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Objective: To investigate the impact of national income level and sex on mortality trends from aortic aneurysm and dissection in addition to all aortic disease as a whole. Methods: Using data from the World Health Organization mortality database, we conducted an analysis of mortality trends from aortic disease between 2000 and 2019, Countries were categorized into middle-income and high-income countries (MICs and HICs) on the basis of income level. Age-standardized and sex-specific age-standardized mortality rates per 100,000 persons, along with male-to-female mortality ratios, were calculated. Trends over the study period were analyzed using joinpoint regression. Results: Our analysis comprised 29 MICs and 46 HICs, with an average population of 595 million and 1042 million during the observation period. During the observation period, age-standardized mortality rates from aortic disease decreased to 2.21 (2.17-2.25) and 2.28 (2.26-2.30) in MICs and HICs, respectively (average annual percentage change of −0.5% in MICs and −1.8% in HICs, P

This study examined the effects of bottom-up instruction (BI) on a high-stakes listening test for second language (L2) listeners and compared these effects with those of strategy instruction (SI) in relation to their proficiency levels. Two intact classes (48 L2 listeners) of different L2 listening proficiency levels received five weeks of BI and two weeks of SI. BI offered explicit knowledge of spoken English combined with reproduction practice, whereas SI helped learners deploy metacognitive knowledge and test-taking strategies. The data were collected three times: before the intervention (pre-test) and after each instruction (mid- and post-test). A common-item design that permits Rasch analysis was used. The results showed that BI improved L2 ­listeners' test performances regardless of their proficiency levels, ­highlighting the usefulness of BI in boosting listening proficiency. Conversely, SI benefited only high proficiency L2 listeners, which supports the threshold hypothesis claiming that L2 listeners require a certain level of L2 proficiency to deploy metacognitive knowledge and test-taking strategies successfully.

Abstract Background Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure. Methods In this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg). Results Ninety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026). Conclusions These findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure.

Introduction: We retrospectively analyzed convulsive patient outcomes transported by a physician-staffed Helicopter Emergency Medical Service (doctor helicopter [DH]) using the keyword-triggered dispatch with data from the Japan DH Registry System (JDRS). Upon receiving an emergency call containing critical keywords, such as an ongoing convulsion at the firefighting central command room, immediate dispatch of the DH is requested, in addition to dispatching an ambulance. The keyword-triggered dispatch relied on data obtained from the JDRS. Methods: Details from the JDRS database included patient age, sex, cardiac arrest presence upon DH contact, vital signs, DH dispatch timing (keyword-triggered dispatch/emergency medical technician [EMT]-triggered dispatch), medical intervention details, and 1-month outcomes (cerebral performance category [CPC]; CPC1, 2: Good; CPC 3–5: Poor). Subjects were divided into keyword (keyword-triggered dispatch) and control (EMT-triggered dispatch) groups for comparison. Results: Of 1201 patients, all evacuated from the scene, 617 were in the keyword group, and 584 in the control group. No significant differences existed between groups for cardiac arrest, respiratory and heart rates, CPC, or mortality. The keyword group had lower average age, systolic blood pressure, and medical intervention ratio but a higher median Glasgow Coma Scale and good outcome ratio. Conclusion: This first report on the keyword-triggered dispatch as a prognostic factor for convulsive patients evacuated by DH using the JDRS.

Abstract We examined the association between texture features using three-dimensional (3D) io-dine density histogram on delayed phase of dual-energy CT (DECT) and expression of programmed death-ligand 1 (PD-L1) using immunostaining methods in non-small cell lung cancer. Consecutive 37 patients were scanned by DECT. Unenhanced and enhanced (3 min delay) images were obtained. 3D texture analysis was performed for each nodule to obtain 7 features (max, min, median, mean, standard deviation, skewness, and kurtosis) from iodine density mapping and extracellular volume (ECV). A pathologist evaluated a tumor proportion score (TPS, %) using PD-L1 immunostaining: PD-L1 high (TPS ≥ 50%) and low or negative expression (TPS

