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Abstract Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8+ T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.

Background Immune checkpoint inhibitors (ICIs) are therapeutically effective for hepatocellular carcinoma (HCC) but are individually selective. This study examined the role of specific common fragile sites (CFSs) related gene in HCC immunotherapy.Methods We analyzed HCC tissues using next-generation sequencing and flow cytometry via time-of-flight technology. A humanized orthotopic HCC mouse model, an in vitro co-culture system, untargeted metabolomics and a DNA pulldown assay were used to examine the function and mechanism of WWOX in the tumor immune response.Results WWOX was the most upregulated CFS-related gene in HCC patients responsive to ICIs. WWOX deficiency renders HCC resistant to PD-1 treatment in humanized orthotopic HCC mouse model. Macrophage infiltration is increased and CD8 T-cell subset infiltration is decreased in WWOX-deficient HCC patients. HCC-derived oleic acid (OA) promotes macrophage conversion to an immunosuppressive phenotype. Mechanistically, WWOX deficiency promoted OA synthesis primarily via competitive binding of NME2 with KAT1, which promoted acetylation of NME2 at site 31 and inhibited NME2 binding to the SCD5 promoter region. Pharmacological blockade of SCD5 enhanced the antitumor effects of anti-PD-1 therapy.Conclusions WWOX is a key factor for immune escape in HCC patients, which suggests its use as a biomarker for stratified treatment with ICIs in clinical HCC patients.

Abstract Objective We aim to determine the effect of region of residence (urban vs. rural) on the odds of receiving standard of care treatment for locally advanced BCa in Louisiana and its impact on survival outcomes. Methods Using the Louisiana Tumor Registry, we identified American Joint Committee on Cancer (AJCC) stage II or III, BCa diagnoses in Louisiana residents between 2010 and 2020. Treatment received was classified as standard or non‐standard of care according to American Urological Association (AUA) guidelines and location of residence was determined using Rural Urban Commuting Area‐Tract‐level 2010 (RUCA). Multivariable logistic regression analyses and multivariate cox proportional hazard analyses were performed. Results Of 983 eligible patients, 85.6% (841/983) lived in urban areas. Overall, only 37.5% received standard‐of‐care (SOC) for the definitive management of locally advanced bladder cancer. Individuals living in rural areas (OR 0.53, 95% CI: 0.31–0.91, p = 0.02) were less likely to receive standard of care treatment. Both rural residence and receipt of non‐standard of care therapy were associated with an increased risk of bladder cancer‐specific (adj HR 1.53, 95% CI: 1.09–2.14, p = 0.01 and adj HR: 1.85, 95% CI: 1.43–2.39,

Abstract Primary liver cancer (PLC) poses a leading threat to human health, and its treatment options are limited. Meanwhile, the investigation of homogeneity and heterogeneity among PLCs remains challenging. Here, using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). Taking a high-resolution perspective, our observations revealed that CHC cells exhibit internally discordant phenotypes, whereas ICC and HCC exhibit distinct tumor-specific features. Specifically, ICC was found to be the primary source of cancer-associated fibroblasts, while HCC exhibited disrupted metabolism and greater individual heterogeneity of T cells. We further revealed a diversity of intermediate-state cells residing in the tumor-peritumor junctional zone, including a congregation of CPE+ intermediate-state endothelial cells (ECs), which harbored the molecular characteristics of tumor-associated ECs and normal ECs. This architecture offers insights into molecular characteristics of PLC microenvironment, and hints that the tumor-peritumor junctional zone could serve as a targeted region for precise therapeutical strategies.

Abstract Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is used for the clinical treatment of leukemia, yet it is ineffective for the treatment of solid tumors, the reasons for which remain unclear. Here we show that Snail1, a key factor in the regulation of epithelial-to-mesenchymal transition, plays a pivotal role in cellular surveillance response upon ribotoxic stress. Mechanistically, ribotoxic stress activates the JNK-USP36 signaling to stabilize Snail1 in the nucleolus, which facilitates ribosome biogenesis and tumor cell survival. Furthermore, we show that HHT activates the JNK-USP36-Snail1 axis in solid tumor cells, but not in leukemia cells, resulting in solid tumor cell resistance to HHT. Importantly, a combination of HHT with the inhibition of the JNK-USP36-Snail1 axis synergistically inhibits solid tumor growth. Together, this study provides a rationale for targeting the JNK-USP36-Snail1 axis in ribosome inhibition-based solid tumor therapy.

Volume parameters such as the volume of voids (VV), voids filled with asphalt (VFA), and voids in mineral aggregates (VMA) all have significant impact on asphalt mixtures. In this study, the vertical vibration compaction method (VVCM) was employed to produce a large-particle-size asphalt mixture (LSAM-50). The correlations between the mechanical strengths of VVCM specimens, static compression test (PCT) specimens, and in situ core samples were verified. Additionally, the influence of volumetric parameters on the mechanical properties of VVCM specimens was assessed. Based on the principle of optimal mechanical properties, volume parameter design standards for the LSAM-50 asphalt mixture were proposed. Results indicated that the mechanical properties correlation between VVCM specimens and in situ core samples was substantial, reaching over 90%. With increasing VV and VFA, the compressive strength, splitting strength, and dynamic stability of the LSAM-50 asphalt mixture initially increased and then decreased. The design standards for VV were proposed to be between 3.5% and 4.8%, and for VFA between 49.7% and 52.9%. There was no clear correlation between VMA and the mechanical properties of the mixture; hence, based on the standards, the minimum design value for VMA was set at 7.5%.

Pile foundations are vastly utilized in construction projects where their capacities (pile bearing capacity, PBC) should be determined in different stages of construction. A highly reliable and accurate prediction model can lead to many advantages, such as reducing the construction cost, shortening the construction timeline, and providing safety construction. Hence, the aim of this study is the developments of statistical and artificial intelligence (AI) models for predicting bearing capacities of 141 piles. At the preliminary of the study, features or inputs of this study to predict PBC were selected trough simple regression analysis. Then, this study presents different kernels of support vector machine (SVM) technique, i.e., the dot, the radial basis function (RBF), the polynomial, the neural, and the ANOVA to predict the PBC. The aforementioned models were evaluated by several performance indices and their results were compared using a simple ranking system. The results showed that the SVM-RBF model is able to achieve the highest coefficient of determination, R2 values which are 0.967 and 0.993 for training and testing stages, respectively. It is important to mention that a multiple regression model was also employed to predict PBC values. The other SVM kernels were provided a high degree of accuracy for estimating PBC, however, the SVM-RBF model is recommended to be used as a powerful, highly reliable, and simple solution for PBC prediction.

