 424 patients (70.5 ± 10.1 years) were evaluated. The 80-kVp protocol showed non-inferiority in lesion detectability and diagnostic ability for HCC (sensitivity, 85.7–89.3%; specificity, 96.3–98.6%) compared with the 120-kVp protocol (sensitivity, 91.0–93.3%; specificity, 93.6–97.3%) (p < 0.001–0.038). The ratio of fair image quality in the 80-kVp protocol also showed non-inferiority compared with that in the 120-kVp protocol in assessments by both readers (p < 0.001). HCC-to-liver contrast showed no significant differences for all phases (p = 0.309–0.705) between the two protocols. Conclusion: The 80-kVp protocol with hybrid iterative reconstruction for hepatic dynamic CT can decrease iodine doses while maintaining diagnostic performance and image quality compared with the 120-kVp protocol. Advances in knowledge: The 80- and 120-kVp protocols showed equivalent hepatic lesion detectability, diagnostic ability for HCC, image quality, and HCC-to-liver contrast. The 80-kVp protocol showed a 38.3% reduction in iodine dose compared with the 120-kVp protocol.

Parasomnias are undesirable behaviors or experiences during sleep that manifest clinically as abnormal behavior, emotions, and nightmares. We herein report four elderly parasomnia patients who were successfully treated for abnormal nocturnal behaviors, including rapid eye movement (REM) sleep behavior disorders, with Keishikaryukotsuboreito (KRB), a Japanese traditional herbal medicine. KRB resolved nocturnal violent behaviors and sleep walking without any adverse effects. In one patient, occipital dominant spike-wave complexes induced by 3-Hz photic stimulation were reduced after KRB treatment, suggesting that KRB has inhibitory effects on brain irritability. KRB may represent a safe therapeutic option for treating parasomnias in the elderly.

Wireless power transfer (WPT) is a well-known technique for electric vehicle (EV) charging. In this context, the power transfer profile is the key factor especially for the dynamic wireless power transfer (DWPT), where the time of magnetically coupling between track and pickup coils is significantly less. In this regard, this paper has proposed a three-element compensation network (3ECN) capable to transfer nominal power in the large portion of coupling, in other words, nominal power transfer is possible in the considerably large interval of mutual inductance. The paper has also included 1ECN and 2ECN and moved to 3ECN with a proper description of every CN and step-wise consideration and evolvement based on supply voltage limit, power transfer limit, and supply current limit. Simulation has been carried out in the MATLAB simulation environment considering the fundamental theory.

Background Despite recently developed clinical therapies, vascular remodelling in pulmonary arterial hypertension (PAH) progressively worsen. Hemodynamic unloading has been proposed to normalize the remodelled pulmonary vascular structures in the lungs. Recently, it has been reported that cellular senescence was associated with the irreversibility of pulmonary vascular structures after hemodynamic unloading. Purpose This study aims to elucidate the role of senescent endothelial cells (ECs) in the pathogenesis of PAH. Methods We generated EC-specific progeroid mice in which ECs undergo premature senescence by overexpressing the dominant-negative form of telomere repeat-binding factor 2 under the control of the VE-cadherin promoter. Following three weeks of hypoxia exposure, the PH phenotypes were assessed by RVSP, lung histology, and RT-qPCR. The interaction of human pulmonary artery ECs (hPAECs) and human pulmonary artery smooth muscle cells (hPASMCs) was indirectly and directly explored through the co-culture system. Gamma-secretase inhibitor (DAPT) was administrated to inhibit Notch signalling both in the in-vitro and in-vivo study. Results EC-specific progeroid mice showed exacerbated pulmonary hypertension after chronic hypoxia exposure, accompanied by the enhanced medial SMCs proliferation in the distal pulmonary arteries. Contact-mediated interaction with senescent hPAECs increased proliferation and migration capacities in hPASMCs, while no such effects were detected in the absence of ECs-SMCs contact. Consistently, senescent ECs highly expressed Notch ligands, thus activated Notch signalling in hPASMCs, leading to increased Notch target genes in hPASMCs. Pharmacological inhibition of Notch signalling attenuated the enhanced SMCs proliferation and migration induced by senescent hPAECs, as well as the worsened PH phenotypes in EC-specific progeroid mice. Conclusions Our data established a crucial role of senescent ECs in the PAH pathogenesis through the dysregulated SMC functions via juxtacrine signaling. Senescent ECs are attracting targets for further pathological-targeted therapy to cure PAH completely. Funding Acknowledgement Type of funding sources: None.