Abstract A 61‐year‐old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He received chemotherapy up to the fourth line, but both the primary tumor and lymph node metastases increased in size. Nivolumab, administered as the fifth line, resulted in a complete response (CR) that continued for 2 years and 8 months. Treatment was stopped due to the appearance of common terminology criteria for adverse events grade 1 pneumonitis. He was followed up without treatment for 3 years and 8 months, but a left supraclavicular fossa lymph node metastasis appeared. Retreatment with nivolumab was initiated, and the patient achieved CR again. One year and 6 months after retreatment, CR was maintained with nivolumab. This case represents a rare instance in which nivolumab yielded a significant response after a prolonged immune checkpoint inhibitor (ICI)‐free interval. Our experience has shown that the long‐term response to ICIs may deteriorate in the future. Therefore, retreatment with ICIs may be effective when the initial therapy is successful.

Canola (Brassica napus) is cultivated for oil as a biofuel crop. Few quantitative data concerning its tolerance to abiotic stresses has been presented. We evaluated the tolerances of canola to drought and salinity stresses in terms of parameter values in a macroscopic root water uptake model. We conducted an experiment using nine columns with two plants in each: three columns were under drought stresses, another three were under saline stress and others provided potential transpiration. Two soil moisture and salinity probes were inserted into each of the six columns under stress to monitor water content and electrical conductivity. Weight of the columns was manually measured to obtain daily transpiration. Water uptake at each depth and time was calculated by substituting linearly interpolated matric and osmotic potentials into the stress response function. Determined stress response functions indicated that canola is more sensitive to drought compared to Jatropha. While, it was found to be as tolerant as Jatropha to salinity stress in terms of transpiration. Matric potential was more determining than osmotic potential to root water uptake of canola.

ABSTRACT Background Inflammation is one of the hallmarks of cancer and is associated with tumor growth. Tumor endothelial cells (TECs) demonstrate inflamed phenotypes. Endothelial inflammation initiates thrombus formation, which is the second cause of cancer‐related deaths. Epigallocatechin‐3‐O‐gallate (EGCG), a natural compound in green tea, has demonstrated an anti‐inflammatory effect. However, the tumor progression inhibition effect of EGCG by targeting TEC inflammation remains unclear. This study addresses the anti‐tumor effect of EGCG, especially its anti‐inflammatory role in TECs. Methods In vitro, the effect of EGCG on TECs were studied using real‐time quantitative PCR and immunofluoresence to analyza gene and protein expression. In vivo, a cyclic RGD liposome delivery system (MEND) was employed to efficiently deliver EGCG to TECs in tumor‐bearing mice. Results In vitro, EGCG significantly reduces inflammatory cytokine expression, including tumor necrosis factor‐α, interleukin‐6, IL‐8, and IL‐1β through NF‐κB signaling inhibition. Additionally, von Willebrand factor reduction in TECs, which is involved in platelet adhesion and thrombosis formation, was analyzed. Our results revealed that EGCG‐MEND significantly inhibited TEC inflammation and thrombus formation in tumors. Additionally, EGCG‐MEND improved tumor immunity by reducing programmed death‐ligand 1 expression and promoting high endothelial venule formation by recruiting CD8+ T cells. Conclusion Our results indicate the anti‐tumor potential of EGCG‐MEND in normalizing the inflammatory immune microenvironment and inhibiting thrombosis by targeting TEC.