Abstract Background Mounting evidence suggests that there is a complex regulatory relationship between long non-coding RNAs (lncRNAs) and the glycolytic process during glioma development. This study aimed to investigate the prognostic role of glycolysis-related lncRNAs in glioma and their impact on the tumor microenvironment. Methods This study utilized glioma transcriptome data from public databases to construct, evaluate, and validate a prognostic signature based on differentially expressed (DE)-glycolysis-associated lncRNAs through consensus clustering, DE-lncRNA analysis, Cox regression analysis, and receiver operating characteristic (ROC) curves. The clusterProfiler package was applied to reveal the potential functions of the risk score-related differentially expressed genes (DEGs). ESTIMATE and Gene Set Enrichment Analysis (GSEA) were utilized to evaluate the relationship between prognostic signature and the immune landscape of gliomas. Furthermore, the sensitivity of patients to immune checkpoint inhibitor (ICI) treatment based on the prognostic feature was predicted with the assistance of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Finally, qRT-PCR was used to verify the difference in the expression of the lncRNAs in glioma cells and normal cell. Results By consensus clustering based on glycolytic gene expression profiles, glioma patients were divided into two clusters with significantly different overall survival (OS), from which 2 DE-lncRNAs, AL390755.1 and FLJ16779, were obtained. Subsequently, Cox regression analysis demonstrated that all of these lncRNAs were associated with OS in glioma patients and constructed a prognostic signature with a robust prognostic predictive efficacy. Functional enrichment analysis revealed that DEGs associated with risk scores were involved in immune responses, neurons, neurotransmitters, synapses and other terms. Immune landscape analysis suggested an extreme enrichment of immune cells in the high-risk group. Moreover, patients in the low-risk group were likely to benefit more from ICI treatment. qRT-PCR results showed that the expression of AL390755.1 and FLJ16779 was significantly different in glioma and normal cells. Conclusion We constructed a novel prognostic signature for glioma patients based on glycolysis-related lncRNAs. Besides, this project had provided a theoretical basis for the exploration of new ICI therapeutic targets for glioma patients.

This contribution reviews the newly revised biostratigraphy of MiddleâUpper Ordovician marine shelf successions from the JuneeâNarromine Volcanic Belt in central New South Wales, based on conodont studies from four areas covering the northern, central and southern sectors of the Belt. Seven conodont biozones ranging from the middle Darriwilian (Histiodella holodentata-Eoplacognathus pseudoplanus Biozone) to the lower Katian (Taoqupognathus blandus Biozone) are recognized in the Billabong Creek Formation exposed in the Gunningbland area. This includes the first known biostratigraphic succession in Australia that extends continuously from the middle Darriwilian to the basal Sandbian. These new data are crucial for a better understanding of the geological evolution of this region in central New South Wales, and for the enhanced correlation of Ordovician rocks throughout the Macquarie Volcanic Province, which hosts substantial porphyry CuâAu mineral deposits.

Abstract Background Effective and scalable prevention approaches are urgently needed to address the rapidly increasing rates of e-cigarette use among adolescents. School-based eHealth interventions can be an efficient, effective, and economical approach, yet there are none targeting e-cigarettes within Australia. This paper describes the protocol of the OurFutures Vaping Trial which aims to evaluate the efficacy and cost-effectiveness of the first school-based eHealth intervention targeting e-cigarettes in Australia. Methods A two-arm cluster randomised controlled trial will be conducted among Year 7 and 8 students (aged 12–14 years) in 42 secondary schools across New South Wales, Western Australia and Queensland, Australia. Using stratified block randomisation, schools will be assigned to either the OurFutures Vaping Program intervention group or an active control group (health education as usual). The intervention consists of four web-based cartoon lessons and accompanying activities delivered during health education over a four-week period. Whilst primarily focused on e-cigarette use, the program simultaneously addresses tobacco cigarette use. Students will complete online self-report surveys at baseline, post-intervention, 6-, 12-, 24-, and 36-months after baseline. The primary outcome is the uptake of e-cigarette use at 12-month follow-up. Secondary outcomes include the uptake of tobacco smoking, frequency/quantity of e-cigarettes use and tobacco smoking, intentions to use e-cigarettes/tobacco cigarettes, knowledge about e-cigarettes/tobacco cigarettes, motives and attitudes relating to e-cigarettes, self-efficacy to resist peer pressure and refuse e-cigarettes, mental health, quality of life, and resource utilisation. Generalized mixed effects regression will investigate whether receiving the intervention reduces the likelihood of primary and secondary outcomes. Cost-effectiveness and the effect on primary and secondary outcomes will also be examined over the longer-term. Discussion If effective, the intervention will be readily accessible to schools via the OurFutures platform and has the potential to make substantial health and economic impact. Without such intervention, young Australians will be the first generation to use nicotine at higher rates than previous generations, thereby undoing decades of effective tobacco control. Trial registration The trial has been prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12623000022662; date registered: 10/01/2023).

Plain English Summary This review aimed to investigate the association between eating disorders (ED) and mental health problems. A review of existing systematic reviews was conducted to provide a top-level synthesis of the current evidence in this area. Our review found a total of 18 systematic reviews, which investigated the association between ED and a wide range of mental health problems. These conditions include depression and anxiety, obsessive-compulsive symptoms, attention deficit hyperactivity disorder (ADHD), social anxiety, personality disorders, suicidal-related outcomes, bipolar disorders and non-suicidal self-injury. Depression, social anxiety and ADHD are likely to have a stronger strength of association with ED relative to other mental health problems.