To discuss appropriate physical activity (PA) levels during pregnancy, this prospective cohort study examined the relationships between PA levels before and during pregnancy and physical and mental health status. Fixed data for 104,102 pregnant women were used from the Japan Environment and Children’s Study, of which data for 82,919 women were analyzed after excluding women with multiple birth and pregnancy complications. PA levels were measured using the International Physical Activity Questionnaire-Short Form. The 8-Item Short Form Health Survey was used to measure outcomes. Logistic regression with multiple imputations showed that moderate PA for over 720 min/wk and vigorous PA before pregnancy were associated with poorer mental health in the first trimester (adjusted odds ratio (AOR): 1.087–1.376. Walking in the second and third trimesters was associated with better physical and mental health (AOR: 0.855–0.932). Moderate PA over 1080 min/wk and vigorous PA in the second and third trimesters were associated with poorer mental health (AOR: 1.223–1.873). Increases over 4135.4 MET–min/wk and decreases in PA levels were associated with poorer mental and physical health (AOR: 1.070–1.333). Namely, pregnant women receiving health benefits prefer continuous walking in addition to avoiding vigorous PA and excessive changes in PA levels during pregnancy.

Background This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. Methods HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose. Results Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. Conclusions This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

Synthesis of anisotropic Ag nanoprisms (AgPRs) contributes to the development of high performance plasmonic devices. The localized surface plasmon resonance wavelength of AgPRs was successfully tun...

In sake brewing, the quality of rice koji is evaluated by experienced sake brewers based on visual inspection of the haze, which is defined by the extent of fungal hyphae spread on/into the rice grains. There is an increasing interest in understanding the factors that affect the quality of rice koji, which is dependent on its making process. Several studies have focused on the degree of mycelial penetration (haze-komi) and enzyme production during rice koji production. However, there are limited analytical methods available to monitor hyphal growth on a solid surface. Here we used a β-glucuronidase (GUS)-expressing strain of Aspergillus oryzae to visualize and map the fungal growth on rice koji grains. Observation of indigo color revealed that A. oryzae hyphae penetrated the steamed rice grain in the early stage (24 h) of rice koji-making before spreading on the surface during the later stages. Additionally, hyphae penetrated along the endosperm cells and penetrated the cells to form the sou-haze. Furthermore, mass spectrometry imaging (MSI) of glucose demonstrated that the area of mycelial penetration is directly correlated with the spread of glucose during fermentation. This is the first report on utilizing new tools such as GUS-body-mapping of A. oryzae and MSI to monitor fungal growth during rice koji making.

To accelerate high-resolution diffusion-weighted imaging with a multi-shot echo-planar sequence, we propose an approach based on reduced averaging and deep learning. Denoising convolutional neural networks can reduce amplified noise without requiring extensive averaging, enabling shorter scan times and high image quality. The preliminary experimental results demonstrate the superior performance of the proposed denoising method over state-of-the-art methods such as the widely used block-matching and 3D filtering.

Size control is critical in the synthesis of quantum-confined semiconductor nanocrystals, otherwise known as quantum dots. The achievement of size-uniformity and narrow spectral line-width in quantum dots conventionally relies on a very precise kinetic control of the reactions, where reaction time plays a significant role in defining the final crystal sizes and distribution. Here, we show that synthesis of quantum-confined perovskite nanostrips could be achieved through a thermodynamically controlled reaction, using a low-temperature and ligand-rich approach. The nanostrip growth proceeds through an initial one-dimensional (1D) nanorod stage, followed by the lateral widening of the rod to form a two-dimensional (2D) nanostrip. The spectral characteristics of the final product remain unchanged after prolonged reaction, indicating no signs of crystal ripening and confirming the thermodynamic nature of this reaction. The CsPbBr3 perovskite nanostrips were highly uniform and emit at a deep-blue wavelength of 462 nm with a remarkably narrow line-width of 13 nm. This corresponds to color coordinates of (0.136, 0.049) on the CIE 1931 color space, which fulfils the stringent Rec. 2020 standard for next-generation color displays. The well-passivated nanostrips also possess negligible defects and provide a near-unity photoluminescence quantum yield at 94%. Crucially, the achievement of blue emission through a pure-halide perovskite circumvents the problems of spectral instability that are frequently experienced in mixed-halide perovskite systems. The convenience and scalability of our thermodynamic approach, coupled with the excellent optical attributes, would likely enable these quantum-confined perovskite systems to be the preferred method toward color control in trichromatic display applications.