Anthropogenic land cover change is one of the greatest threats to the persistence of organisms. Therefore, identifying and safeguarding optimal land covers for declining organisms is a major challenge of the Anthropocene. Priority land covers are typically identified through habitat selection studies. These traditionally use land cover and/or topographic features as separate, additive predictors of organismal occurrence, despite the fact that each land cover is superimposed on specific topographic features, such as elevation or slope, which may affect its attractiveness. Here, we tested the importance of considering the largely overlooked interplay between land cover and topography, using as a model a golden eagle Aquila chrysaetos population which is sharply declining due to human-induced land cover alteration. We found that the overlay of a key land cover type (old-growth forest) on underlying terrain known to be favorable for the population (steep slopes at higher elevations than the nest) dramatically increased its attractiveness. Conversely, the matching of the same land cover with unfavorable topography (gentle slopes at lower elevations) deteriorated its attractiveness for the population. Thus, underlying topography acted as the major determinant of land cover suitability for the eagle population. The conservation implications could be profound, because modeling land cover per se could waste conservation resources on low quality sites (old-growth forest on gentle terrain at low elevations) with unlikely benefits for the threatened eagle population. We expect topographic modulators of land cover quality to be more common than previously appreciated in many or most study systems, as numerous organisms inhabiting terrestrial and aquatic environments, regardless of taxonomic group, exhibit selectivity for specific topographic features and specific land cover types. In conclusion, we encourage modelers to take more into account underlying modulators that may drive differences in quality within the same land cover. This would make wildlife-habitat models more realistic, improve their applicability, and enhance the cost-effectiveness of conservation efforts.

Anionic lipid molecules, including phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), are implicated in the regulation of epidermal growth factor receptor (EGFR). However, the role of the spatiotemporal dynamics of PI(4,5)P2 in the regulation of EGFR activity in living cells is not fully understood, as it is difficult to visualize the local lipid domains around EGFR. Here, we visualized both EGFR and PI(4,5)P2 nanodomains in the plasma membrane of HeLa cells using super-resolution single-molecule microscopy. The EGFR and PI(4,5)P2 nanodomains aggregated before stimulation with epidermal growth factor (EGF) through transient visits of EGFR to the PI(4,5)P2 nanodomains. The degree of coaggregation decreased after EGF stimulation and depended on phospholipase Cγ, the EGFR effector hydrolyzing PI(4,5)P2. Artificial reduction in the PI(4,5)P2 content of the plasma membrane reduced both the dimerization and autophosphorylation of EGFR after stimulation with EGF. Inhibition of PI(4,5)P2 hydrolysis after EGF stimulation decreased phosphorylation of EGFR-Thr654. Thus, EGFR kinase activity and the density of PI(4,5)P2 around EGFR molecules were found to be mutually regulated.

Objectives: The linear no-threshold (LNT) model, which has been used for radiation protection purposes, was developed based on the assumption that exposure to even a small amount of radiation may cause cancer. However, although it is known in carcinogenesis that there is variation in radiation sensitivity among individuals, the LNT model does not adequately consider radiosensitive subgroups. In this paper, we represent susceptibility to contract cancer by radiation exposure by means of the threshold of a dose-response function, introduce an assumption that the thresholds are random to represent the variation of the radiosensitivity among individuals in a susceptible subgroup. We propose a novel method, the random threshold (RT) model, for determining the safe dose limit for the subgroup to protect cancer-susceptible individuals from radiation exposure. Conclusion: The proposed method is illustrated by targeting ATM gene (a cancer-susceptible gene) mutation carriers as a radiosensitive subgroup. For cancer risk associated with low-dose radiation exposure, the contribution of radiosensitivity cannot be ignored, thus the RT model would be more suitable for risk protection for radiosensitive subgroups instead of the LNT model. We also notice that it could be widely applicable for risk protection of not only low-dose radiation but also environmental pollutants.