Abstract Background Breast‐conserving surgery plus radiation (BCT) yields equivalent or better survival than mastectomy for early‐stage breast cancer (ESBC) women. However, nationwide mastectomy trends increased in recent decades, attracting studies on underlying causes. Prior research identified that long distance to the radiation treatment facility (RTF) was associated with mastectomy. Still, it is unclear whether such association applies to young and old ESBC women comparably. We sought to delineate such impacts by age. Methods Women diagnosed with stages 0–II breast cancer in 2013–2017 receiving either BCT or mastectomy were identified from the Louisiana Tumor Registry. We assessed the association of surgery (mastectomy vs. BCT) with the distance to the nearest or nearest accessible RTFs using multivariable logistic regression adjusting the socio‐demographic and tumor characteristics. The nearest accessible RTF was determined based on patients' health insurance. For Medicaid, uninsured, and unknown insurance patients, the nearest accessible RTF is the nearest RTF owned by the government. The interaction effect of age and distance was evaluated as well. Results Of 11,604 patients, 46.7% received mastectomy. Compared with distance ≤5 miles to the nearest RTF, those with distance ≥40 miles or 15–40 miles had higher odds of mastectomy (adjusted (adj) OR = 1.39, 95% CI = 1.07–1.82; adj OR = 1.17, 95% CI = 1.02–1.34). To the nearest accessible RTF, the adj ORs were 1.25 (95% CI = 1.03–1.51) and 1.19 (95% CI = 1.04–1.35), respectively. Age‐stratified analysis showed the significant association (p

Abstract Background CD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC. Methods Multi-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis. Results CD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy. Conclusions High expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.

Patient activation, broadly defined as the ability of individuals to manage their health and navigate the healthcare system effectively, is crucial for achieving positive health outcomes. The Patient Activation Measure (PAM), a popularly used tool, was developed to assess this vital component of health care. This review is the first to systematically examine the validity of the PAM, as well as study its reliability, factor structure, and validity across various populations. Following the PRISMA and COSMIN guidelines, a search was conducted in MEDLINE, EMBASE, and Cochrane Library, from inception to 1 October 2023, using combinations of keywords related to patient activation and the PAM. The inclusion criteria were original quantitative or mixed methods studies focusing on PAM-13 or its translated versions and containing data on psychometric properties. Out of 3007 abstracts retrieved, 39 studies were included in the final review. The PAM has been extensively studied across diverse populations and geographical regions, including the United States, Europe, Asia, and Australia. Most studies looked at populations with chronic conditions. Only two studies applied the PAM to community-dwelling individuals and found support for its use. Studies predominantly showed a high internal consistency (Cronbach’s alpha > 0.80) for the PAM. Most studies supported a unidimensional construct of patient activation, although cultural differences influenced the factor structure in some cases. Construct validity was established through correlations with health behaviors and outcomes. Despite its strengths, there is a need for further research, particularly in exploring content validity and differential item functioning. Expanding the PAM’s application to more diverse demographic groups and community-dwelling individuals could enhance our understanding of patient activation and its impact on health outcomes.

Background Substance use disorders negatively affect global disease burden. Effective preventive interventions are available, but whether they provide value for money is unclear. Aims This review looks at the cost-effectiveness evidence of preventive interventions for cannabis use, opioid misuse and illicit drug use. Method Literature search was undertaken in Medline, CINAHL, PsycINFO, EconLit through EBSCOhost and EMBASE, up to May 2021. Grey literature search was conducted as supplement. Studies included were full economic evaluations or return-on-investment (ROI) analyses for preventing opioid misuse, cannabis and illicit drug use. English-language restriction was used. Outcomes extracted were incremental cost-effectiveness ratios (ICER) or ROI ratios, with costs presented in 2019 United States dollars. Quality was assessed with the Drummond checklist. Results Eleven full economic evaluation studies were identified from 5674 citations, with all studies conducted in high-income countries. Most aimed to prevent opioid misuse (n = 4), cannabis (n = 3) or illicit drug use (n = 5). Modelling was the predominant methodology (n = 7). Five evaluated school-based universal interventions targeting children and adolescents (aged

In this study, a novel artificial intervertebral disc implant with modified “Bucklicrystal” structure was designed and 3D printed using thermoplastic polyurethane. The new implant has a unique auxetic structure with building blocks joined “face-to-face”. The accompanied negative Poisson’s ratio enables its excellent energy absorption and stability under compression. The deformation and load distribution behavior of the implant under various loading conditions (bending, torsion, extension and flexion) has been thoroughly evaluated through finite element method. Results show that, compared to natural intervertebral disc and conventional 3D implant, our new implant exhibits more effective stress transfer and attenuation under practical loading conditions. The implant's ability to contract laterally under compression can be potentially used to alleviate the symptoms of lumbar disc herniation. Finally, the biocompatibility of the implant was assessed in vitro and its ability to restore the physiological function of the disc segment was validated in vivo using an animal model.

Abstract Purpose Recent studies have revealed an increase in the incidence rate of non-alcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC). Furthermore, the association of Sphingosine 1-phosphate receptor 2 (S1PR2) with various types of tumours is identified, and the metabolism of conjugated bile acids (CBAs) performs an essential function in the onset and development of HCC. However, the association of CBA and S1PR2 with NAFLD-HCC is unclear. Methods The relationship between the expression of S1PR2 and the prognosis of patients suffering from NAFLD-HCC was investigated by bioinformatics techniques. Subsequently, the relationship between S1PR2 and the biological behaviours of HCC cell lines Huh 7 and HepG2 was explored by conducting molecular biology assays. Additionally, several in vivo animal experiments were carried out for the elucidation of the biological impacts of S1PR2 inhibitors on HCC cells. Finally, We used Glycodeoxycholic acid (GCDA) of CBA to explore the biological effects of CBA on HCC cell and its potential mechanism. Results High S1PR2 expression was linked to poor prognosis of the NAFLD-HCC patients. According to cellular assay results, S1PR2 expression could affect the proliferation, invasion, migration, and apoptosis of Huh 7 and HepG2 cells, and was closely associated with the G1/G2 phase of the cell cycle. The experiments conducted in the In vivo conditions revealed that the overexpression of S1PR2 accelerated the growth of subcutaneous tumours. In addition, JTE-013, an antagonist of S1PR2, effectively inhibited the migration and proliferation of HCC cells. Furthermore, the bioinformatics analysis highlighted a correlation between S1PR2 and the PI3K/AKT/mTOR pathway. GCDA administration further enhanced the expression levels of p-AKT, p-mTOR, VEGF, SGK1, and PKCα. Moreover, both the presence and absence of GCDA did not reveal any significant change in the levels of S1PR2, p-AKT, p-mTOR, VEGF, SGK1, and PKCα proteins under S1PR2 knockdown, indicating that CBA may regulates the PI3K/AKT/mTOR pathway by mediating S1PR2 expression. Conclusion S1PR2 is a potential prognostic biomarker in NAFLD-HCC. In addition, We used GCDA in CBAs to treat HCC cell and found that the expression of S1PR2 was significantly increased, and the expression of PI3K/AKT/mTOR signalling pathway-related signal molecules was also significantly enhanced, indicating that GCDA may activate PI3K/AKT/mTOR signalling pathway by up-regulating the expression of S1PR2, and finally affect the activity of hepatocellular carcinoma cells. S1PR2 can be a candidate therapeutic target for NAFLD-HCC. Collectively, the findings of this research offer novel perspectives on the prevention and treatment of NAFLD-HCC.

Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.

Acute intraoperative cerebral herniation is catastrophic in craniotomy and seriously affects the outcomes of surgery and the prognosis of the patient. Although the probability of its occurrence is low, it can lead to severe disability and high mortality. We describe a rare case of intraoperative cerebral herniation that occurred in a syphilis-positive patient. The patient was diagnosed with both glioma and syphilis. When the glioma was completely removed under the surgical microscope, acute cerebral herniation occurred. An urgent intervention in cerebral herniation identified a collection of colorless, transparent, and protein-rich gelatinous substances rather than a hematoma, which is a more commonly reported cause of intraoperative cerebral herniation in the literature. We have found no previous descriptions of such cerebral herniation during craniotomy in a patient with syphilis and glioma. We suspected that the occurrence of intraoperative cerebral hernia might be related to the patient’s infection with syphilis. We considered the likelihood of an intraoperative cerebral herniation to be elevated when a patient had a disease similar to syphilis that could cause increased vascular permeability.

Background Alcohol use is a leading risk factor for death and disability worldwide. Aims We conducted a systematic review on the cost-effectiveness evidence for interventions to prevent alcohol use across the lifespan. Method Electronic databases (EMBASE, Medline, PsycINFO, CINAHL and EconLit) were searched for full economic evaluations and return-on-investment studies of alcohol prevention interventions published up to May 2021. The methods and results of included studies were evaluated with narrative synthesis, and study quality was assessed by the Drummond ten-point checklist. Results A total of 69 studies met the inclusion criteria for a full economic evaluation or return-on-investment study. Most studies targeted adults or a combination of age groups, seven studies comprised children/adolescents and one involved older adults. Half of the studies found that alcohol prevention interventions are cost-saving (i.e. more effective and less costly than the comparator). This was especially true for universal prevention interventions designed to restrict exposure to alcohol through taxation or advertising bans; and selective/indicated prevention interventions, which involve screening with or without brief intervention for at-risk adults. School-based interventions combined with parent/carer interventions were cost-effective in preventing alcohol use among those aged under 18 years. No interventions were cost-effective for preventing alcohol use in older adults. Conclusions Alcohol prevention interventions show promising evidence of cost-effectiveness. Further economic analyses are needed to facilitate policy-making in low- and middle-income countries, and among child, adolescent and older adult populations.

Background Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development.Methods Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1+ macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing.Results Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1+ macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1+ macrophage-enriched HCCs were characterized by high infiltration of CD8+ T cells with increased programmed death-1 (PD-1) expression. PPT1+ macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1− macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.Conclusions PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1+ macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.

Polyamide 66 was extensively utilized in various applications contributed by its excellent mechanical performance and outstanding durability. However, its high crystallinity renders it to have low transparency, which seriously limits its application in optical devices. Herein, a highly transparent polyamide (PA) 66-based copolymer was reported using 4,4′-diaminodicyclohexylmethane (PACM), adipic acid, and polyamide 66 salt as the reaction monomers. Wide-angle X-ray diffraction (WAXD) analysis revealed that the crystal phase of the synthesized PA66/PACM6 displayed a clear transition from α to γ as the PACM6 increased accompanied by a decreased intensity in the diffraction peak of the copolymer, whose transmittance was successfully adjusted reaching as high as 92.5% (at 550 nm) when the PACM6 was 40 wt%. Moreover, the copolymer with a higher content of PACM6 exhibited larger toughness. On the other hand, the biaxially oriented films of PA66/PACM6 (20 wt%) were also prepared, and it was found that the transparency of the PA66/PACM6 copolymer could be further enhanced via adjusting the stretching ratio of the film. Furthermore, the mechanical strength of the biaxially oriented PA66/PACM6 was also improved with the increase in the orientation degree in the stretching process, indicating that the physical properties of the transparent PA66 were significantly influenced by its alicyclic structure, and the introduction of PACM into PA66 was capable of effectively improving the optical and crystalline characteristics of PA66, revealing that the synthetic strategy has great potential for guiding the design and development of transparent polyamide materials.

Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated the quantification of cell populations, while transcriptome of PBLs was executed utilizing 10× single-cell sequencing technology. Additionally, pertinent cases were curated from the GEO database. Subsequent bioinformatics and statistical analyses were conducted utilizing R (4.2.1) software. Elevated counts of NK cells and CD8+ T cells were observed in both ICC and HCC when compared to benign liver disease (BLD). In the multivariate Cox model, NK cells and CD8+ T cells emerged as independent risk factors for recurrence-free survival. Single-cell sequencing of PBLs uncovered the downregulation of TGFβ signaling in tumor-derived CD8+ T cells. Pathway enrichment analysis, based on differential expression profiling, highlighted aberrations in selenium metabolism. Proteomic analysis of preoperative and postoperative peripheral blood samples from patients undergoing tumor resection revealed a significant upregulation of SELENBP1 and a significant downregulation of SEPP1. Primary liver cancer has a definite impact on PBLs, manifested by alterations in cellular quantities and selenoprotein metabolism.

Abstract Background Preoperative prediction of microvascular invasion (MVI) is critical for treatment strategy making in patients with hepatocellular carcinoma (HCC). We aimed to develop a deep learning (DL) model based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the MVI status and clinical outcomes in patients with HCC. Methods We retrospectively included a total of 321 HCC patients with pathologically confirmed MVI status. Preoperative DCE-MRI of these patients were collected, annotated, and further analyzed by DL in this study. A predictive model for MVI integrating DL-predicted MVI status (DL-MVI) and clinical parameters was constructed with multivariate logistic regression. Results Of 321 HCC patients, 136 patients were pathologically MVI absent and 185 patients were MVI present. Recurrence-free survival (RFS) and overall survival (OS) were significantly different between the DL-predicted MVI-absent and MVI-present. Among all clinical variables, only DL-predicted MVI status and a-fetoprotein (AFP) were independently associated with MVI: DL-MVI (odds ratio [OR] = 35.738; 95% confidence interval [CI] 14.027–91.056; p < 0.001), AFP (OR = 4.634, 95% CI 2.576–8.336; p < 0.001). To predict the presence of MVI, DL-MVI combined with AFP achieved an area under the curve (AUC) of 0.824. Conclusions Our predictive model combining DL-MVI and AFP achieved good performance for predicting MVI and clinical outcomes in patients with HCC.

BackgroundPrecancerous cervical lesion (PCL) is common in working-age and minority women. In Louisiana, 98% of PCL cases were diagnosed at age 18–65 with over 90% of them being human papillomavirus (HPV)-related. PCL women represent those who may be immunocompromised from the precancerous condition and thus more vulnerable to SARS-CoV-2. Most studies evaluating racial disparities for COVID-19 infection have only used data prior to vaccine availability. This study assessed disparities by race/ethnicity and socioeconomic status (SES) in COVID-19 infections among working-age PCL women for pre- and post-COVID-19 vaccine availability.MethodsLouisiana women aged 18–65 with PCL diagnosed in 2009–2021 were linked with the Louisiana statewide COVID-19 database to identify those with positive COVID-19 test. Race/ethnicity was categorized as non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic, and others. The census tract SES quintiles were created based on American Community Survey estimates. Logistic regression was employed to assess the racial/ethnic and SES differences in COVID-19 infections.ResultsOf 14,669 eligible PCL women, 30% were tested COVID-19 positive. NHB had the highest percentage of COVID-19 infection (34.6%), followed by NHW (27.7%). The infection percentage was inversely proportional to SES, with 32.9% for women having the lowest SES and 26.8% for those with the highest SES. NHB women and those with lower SES had higher COVID-19 infection than their counterparts with an aOR of 1.37 (95% CI 1.25–1.49) and 1.21 (95% CI 1.07–1.37), respectively. In the pre-vaccine period, NHB and Hispanic women had higher odds of infection than NHW women. However, after the vaccine was implemented, the significant racial/ethnic and SES differences in COVID-19 infections still existed in PCL women residing in non-Greater New Orleans area.ConclusionsThere are substantial variations in racial/ethnic and SES disparities in COVID-19 infections among working-age women with PCL, even after vaccine implementation. It is imperative to provide public health interventions and resources to reduce this unequal burden for this vulnerable population.

Abstract Background Suicide is the leading cause of death among young Australians, accounting for one-third of all deaths in those under 25. Schools are a logical setting for youth suicide prevention activities, with universal, selective and indicated approaches all demonstrating efficacy. Given that international best practice recommends suicide prevention programmes combine these approaches, and that to date this has not been done in school settings, this study aims to evaluate a suicide prevention programme incorporating universal, selective and indicated components in schools. Methods This study is a trial of a multimodal suicide prevention programme for young people. The programme involves delivering universal psychoeducation (safeTALK) to all students, screening them for suicide risk, and delivering internet-based Cognitive Behavioural Therapy (Reframe IT) to those students identified as being at high risk for suicide. The programme will be trialled in secondary schools in Melbourne, Australia, and target year 10 students (15 and 16 year-olds). safeTALK and screening will be evaluated using a single group pre-test/post-test case series, and Reframe IT will be evaluated in a Randomised Controlled Trial. The primary outcome is change in suicidal ideation; other outcomes include help-seeking behaviour and intentions, and suicide knowledge and stigma. The programme’s cost-effectiveness will also be evaluated. Discussion This study is the first to evaluate a suicide prevention programme comprising universal, selective and indicated components in Australian schools. If the programme is found to be efficacious and cost-effective, it could be more widely disseminated in schools and may ultimately lead to reduced rates of suicide and suicidal behaviour in school students across the region.

The onset process of corona discharge is naturally nonlinear and dynamic. The conventionally physical-based onset model and numerical computation of onset charge distribution are hampered by the computational power and given time. Here, in order to efficiently model this highly nonlinear dynamic process, a long short-term memory (LSTM) neural networks with attention mechanisms is proposed for accelerated charge density prediction under different atmospheric conditions, which adaptively choose charge-related input variables at each time step and hidden states relating to charge density all time steps. Our results demonstrate that this well trained model could make instant predictions with high accuracy under given target atmospheric conditions. Results show that the proposed model substantially reduces the computing time compared to physical-based methods. This work provides insights into applying LSTM neural networks to the charge density prediction of other discharge modes as well.

Introduction: Louisiana has one of the highest incidence and mortality rates of hepatocellular carcinoma (HCC) in the nation. The aim of this study was to analyze the trends in HCC incidence and relative survival rates in Louisiana and compare them with corresponding national rates, which can be used to formulate strategies to improve Louisiana HCC outcomes. Methods: Data on primary invasive HCC diagnosed in patients 20 years or older between 2005 and 2015 were obtained from the Surveillance, Epidemiology and End Results (SEER) program and Louisiana Tumor Registry. Time trends in HCC incidence and 12-month relative survival were analyzed using Joinpoint regression. Case characteristics were compared on 2 time periods (2005–2009 and 2010–2015) using Chi-squared tests. Cause-specific survival was analyzed via log-rank and multivariable Cox proportional hazard model. Results: Over the study period, the average annual percent change (AAPC) in age-adjusted HCC incidence in Louisiana was nearly double that of the national estimate, 6% (95% CI: 4.7, 7.3) compared to 3.1% (95% CI: 2.4, 3.7). 12-month relative survival among HCC patients in Louisiana was 40.7% (95% CI: 38.9, 42.4) which was significantly less than the US rate of 48.2% (95% CI: 47.8, 48.6). Relative survival did improve in Louisiana from 2000 to 2015 at a rate similar to that of the US (AAPC (95% CI): 2.9 (0.7, 5.2) vs. 2.7 (2.3, 3.1), p = 0.8). In multivariable survival analysis, factors amongst Louisianans associated with worse survival were older age at diagnosis, advanced stage of disease, and lack of surgical therapy. Conclusion: The incidence of HCC continues to rise more dramatically in Louisiana than in the US. While some modest improvements in HCC survival have been realized, outcomes remain dismal. Future work identifying the most at-risk populations are needed to inform statewide public health initiatives.

Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.

BackgroundInternet-delivered psychosocial interventions can overcome barriers to face-to-face psychosocial care, but limited evidence supports their cost-effectiveness for people with bipolar disorders (BDs). ObjectiveThis study aimed to conduct within-trial cost-effectiveness and cost-utility analyses of an internet-based intervention for people with BD, MoodSwings 2.0, from an Australian health sector perspective. MethodsMoodSwings 2.0 included an economic evaluation alongside an international, parallel, and individually stratified randomized controlled trial comparing an internet-based discussion forum (control; group 1), a discussion forum plus internet-based psychoeducation (group 2), and a discussion forum plus psychoeducation and cognitive behavioral tools (group 3). The trial enrolled adults (aged 21 to 65 years) with a diagnosis of BD assessed by telephone using a structured clinical interview. Health sector costs included intervention delivery and additional health care resources used by participants over the 12-month trial follow-up. Outcomes included depression symptoms measured by the Montgomery-Åsberg Depression Rating Scale (MADRS; the trial primary outcome) and quality-adjusted life years (QALYs) calculated using the short-form 6-dimension instrument derived from the 12-item version of the short-form health survey. Average incremental cost-effectiveness (cost per MADRS score) and cost-utility (cost per QALY) ratios were calculated using estimated mean differences between intervention and control groups from linear mixed effects models in the base case. ResultsIn total, 304 participants were randomized. Average health sector cost was lowest for group 2 (Aus $9431, SD Aus $8540; Aus $1=US $0.7058) compared with the control group (Aus $15,175, SD Aus $17,206) and group 3 (Aus $15,518, SD Aus $30,523), but none was statistically significantly different. The average QALYs were not significantly different among the groups (group 1: 0.627, SD 0.062; group 2: 0.618, SD 0.094; and group 3: 0.622, SD 0.087). The MADRS scores were previously shown to differ significantly between group 2 and the control group at all follow-up time points (P

PurposeWe aimed to investigate the feasibility of lenvatinib plus anti-PD-1 therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC).MethodsPatients with initially unresectable HCC who received combined lenvatinib and anti-PD-1 antibody between May 2020 and Jan 2022 in Zhongshan Hospital were retrospectively analyzed. Tumor response and resectability were assessed by imaging every two months according to RECIST version 1.1 and modified RECIST (mRECIST) criteria.ResultsA total of 107 patients were enrolled. 30 (28%) of them received conversion surgery within 90.5 (range: 53–456) days after the initiation of lenvatinib plus anti-PD-1 therapy. At baseline, the median largest tumor diameter of these 30 patients was 9.2 cm (range: 3.5-15.0 cm), 26 patients had Barcelona Clinic Liver Cancer stage B-C, and 4 had stage A. Prior to surgery, all cases displayed tumor regression and 15 patients achieved objective response. Pathological complete response (pCR) was observed in 10 patients. No severe drug-related adverse events or surgical complications were observed. After a median follow-up of 16.5 months, 28 patients survived and 11 developed tumor recurrence. Survival analysis showed patients achieving tumor response before surgery or pCR had a longer tumor-free survival. Notably, patients with microvascular invasion (MVI) had significantly higher recurrence rate and poorer overall survival than patients without.ConclusionsLenvatinib combined with anti-PD-1 therapy represents a feasible conversion strategy for patients with initially unresectable HCC. Patients achieving tumor responses are more likely to benefit from conversion resection to access a longer term of tumor-free survival.

In order to adjust the properties of polyamide 6 (PA6) and expand its application, a new strategy of introducing an aromatic imide structure into the PA6 chain through the random copolymerization method is reported. The diimide diacid monomer was first synthesized by the dehydration and cyclization of pyromellitic dianhydride and 6-aminocaproic acid before it reacted with 1,6-hexamethylene diamine to form poly(amide imide) (PAI) salt, and finally synthesized PA6/PAI random copolymers containing an aromatic imide structure by the random copolymerization of ε-caprolactam and PAI salt. The introduction of an aromatic imide structural unit into the PA6 chain could have a great influence on its properties. As the content of PAI increases, the crystallinity (Xc) and melting temperature (Tm) of the PA6/PAI random copolymer gradually decrease, but its glass transition temperature (Tg) increases obviously. When the PAI content is 20 wt%, the copolymer PA6/PAI-20 has the best comprehensive performance and not only has high thermal stabilities but also excellent mechanical properties (high strength, high modulus, and good toughness) and dielectric properties (low dielectric constant and dielectric loss). Moreover, these properties are significantly superior to those of PA6. Such high-performance PA6 random copolymers can provide great promise for the wider applications of PA6 materials.

Abstract Targeted therapy has greatly improved both survival and prognosis of cancer patients. However, while therapeutic treatment of adenocarcinoma has been advanced greatly, progress in treatment of squamous cell carcinoma (SCC) has been slow and ineffective. Therefore, it is of great importance to decipher mechanisms and identify new drug targets involved in squamous cell carcinoma development. In this study, we demonstrate that E47 plays the distinctive and opposite roles on cell proliferation in adenocarcinoma and squamous cell carcinoma. While E47 suppresses cell proliferation in adenocarcinoma cells, it functions as a oncoprotein to promote cell proliferation and tumor growth of squamous cell carcinoma. Mechanistically, we show that E47 can directly bind to the promoter and transactivate ΔNp63 gene expression in squamous cell carcinoma cells, resulting in upregulation of cyclins D1/E1 and downregulation of p21, and thereby promoting cell proliferation and tumor growth. We further show that expression of E2A (E12/E47) is positively correlated with p63 and that high expression of E2A is associated with poor outcomes in clinical samples of squamous cell carcinoma. These results highlight that the E47-ΔNp63α axis may be potential therapeutic targets for treatment of squamous cell carcinoma.