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies.Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed.The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876–16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2− subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group.The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

Cardiovascular disease is one of the most important complications in girls and women with Turner syndrome (TS). Although the latest international guideline provides useful suggestions for the management of cardiovascular diseases in TS, some unknown cardiac conditions warrant physicians’ attention and awareness. Here, we have reported two adult cases wherein significant cardiovascular diseases were detected during the transition period. The first case patient was diagnosed with aortic crank deformity and left subclavian artery aneurysm at 14 years based on the report of cardiac catheterization, computed tomography angiography, and cardiac magnetic resonance imaging, which had remained undetected by annual evaluations using transthoracic echocardiography (TTE). This case emphasizes the importance of cardiac reevaluation during the transition period. The second case patient was diagnosed with moderate mitral valve regurgitation (MR) due to mitral valve prolapse at 18 years through TTE, although the first evaluation at 7 years by TTE detected slight MR without any clinical concerns. The condition however progressed to severe MR at 28 years, requiring mitral valvuloplasty. MR is the most common valve disease worldwide, which makes it challenging to comprehend whether the condition is a complication. However, the condition requiring surgery at this age is extremely rare, which implies the possibility of early progression. Because almost all literature on cardiovascular complications in TS is cross-sectional, further information about longitudinal cardiovascular conditions is vital for optimal care for girls and women with TS. The two cases reported in this article provide significant information for improving lifelong cardiovascular health issues in TS.

Heat stress reduces the developmental competence of bovine oocytes during the growth phase; however, the detailed mechanisms remain unclear. Amino acids play various critical roles in follicular development, including protein synthesis and as energy sources. We performed in vitro growth (IVG) culture of oocyte–cumulus–granulosa complexes (OCGCs) to assess the amino acid metabolism of small follicles at high temperatures. We isolated OCGCs from early antral follicles (0.5–1.0 mm) and subjected them to IVG culture for 12 days. OCGCs in the heat shock group were cultured under a temperature cycle of (38.5°C: 5 h, 39.5°C: 5 h, 40.5°C: 5 h, and 39.5°C: 9 h) to reproduce the body temperature of lactating cows under a hot environment. OCGCs in the control group were cultured at a constant temperature of 38.5°C for 24 h. Of the surviving OCGCs, those showing similar morphology and size between the groups were selected for amino acid analysis. We analyzed the free amino acids and their metabolites in the culture medium and calculated the depletion or appearance of molecular species. The depletion of three essential amino acids (isoleucine, leucine, and valine), two non-essential amino acids (aspartic acid and glycine), and ornithine was higher in the heat shock group (P < 0.05). Alanine depletion was lower in the heat shock group (P < 0.05). We concluded that heat exposure alters the amino acid metabolism of OCGCs isolated from early antral follicles, which might be involved with the diminished developmental potential of oocytes during summer.

AbstractThe recognition by cytotoxic T cells (CTLs) is essential for the clearance of SARS-CoV-2 virus-infected cells. Several viral proteins have been described to be recognized by CTLs. Among them, the spike (S) protein is one of the immunogenic proteins. The S protein acts as a ligand for its receptors, and several mutants with different affinities for its cognate receptors have been reported, and certain mutations in the S protein, such as L452R and Y453F, have been found to inhibit the HLA-A24-restricted CTL response. In this study, we conducted a screening of candidate peptides derived from the S protein, specifically targeting those carrying the HLA-A24 binding motif. Among these peptides, we discovered that NF9 (NYNYLYRLF) represents an immunogenic epitope. CTL clones specific to the NF9 peptide were successfully established. These CTL clones exhibited the ability to recognize endogenously expressed NF9 peptide. Interestingly, the CTL clone demonstrated cross-reactivity with the Y453F peptide (NYNYLFRLF) but not with the L452R peptide (NYNYRYRLF). The CTL clone was able to identify the endogenously expressed Y453F mutant peptide. These findings imply that the NF9-specific CTL clone possesses the capability to recognize and respond to the Y453F mutant peptide.

Abstract Background A rare case of neuroendocrine cell tumor (NET) having both conventional and mucinous components was reported. Mucinous NET is rarely encountered in the pathological diagnosis of gastrointestinal (GI) tumors. Here we examined the mechanism for transformation of conventional NETs into mucinous NETs. Case presentation: Macroscopic examination revealed a tumor with ulceration in the ampulla of Vater that measured 1.7 cm in its largest diameter. Histologically, the tumor comprised two components: a tubular/ribbon-like feature and small nests floating in a mucinous lake. The tumor nests showed sheet, nest and ribbon-like structures of small cells having eosinophilic cytoplasm as well as small-sized nuclei with dense hyperchromatin. Immunohistochemical analysis showed tumor cells positive for pan-endocrine markers (synaptophysin, CD56, INSM1 and chromogranin). Based on the histological findings, the solid and mucinous components were diagnosed as conventional and mucinous NETs, respectively. Grading was NET G2 based on 12.8% and 13.2% Ki-67-positive cells in the solid and mucinous components, respectively. Immunohistochemically, the mucin phenotype of this tumor was gastric and intestinal. Only the mucinous NET component had cytoplasmic CD10 expression. Examination using a customized gene panel detected only a DPC4 mutation, which was limited to the mucinous component. Conclusions: Coexistence of conventional and mucinous NETs could provide important insight into evaluating the NET subtype histogenesis. Moreover, molecular alterations including cytoplasmic expression of CD10 and the DPC4 mutation can contribute to interpretation of tumor pathogenesis.

Abstract Background A population-wide, systematic screening initiative for tuberculosis (TB) was implemented on Daru island in the Western Province of Papua New Guinea, where TB is known to be highly prevalent. The initiative used a mobile van equipped with a digital X-ray device, computer-aided detection (CAD) software to identify TB-related abnormalities on chest radiographs, and GeneXpert machines for follow-on diagnostic testing. We describe the results of the TB screening initiative, evaluate its population-level impact and examine risk factors associated with TB detection. Methods Through a retrospective review of screening data, we assessed the effectiveness of the screening by examining the enrolment coverage and the proportion of people with TB among screened subjects. A cascade analysis was performed to illustrate the flow of participants in the screening algorithm. We conducted univariate and multivariate analyses to identify factors associated with TB. Furthermore, we estimated the number of additional cases detected by the project by examining the trend of routine TB case notifications during the intervention period, compared to the historical baseline cases and trend-adjusted expected cases. Results Of the island’s 18,854 residents, 8,085 (42.9%) were enrolled and 7,970 (98.6%) had chest X-ray interpreted by the CAD4TB software. A total of 1,116 (14.0%) participants were considered to have abnormal CXR. A total of 69 Xpert-positive cases were diagnosed, resulting in a detection rate of 853 per 100 000 population screened. 19.4% of people with TB had resistance to rifampicin. People who were in older age groups (aOR 6.6, 95%CI: 1.5–29.1 for the 45–59 age group), were severely underweight (aOR 2.5, 95%CI:1.0-6.1) or underweight (aOR 2.1, 95%CI: 1.1–3.8), lived in households

Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients’ quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patient’s lung cancer treatment. In cases where a patient’s pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.

We investigated a newly developed digitized Trail Making Test using an iPad (iTMT) as a brief cognitive function screening test. We found that the iTMT part-A (iTMT-A) can estimate generalized cognitive function in rehabilitation inpatients examined using the Mini-Mental State Examination (MMSE). Forty-two hospitalized participants undergoing rehabilitation (rehab participants), 30 of whom had cerebral infarction/hemorrhage (stroke participants), performed the iTMT five times (first three times: iTMT-A; fourth: paper version of TMT-A; fifth: the inverse version of iTMT-A) and the MMSE once. Each iTMT-A trial's completion time was divided into the move and dwell times. A linear mixed model following post-hoc tests revealed that the completion time of the third and fourth iTMT-A was faster compared to that of the first iTMT-A, suggesting the presence of a learning effect. In the partial least squares (PLS) regression analysis, the coefficient of determination for estimating the MMSE score was increased by using the dwell and move times extracted from the repeated iTMT-A and the availability of TMT-B, even for subjects with low MMSE scores. These findings indicate that the dwell time of iTMT-A may be important for estimating cognitive function. The iTMT-A extracts significant factors temporally and spatially, and by incorporating the learning effect of repeated trials, it may be possible to screen cognitive and physical functions for rehabilitation patients.