Abstract Cancer-associated fibroblasts (CAFs) are commonly acquired activated extracellular matrix (ECM)-producing myofibroblasts, a phenotypes with multiple roles in hepatic fibrogenesis and carcinogenesis via crosstalk with cohabitating stromal/cancer cells. Here, we discovered a mechanism whereby CAF-derived cytokines enhance hepatocellular carcinoma (HCC) progression and metastasis by activating the circRNA-miRNA-mRNA axis in tumor cells. CAFs secreted significantly higher levels of CXCL11 than normal fibroblasts (NFs), and CXCL11 also had comparatively higher expressions in HCC tissues, particularly in metastatic tissues, than para-carcinoma tissues. Both CAF-derived and experimentally introduced CXCL11 promoted HCC cell migration. Likewise, CAFs promoted tumor migration in orthotopic models, as shown by an increased number of tumor nodules, whereas CXCL11 silencing triggered a decrease of it. CXCL11 stimulation upregulated circUBAP2 expression, which was significantly higher in HCC tissues than para-carcinoma tissues. Silencing circUBAP2 reversed the effects of CXCL11 on the expression of IL-1β/IL-17 and HCC cell migration. Further downstream, the IFIT1 and IFIT3 levels were significantly upregulated in HCC cells upon CXCL11 stimulation, but downregulated upon circUBAP2 silencing. IFIT1 or IFIT3 silencing reduced the expression of IL-17 and IL-1β, and attenuated the migration capability of HCC cells. Herein, circUBAP2 counteracted miR-4756-mediated inhibition on IFIT1/3 via sponging miR-4756. miR-4756 inhibition reversed the effects induced by circUBAP2 silencing on the IL-17 and IL-1β levels and HCC cell migration. In orthotopic models, miR-4756 inhibition also reversed the effects on metastatic progression induced by silencing circUBAP2.

As a result of their cell structures, elastomeric foams exhibit high compressibility and are frequently used as buffer cushions in energy absorption. Foam pads between two surfaces typically withstand uniaxial loads. In this paper, we considered the effects of porosity and cell size on the mechanical behavior of random elastomeric foams, and proposed a constitutive model based on an artificial neural network (ANN). Uniform cell size distribution was used to represent monodisperse foam. The constitutive relationship between Cauchy stress and the four input variables of axial stretch λU, lateral stretch λL, porosity φ, and cell size θ was given by con-ANN. The mechanical responses of 500 different foam structures (20% < φ < 60%, 0.1 mm < θ < 0.5 mm) under compression and tension loads (0.4 < λU < 3) were simulated, and a dataset containing 100,000 samples was constructed. We also introduced a pre-ANN to predict lateral stretch to address the issue of missing lateral strain data in practical applications. By combining physical experience, we chose appropriate input forms and activation functions to improve ANN’s extrapolation capability. The results showed that pre-ANN and con-ANN could provide reasonable predictions for λU outside the dataset. We can obtain accurate lateral stretch and axial stress predictions from two ANNs. The porosity affects the stress and λL, while the cell size only affects the stress during foam compression.

Semiconductor optical amplifiers (SOAs) offer direct electrical injection, power consumption, integration, and anti-radiation advantages over optical fiber amplifiers. However, saturation output power and gain bandwidth have been limited in traditional structure SOAs. We demonstrate a monolithic integrated SOA with broad spectrum, high power, high gain, and small spectral linewidth expansion. The device adopts a two-stage amplified large optical cavity structure, and a lower optical field confinement factor is obtained by adjusting the thickness of the waveguide layer. The lower optical field confinement factor is conducive to improving the coupling efficiency and the maximum output power. Our device, fabricated only by standard i-line lithography with micron-scale precision, obtains excellent and stable performance. When the input power is set to 1 mW, the output power is 419 mW with a gain of 26.23 dB. When the input power is set to 25 mW at 25 °C, the output power increases to 600 mW with a gain of 13.8 dB. The corresponding gain bandwidth of 3 dB measures at least 70 nm. The spectral linewidth after the SOA is 1.15 times wider than that of the seed laser.

Abstract In recent years, there have been advancements in traditional patterns of tumor therapy with the adoption of immunotherapy. Its application with or without other combined regimens has attracted attention from clinicians. Sintilimab (Tyvyt®), a highly selective fully human IgG4 monoclonal antibody, blocks the binding site of programmed cell death protein 1 (PD-1), thereby, inhibiting the interaction between PD-1 and its ligands (PD-L1/2) to restore the endogenous anti-tumor T cell responses. Sintilimab has been proven to be clinically beneficial in multiple solid tumor therapies. Combination therapy and monotherapy have shown potential and encouraging anti-tumor efficacy with controllable and acceptable toxicities. The combination therapy is more likely to be a novel and promising therapeutic option. This study provides an overview of the status of sintilimab-based clinical trials in various solid tumors.

PurposeTo dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level.MethodsSingle-cell RNA sequencing (scRNA-seq) data of 10 ICC patients for the ICB clinical trial were extracted from GSE125449 and systematically reanalyzed. Bulk RNA-seq data of 255 ICC patients were analyzed. Infiltration levels of SPP1+CD68+ tumor-associated macrophages (TAMs) were examined by dual immunofluorescence (IF) staining in 264 resected ICC samples. The correlation between SPP1+ TAMs and clinicopathological features as well as their prognostic significance was evaluated.ResultsAmong the 10 patients, five received biopsy at baseline, and others were biopsied at different timings following ICBs. Single-cell transcriptomes for 5,931 cells were obtained. A tighter cellular communication network was observed in ICB-treated ICC. We found a newly emerging VEGF signaling mediated by PGF-VEGFR1 between cancer-associated fibroblasts (CAFs) and endothelial cells in ICC following ICBs. SPP1 expression was dramatically upregulated, and SPP1+ TAM gene signatures were enriched in TAMs receiving ICB therapy. We also identified SPP1+ TAMs as an independent adverse prognostic indicator for survival in ICC.ConclusionOur analyses provide an overview of the altered tumor ecosystem in ICC treated with ICBs and highlight the potential role of targeting CAFs and SPP1+TAMs in developing a more rational checkpoint blockade-based therapy for ICC.

Studies show that visualisation while reading has a positive impact on both L1 and L2 reader’s comprehension of a text and that visualisation improves L1 learners’ writing, but there are no studies relating to whether visualisation may help L2 learners’ writing. Using visualisation as a learning strategy, this paper reports on how visualisation training might affect a group of Chinese intermediate EFL learners’ narrative writing. Quantitative data from the pre-test and post-test did not show statistical significance, but the analysis of the qualitative data from learners’ written reflections indicated a positive correlation between the use of visualisation and engagement with narrative writing and higher levels of classroom enthusiasm and participation. This study highlights the need for further work to differentiate the most effective aspects of visualisation training for enhancing the quality of narrative writing. It also suggests potential for the integration of visualisation into different writing development curricula and to promote the role of visualisation in the wider process of second or foreign language learning.

Atmosphere ion mobility is an important electrical parameter related to the filamentary ion flow field of high voltage direct current (HVDC) transmission lines and other characteristics of the glow and streamer corona discharge. Many machine learning (ML)-based algorithms have already been widely used in the prediction of air discharge. This article proposes a genetic algorithm (GA)-support vector regression (SVR) combined with kernel principal components analysis (PCA) to predict the ion mobility, involving dimensionality reduction, feature selection, parameter optimization of SVR. Kernel PCA could reduce the dimension of data and GA with adaptive probability parameters is employed to optimize the parameters of SVR model. An improved parallel-plates ion generator is employed to produce corona discharge and then measure the saturation ion current density and then obtain the training data and testing data of ion mobility. The prediction results show that the proposed algorithm outperforms the other methods in terms of mean relative error and mean squared error criteria. In addition, the parameters of model and data features have a major influence on the performance of the prediction algorithm. Based on the measured data and reference data, the prediction result obtained on ion mobility under different humidity shows a satisfactory generalization and effectiveness of proposed model for the prediction.

Background Target-D, a new person-centred e-health platform matching depression care to symptom severity prognosis (minimal/mild, moderate or severe) has demonstrated greater improvement in depressive symptoms than usual care plus attention control. The aim of this study was to evaluate the cost-effectiveness of Target-D compared to usual care from a health sector and partial societal perspective across 3-month and 12-month follow-up. Methods and findings A cost-utility analysis was conducted alongside the Target-D randomised controlled trial; which involved 1,868 participants attending 14 general practices in metropolitan Melbourne, Australia. Data on costs were collected using a resource use questionnaire administered concurrently with all other outcome measures at baseline, 3-month and 12-month follow-up. Intervention costs were assessed using financial records compiled during the trial. All costs were expressed in Australian dollars (A$) for the 2018–19 financial year. QALY outcomes were derived using the Assessment of Quality of Life-8D (AQoL-8D) questionnaire. On a per person basis, the Target-D intervention cost between $14 (minimal/mild prognostic group) and $676 (severe group). Health sector and societal costs were not significantly different between trial arms at both 3 and 12 months. Relative to a A$50,000 per QALY willingness-to-pay threshold, the probability of Target-D being cost-effective under a health sector perspective was 81% at 3 months and 96% at 12 months. From a societal perspective, the probability of cost-effectiveness was 30% at 3 months and 80% at 12 months. Conclusions Target-D is likely to represent good value for money for health care decision makers. Further evaluation of QALY outcomes should accompany any routine roll-out to assess comparability of results to those observed in the trial. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616000537459).

The Ediacaran–Cambrian transition and the following Cambrian Explosion are among the most fundamental events in the evolutionary history of animals. Understanding these events is enhanced when phylogenetic linkages can be established among animal fossils across this interval and their trait evolution monitored. Doing this is challenging because the fossil record of animal lineages that span this transition is sparse, preserved morphologies generally simple and lifestyles in the Ediacaran and Cambrian commonly quite different. Here, we identify derived characters linking some members of an enigmatic animal group, the cloudinids, which first appeared in the Late Ediacaran, to animals with cnidarian affinity from the Cambrian Series 2 and the Miaolingian. Accordingly, we present the first case of an animal lineage represented in the Ediacaran that endured and diversified successfully throughout the Cambrian Explosion by embellishing its overall robustness and structural complexity. Among other features, dichotomous branching, present in some early cloudinids, compares closely with a cnidarian asexual reproduction mode. Tracking this morphological change from Late Ediacaran to the Miaolingian provides a unique glimpse into how a primeval animal group responded during the Cambrian Explosion.

In the original publication [...]

Accumulating evidence has revealed that dysregulated lncRNA expression contributes to the onset and progression of cancer. However, the mechanistic role of lncRNA in glioma progression and tumor immunology remains largely unknown. This study aimed to evaluate the significance of maternally expressed gene 3 (MEG3) in the prognosis of and its immune-related roles in gliomas. The expression levels of MEG3 were analyzed using Oncomine and TIMER database. As an important imprinted gene, the copy number variation (CNV) of MEG3 in both glioblastoma multiforme (GBM) and low-grade glioma (LGG) were analyzed using GSCALite database, whereas its prognostic significance was assessed using PrognoScan and GEPIA databases. The relationship between MEG3 and tumor-infiltrated immune cells was analyzed using TIMER. Results showed that MEG3 expression was lower in most of the human cancer tissues than in the normal tissues. We also found that heterozygous deletion of MEG3 occurred more frequent than heterozygous amplification in gliomas, and mRNA expression of MEG3 was significantly positively correlated with its CNV in both the GBM and LGG group. Survival analysis showed that the CNV level of MEG3 had significant correlation with overall survival (OS) and progression-free survival (PFS) compared with wild type in LGG. Lower MEG3 expression was related with poor prognosis. Further analysis showed that in GBM, MEG3 expression level was significantly positively correlated with that of infiltrating CD8+ T cells and significantly negatively correlated with that of infiltrating dendritic cells. In LGG, MEG3 expression level was significantly negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Univariate Cox survival analysis demonstrated that only the level of infiltrating dendritic cells significantly affected the survival time of patients with GBM, while all six types of immune cells had a significant effect on the survival time of patients with LGG. Furthermore, MEG3 expression showed strong correlations with multiple immune markers in gliomas, especially in LGG. The current findings suggest that MEG3 expression might serve as a possible prognostic marker and potential immunotherapeutic target for gliomas.

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC. Methods Expression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort. Results Expression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts. Conclusions Compared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients.