Inflammation of the myocardium (myocarditis), pericardium (pericarditis), or both (myopericarditis) is a rare but potentially lethal side effect of mesalamine, a drug widely used in the treatment of inflammatory bowel disease (IBD).A 64-year-old female with a history of ulcerative colitis on mesalamine presented with dyspnea and chest pain. The patient was found to have mild to moderate pericardial effusion with signs of pericarditis. Further workup revealed positive rheumatoid factor, antineutrophil cytoplasmic autoantibody, cytoplasmic (c-ANCA), and antinuclear antibodies (ANA), raising suspicion for rheumatoid-associated pericarditis. She was discharged with a prednisone taper and an outpatient rheumatology follow-up. However, the patient presented again in three months with similar complaints and was found to have recurrent pericarditis. On this admission, mesalamine-induced pericarditis was considered in the differential diagnosis, and it was stopped on discharge. On a three-month follow-up, the patient showed complete resolution.Mesalamine-induced pericarditis is a rare side effect of this drug, and prompt recognition and appropriate intervention are important to prevent the progression of the inflammation and avoid adverse cardiovascular outcomes. The association of IBD with extra-intestinal cardiac manifestations can delay early diagnosis and treatment.  Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that primarily involves the bowel and is associated with extra-intestinal manifestations in other organ systems. Cardiac involvement  is a rare and life-threatening manifestation if left untreated. Mesalamine  is a 5-aminosalicylic acid (ASA) compound that is the first-line treatment for patients with mild-to-moderate UC. Myopericarditis, a side effect of mesalamine, a drug widely used in the treatment of IBD, is an infrequent but potentially lethal complication . Timely A 64-year-old female with UC on mesalamine (started one year ago) presented to the hospital with dyspnea and chest pain. The patient had been having recurrent episodes of chest pain over the last three weeks. The pain was located in the precordium without any radiation to the jaw or left arm. The episodes started spontaneously at rest and were exacerbated by exercise and deep breathing.The patient’s pain was only relieved after rest and morphine. This was accompanied by progressively worsening shortness of breath with exertion. She also reported night sweats; however, she did not report any fever or recent upper respiratory tract infections. The patient had no history of coronary artery disease and no risk factors for the disease. She had an irregular, rapid rhythm on the exam, but no murmurs or friction rubs were found. No rashes were noted either. The labs on presentation were consistent with an elevated D dimer of 1740 ng/ml, an erythrocyte sedimentation rate (ESR) of 71 mm/hr, and a negative troponin. The electrocardiogram revealed atrial fibrillation, rapid ventricular response, and nonspecific ST and T wave abnormalities. An echocardiogram showed normal left ventricular size, systolic function, and trace pericardial effusion. A CT angiogram showed mild to moderate pericardial effusion along with irregular pericardial thickening and patchy areas of fat stranding, which was concerning for pericarditis, and a small left pleural effusion , antineutrophil cytoplasmic autoantibody, cytoplasmic (c-ANCA), and proteinase 3 (PR 3), after which rheumatology was consulted. The patient was discharged with a prednisone taper per rheumatology recommendations and an outpatient follow-up for possible rheumatoid arthritis (RA)-related pleuro-pericardial effusion.The patient presented again after three months with continued exertional dyspnea and chest pain. Rheumatology reevaluated the patient and concluded that RA was less likely to be the cause of pericarditis given the absence of joint pain or swelling and no response to steroids. ANA was likely a false positive, and c-ANCA and PR-3 positivity were attributed to mesalamine use. A suspicion of mesalamine-induced recurrent pericarditis was raised. Gastroenterology was consulted, and they were in agreement to stop mesalamine.The patient’s symptoms significantly improved after discontinuing mesalamine. She was evaluated in the clinic for three weeks, followed up at three months after discharge, and achieved complete recovery. She was switched to adalimumab for UC and did not have any further episodes of pleuro- pericarditis.Mesalamine has long been the cornerstone of IBD treatment, especially for milder forms of UC . CardiotThe mechanism of 5-ASA-related cardiac side effects is not clearly known, and the proposed pathophysiology includes direct toxic effects and humoral or cell-mediated mechanisms . Due to The diagnosis of mesalamine-induced myocarditis and pericarditis is made by ruling out other common causes of myocarditis and pericarditis and by observing the resolution of symptoms after cessation of treatment. Generally, the clinical features are seen within one to two weeks of starting mesalamine, and they can persist for up to four weeks or more ,4. SymptLab studies can show leukocytosis, elevated ESR/C-reactive protein (CRP), and elevated troponin ,6. Some Multiple cases of mesalamine-induced myocarditis, pericarditis, and pleural and pericardial effusions have been reported in the literature. Recurrent attacks of myopericarditis have been reported with continued exposure to mesalamine. No dose-effect relationship has been demonstrated in the literature. For confirmation of the diagnosis of drug-induced inflammation, discontinuation of the 5-ASA product is generally enough . A shortIBD (UC and Crohn’s disease) is known to be associated with extra-intestinal manifestations, affecting multiple organ systems. These can affect the musculoskeletal system, eye, skin, hepatobiliary, hematopoietic, pulmonary, and cardiac systems. Cardiac manifestations include myocarditis and pericarditis. Extra-intestinal manifestations are found on initial presentation in less than 10% of patients, and 25% of patients develop extra-intestinal manifestations in their lifetime . These mMesalamine-induced pericarditis and myocarditis are rare but life-threatening complications. Early recognition is vital to prevent progression. There is no single lab test to prove mesalamine as the cause of pericarditis. It is a diagnosis of exclusion and other common causes of pericarditis should be ruled out first. The association of IBD with extra-intestinal cardiac manifestations of myocarditis and pericarditis poses a diagnostic challenge when the patients are on mesalamine. Physician awareness is necessary to differentiate between IBD-associated pericarditis and mesalamine-associated pericarditis for accurate diagnosis and management. Patients should be educated about the cardiovascular side effects of mesalamine and advised to seek medical attention if cardiac symptoms arise.


The new phenomena observed in nanodevices and the related technological challenges of fabrication and manipulation at the nanoscale have spurred intense theoretical, simulation and experimental research activity. New device structures, materials, simulation and characterization techniques have emerged.The Special Issue entitled “Electronic Nanodevices” focuses on the design, simulation, fabrication, and modeling of new nanodevices for electronic, optoelectronic and energy applications; it includes articles dealing with nanoscale transistors, phototransistors, memories, and solar cells.The effects of down-scaling and the introduction of new materials, architectures and fabrication processes in transistors and phototransistors are widely investigated.High-electron-mobility transistors (HEMTs) are devices designed for high-frequency and high-power applications. An experimental study by P. Cui and Y. Zheng checked the impact of vertical and lateral scaling on low-field electron mobility in GaN HEMTs . AlthougOwing to their great mechanical, electronic, and carrier transport properties, two-dimensional 2D) materials such as graphene, black phosphorus and transition metal dichalcogenides D materia,4,5,6, aM. La Mura and coworkers numerically investigated the effects of device geometry and graphene quality variations on the performance of graphene-field effect transistors (GFETs) . The pooM. Poljak and coworkers dealt with the contact resistance in black phosphorus nanoribbons (PNRs) with edge contacts using atomistic quantum transport simulations . The acc2 with Cr contacts and presented their optoelectronic characterization [2 conduction band. It is demonstrated that the ReSe2 FETs are strongly affected by air pressure and undergo a dramatic increase in conductivity when the air pressure is lowered below the atmospheric pressure. The exposure to air suppresses the channel conductivity as an effect of electron capture by oxygen and water molecules adsorbed on the material surface. The reversible pressure behavior allows the devices to be used as air pressure gauges. Finally, a negative photoconductivity in the ReSe2 channel is found and explained as back-gate-dependent trapping of the photo-excited charges.E. Faella et al. fabricated back-gated FETs based on few-layer ReSerization . The devK. Tamersit and coworkers performed numerical simulations by self-consistently solving the Poisson equation with the mode space non-equilibrium Green’s function formalism in the ballistic limit to investigate carbon nanotube/nanoribbon junctionless phototransistors, endowed with sub-10 nm photogate lengths . The ligThe same group in another computational work proposed an efficient approach based on the synergy of electrostatic and chemical-doping engineering to boost the subthreshold and switching performance of sub–10 nm junctionless-carbon-nanotube-tunnel field-effect transistors . Their dFerroelectric gates are also considered by M. Takahashi and S. Sakai who fabricated a new strontium bismuth tantalate (SBT) ferroelectric-gate FET with channel lengths of 85 nm by a replacement-gate process . Their dMemory devices are also treated in a review paper by Juan B. Roldán and coworkers, dedicated to resistive random access memories (RRAMs) . RRAMs aDriven by the ever-increasing need for sustainable energy sources, the design, fabrication, and characterization of solar cells have also attracted a great deal of research endeavor.S. Bernardes and coworkers numerically studied the lattice-matched GaInP/GaInAs/Ge triple-junction solar cell, which is currently being used in most satellites and concentrator photovoltaic systems . They fi® software to study nanometric optical antennas, with dimensions smaller than the wavelength of the incident electromagnetic wave, for solar energy harvesting on photovoltaic cells [F. Duarte and coworkers used COMSOL Multiphysicsic cells . The useEfficient solar cells can also be achieved through the development of innovative materials. Among them, two-dimensional metal MXenes, consisting of transition-metal nitrides or carbides, have emerged for their outstanding transparency, metallic electrical conductivity, and mechanical characteristics. Recent applications of MXene materials in solar cells and new perspectives to achieve higher power conversion efficiency with an excellent quality–cost ratio are offered in a review paper by T. F. Alhamada and coworkers . The rev2 and MoO3 are considered as promising anode materials for LIBs due to the broad spectrum of electrical properties ranging from metallic (MoO2) to wide band gap semiconducting (MoO3) character. In this direction, H. Wang and coworkers used orange peel extract as an effective chelating agent to synthesize molybdenum oxides [2 and MoO3 are prepared in vacuum and in air, respectively, at a temperature of 450 °C. Extensive morphological and structural characterization along with electrical and electrochemical analysis are performed to show their outstanding properties in terms of capacity upgrading upon cycling and as an anode in material for Li-ion batteries.Efficient energy storage is another important aspect of the sustainable development. Currently, lithium-ion batteries (LIBs) have become one of the most important energy storage technologies and their progress requires the development of high-capacity electrode materials . Molybdem oxides . MoO2 anIn summary this Special Issue offers a good overview of the recent research in nanoscale transistors, based on 1D and 2D materials, solar cells, memory devices, and electrochemical devices.


Deep-sea water (DSW) contains multiple minerals and is widely used as drinking water, for cosmetic purposes, and as seasoning. In this study, several types of extract-added water with different levels of hardness  were prepared from DSW collected off the coast of Muroto City, Kochi Prefecture. We administrated it to obese mice for two months and tested it for several effects. Although there was no anti-obesity effect for any hardness level in obese mice, the cognitive functions of each DSW-extract-added water-treated group were significantly improved compared to control obese mice in the water maze test. Time-to-fall by the rota-rod test was also dramatically improved in the DSW-extract-added water-treated groups. The levels of triglycerides and blood urea nitrogen were significantly decreased in DSW-extract-added water-treated obese mice. However, these results did not depend on the hardness. Hardness levels of 200 or 300 of DSW-extract-added water had greater effects on cognitive function and serum scores compared to a level of 500. We analyzed DSW using inductively coupled plasma atomic emission spectroscopy and inductively coupled plasma mass spectrometry. High concentrations of magnesium and potassium were detected, but sodium was not detected at very high concentrations. Although the detailed mechanisms of its effects are not yet understood, chronic intake of DSW-extract-added water may have a beneficial effect on health. Over 95% of our body comprises carbon, hydrogen, oxygen, and nitrogen, and the remaining 4% is minerals ,2. MinerOne beverage sold as a mineral supplement is deep-sea water (DSW). To be exact, it is sold as water to which a mineral extract obtained from DSW is added. DSW is characterized by a high mineral content of potassium, calcium, and magnesium, and high purity and, low temperature . DSW, whBefore starting this study, all design of experiments was submitted and approved by the Animal Protection and Ethics Committee of Shibaura Institute of Technology . Four-week-old C57BL/6J male mice were purchased from Sankyo Labo Service Corp. Inc. . Mice were randomly assigned to one of five dietary groups: control diet (Ctrl), high fat diet (HFD), HFD + supplemented with hardness 200 mg/L water (Ctrl + 200), HFD + supplemented with hardness 300 mg/L water (Ctrl + 300), and HFD + supplemented with hardness 500 mg/L water (Ctrl + 500). The different hardness waters were provided by Dydo-Takenaka Beverage Co. Ltd. . HFD model mice were generated by feeding a diet  containing 5.24 kcal/g, with 60% of the calories from fat, 20% from protein, and 20% from carbohydrates to normal four-week-old mice until 12 weeks of age . A contrThe feeding period of these drinking waters was the same as with the HFD, until 12 weeks old. Mice were bred under conditions of a 12-h light/dark cycle and a temperature of 24 ± 2 °C. During the study period, all animals had free access to food and water. Food and water intake volumes and body weights were measured weekly. After the feeding period, we performed each behavioral test. The mice were anesthetized by ether and sacrificed quickly by decapitation, and the cerebral cortex, hippocampus, and liver were removed, and serum samples were taken. All chemical reagents were obtained from either FUJIFILM Wako Pure Chemical Industries, Ltd.  or Sigma-Aldrich Corp. .DSW-extract-added waters of different hardness were made and provided by Dydo-Takenaka Beverage Co. Ltd. DSW was collected from offshore of Cape Muroto in Kochi Prefecture . The extCognitive function, especially learning ability was measured using a Morris water maze apparatus  ,19. The Motor coordination ability was determined by a rota-rod  test, as described previously, with some modifications . The rodTo the judgment of short-term memory, a Y-maze apparatus  was used . The mouEach brain region  was homogenized in RIPA buffer and used in western blotting as described previously , with soThe quantitative analysis of the metals contained in various waters was performed by inductively coupled plasma atomic emission spectroscopy (ICP-AES)  and inductively coupled plasma mass spectrometry (ICP-MS)  by an external inspection agency .p-values of less than 0.05 were considered statistically significant. The detailed statistical methods are described in the individual figure captions.Data are expressed as means ± standard error (SE) and were analyzed using GraphPad Prism software . Mice were fed three different kinds of hard water and high-fat diets from 4 to 12 weeks of age. The body weights of all mice gradually increased in a time-dependent manner A. The boTo clarify the biological benefit of DSW-extract-added water, we measured cognitive function using the Morris water maze task. The daily average goal time gradually decreased in all mouse groups and confirmed that all mice learned the place of the escape platform A. The raDSW-extract contains many minerals. To further clarify DSW-extract-added water benefits, we measured mouse coordination ability using a rota-rod apparatus. Time-to-fall from the rod in HFD-treated mice was significantly faster than for the controls in the presence or absence of DSW-extract-added water A,B. GeneWe measured the exploratory behavior using the Y-maze task. There were no significant differences in the number of arm entries A and altTreatment with DSW-extract-added water reduced cognitive dysfunction in HFD-treated mice. To clarify the mechanism, after several maze tasks, we measured the expressions of neurotrophic factors such as NGF and BDNF and their receptors . NGF expAfter several maze tasks, we measured serum parameters . Blood uAfter the maze task, the livers were removed, and imaged A. TreatmQuantitative analysis of the metals contained in various waters was performed by ICP-AES and ICP-MS by an external inspection agency . Since tIn this study, we evaluated the beneficial effects of DSW-extract-added water in obese mice. Some researchers have studied the biological functions of this water and have found that the main reason for its benefit is that it contains abundant minerals and is free of fats, proteins, and carbohydrates . While sIn this study, we fed water of three different hardness to obese mice for two months. Water and food intake volumes were not significantly different among any mouse groups. These results indicate that there was no significant difference in the taste of water at different hardness and that it did not affect mice’s appetites. This result is supported by Hsu et al. , who admIn the Morris water maze, the goal time gradually decreased in all mouse groups . The goaTo clarify the coordination ability of the mice, the rota-rod test was used to measure the time to fall and the rod speed when the mice fell from the rod . Both scTo determine the mechanism of cognitive improvement in the Morris water maze and the rota-rod test, the expressions of neurotrophic factors (NGF and BDNF) and their receptors in the cerebral cortex and hippocampus were measured using western blotting . The expThere are several reports on the relationship between minerals and cognition, including for long-term, short-term, and working memory. Slutsky et al. reported that increasing the brain magnesium concentration enhances cognition via enhancement of synaptic plasticity in the hippocampal CA1 and DG region in Sprague Dawley rats . The celIn the serum indexes, treatment with different hardness of DSW-extract-added water significantly decreased blood urea nitrogen and inorganic phosphorus . The creTo clarify the beneficial functions of DSW-extract-added water, an elemental quantitative analysis (hardness 300) was performed using ICP-MS and ICP-AES. Twenty-one elements were detected in hardness 300 water with DSW-extract. The magnesium and potassium levels of the DSW-extract-added water were 11 and 7 times greater than filtered tap water. Generally, tap water in European countries is harder and contains calcium and magnesium, but our DSW-extract-added water was not high in calcium. However, the sodium level for the DSW-extract-added water was only 2.5 times more than the controls. In general, it is important to keep the increase in sodium ion concentrations low when concentrating DSW. Serum sodium ion concentrations in each group of DSW-extract-added water-treated mice were not increased compared to the two untreated groups. Interestingly, treatment with hardness 300 water resulted in significantly decreased serum sodium levels compared to the HFD-treated group. It is well known that high sodium levels are a high-risk factor for diabetes , high blIn this study, we determined the biological effects of different levels of hardness of DSW-extract-added water on obese mice. Several effects were not concentration dependent. In our model, hardness 200 or 300 may be the best for chronic intake based on the experimental data. Recently, due to changes in lifestyle, the intake of minerals has become insufficient, and the mineral balance in the body has been disturbed. Continued intake of beverages containing moderate mineral levels may help maintain proper health.


Single-cell RNA sequencing (scRNA-seq) is a novel technology that characterizes molecular heterogeneity at the single-cell level. With the development of more automated, sensitive, and cost-effective single-cell isolation methods, the sensitivity and efficiency of scRNA-seq have improved. Technological advances in single-cell analysis provide a deeper understanding of the biological diversity of cells present in tissues, including inflamed skin. New subsets of cells have been discovered among common inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis. ScRNA-seq technology has also been used to analyze immune cell distribution and cell-cell communication, shedding new light on the complex interplay of components involved in disease responses. Moreover, scRNA-seq may be a promising tool in precision medicine because of its ability to define cell subsets with potential treatment targets and to characterize cell-specific responses to drugs or other stimuli. In this review, we briefly summarize the progress in the development of scRNA-seq technologies and discuss the latest scRNA-seq-related findings and future trends in AD and psoriasis. We also discuss the limitations and technical problems associated with current scRNA-seq technology. Inflammatory skin diseases are induced by skin barrier disorders and dysregulation of innate and adaptive immunity. Atopic dermatitis (AD) and psoriasis are two of the most common chronic inflammatory skin diseases , 2. The Bulk RNA sequencing is an indispensable tool for analyzing transcriptional variations, which determine the average gene expression among pooled populations of cells and reported as single data. However, tissues consist of multiple cell types in various states; hence, the results of such a technique can be misleading. Newly developed single-cell RNA sequencing (scRNA-seq) technologies facilitate the analysis of transcriptional activity at the single-cell level . scRNA-sscRNA-seq is a powerful tool for providing precision and detail to individual cells . The worMethods of traditional single-cell isolation have eventually developed after many optimizations. Micromanipulation is a classic technique for manually capturing under a microscope , 8. It cNovel single-cell capture methods based on microfluidics include integrated fluidic circuits (IFCs), droplets, microwells, traps, and the SlipChip . Popularvia scRNA-seq appears to promote B- cell responses within the inflamed skin of patients with systemic sclerosis  is one of the most common inflammatory skin diseases. The prevalence of AD has been reported up to 20% among children and 10% among adults , and theIn addition to the unclear specific pathogenic mechanisms of AD, the treatment options for this disease vary. Targeted therapies for specific AD endotypes, such as those directed against Th2/Tc2, and Th17 cells and general anti-inflammatory agents, have been proved by the FDA or are currently in different phases of clinical trials . Additio+COL18A1 +COL6A5 fibroblast, which express the cytokines CCL2 and CCL19, were a novel cell subpopulation unique to AD lesional skin. A dendritic cell population that expresses the CCL19 receptor CCR7 is also unique to AD lesions , including inflammatory dendritic epidermal cells, form the most expanded immune cell population in AD lesions . It has AD typically starts in infancy or early childhood, showing spontaneous regression after puberty in a subset of patients while waxing and waning for life in many others. However, the factors that modify the natural course of spontaneous remission remain to be elucidated. The overall cell composition of patients with spontaneously healed AD was comparable to that of healthy individuals. Compared to healthy controls, melanocytes exhibit many differentially expressed genes in all cell types in spontaneously healed atopic dermatitis. Specifically, the expression of the potential anti-inflammatory, maker PLA2G7 (Lipoprotein-associated phospholipase A2 or “platelet-activating factor acetylhydrolase) is increased. Regulatory markers are also upregulated in conventional T-cells . MoreoveBased on previous studies, innate immune cells (ILC2s and DCs), fibroblasts, and KCs, as well as their interplay and interactions, play a role in AD development. Melanocytes and skin-resident memory T cells may contribute to the specific regulatory microenvironment in the spontaneous remission and recurrence of AD, respectively.via single-cell transcriptomics. CXCL13- expressing Tc17 cells appear to be specific to psoriatic lesions and are associated with disease severity  are divided into three groups: Langerhans cells in the epidermis, classical dendritic cell type 1(cDC1) and cDC2 in the dermis, and macrophages . A new sEven though immune cell infiltration plays a fundamental role in cutaneous inflammation, KCs can also influence the inflammatory microenvironment . scRNA-sSince 2009, the first conceptual and technical breakthrough of the single-cell RNA sequencing method was made by Tang et al. . An incrMost of studies related in this review prepare the libraries and sequence depending on 10X Genomics platform. These findings highlight KCs, fibroblasts, and different types of immune cells in mechanisms for coping with the different stages of AD and psoriasis. scRNA-seq offers a novel method to identify the receptors, ligands, and cytokines expressed in each cell type to further highlight intercellular communication in the skin microenvironment. However, the detailed mechanisms driving the pathogenicity of these cells and the relationship between them require further study. And the clinical characteristics of AD and psoriasis varied. Therefore, more specific studies are necessary to elucidate the characteristics of AD and psoriasis based on the differences in the stages and subtypes of these diseases. Patients with clinical characteristics of both AD and psoriasis have been described as having psoriasis dermatitis, typically found in children . In addiAnalyzing the non-coding RNAs (ncRNAs) with scRNA-seq and combining proteomics with epigenomics will get closer to a ture global examination of single cell. In addition, the analysis of minimally invasive or non-invasive samples, such as blood or urine specimens, may also hold promise in diagnosis process and treatment response prediction. Considering the rapid development of sequencing methods, scRNA-seq can be expected to enter the clinics soon and facilitate personalized therapeutic decisions for patients with inflammatory skin diseases.via scRNA-seq are specific biological findings, or a biased subset clustering data that is prone to misinterpretation (Although scRNA-seq can identify cell type-specific transcriptional regulation and cellular heterogeneity, its limitations can be challenged. Firstly, high-throughput single-cell analysis requires cell dissociation, quality control, and are largely tend to examine freshly isolated cells. More research will use such technology to explore cryopreserved and fixed tissue samples. And the preparation of single-cell suspensions destroys spatial information of tissues. In addition, researchers have mostly focused on protein-coding RNA. An increasing number of studies have indicated that ncRNAs have important roles in cell function and specialization –69. Evenretation , 73. Theretation , there aIn recent years, transcriptomics has made a great leap from bulk RNA-seq, which measures the average gene expression, to analyzing gene expression data in individual cells. This mini-review summarizes and discusses the applications of scRNA-seq in AD and psoriasis Figure 1DX wrote the manuscript. YW, YX, and WL contributed to the revision of the manuscript. All authors approved the final submitted version.1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The purpose of this study was to systematically review the current evidence on apatinib and offer a better understanding of its safety and efficacy in metastatic colorectal cancer (mCRC) patients who have not responded to standard chemotherapies. This systematic review was conducted using research from the last 10 years  and was obtained from the following databases: PubMed, PubMed Central (PMC), ScienceDirect, and Google Scholar. After removing duplicates, screening titles and abstracts, and applying eligibility criteria and quality appraisal, 11 articles were left for this systematic review . Out of the 11 studies, six were on apatinib monotherapy, while three were on apatinib combination therapy. Apatinib has demonstrated efficacy in the monotherapy and combination therapy trials and has exhibited an acceptable safety profile as the adverse events were predominantly graded 1-2 and could be easily managed. Therefore, apatinib is an encouraging candidate for third-line therapy in chemotherapy-refractory mCRC patients. This conclusion should be confirmed and validated by studies with larger, randomized clinical trials to gain better insight and to directly compare the efficacy and safety of apatinib with all current third-line therapies together so that clinicians can easily assess which treatment modality is superior for chemotherapy-refractory mCRC patients. Colorectal cancer (CRC) is the third most common cancer in the United States and is the second most deadly cancer . DespiteThe main treatments available for patients in early or locally advanced stages of CRC are surgery, radiation therapy, and chemotherapy . HoweverThe first- and second-line therapy for metastatic colorectal cancer (mCRC) consists of fluorouracil-based doublet regimens  and biologic-targeted therapies including either endothelial growth factor receptor (cetuximab or panitumumab) targeted treatment or vascular endothelial growth factor , or programmed cell death protein 1 (PD-1) inhibitors -8.After two or more lines of systemic treatment, most mCRC patients experience disease progression . NonetheAngiogenesis, primarily controlled by the VEGF pathway, plays a crucial role in the progression of CRC, and anti-angiogenesis therapy has been a vital treatment option in mCRC . Anti-VEApatinib mesylate, also known as YN968D1 and rivoceranib, is a novel anti-angiogenic oral small molecule drug that inhibits VEGF receptor-2 (VEGFR-2) and the tyrosine kinases: cellular sarcoma (c-SRC) and type III receptor tyrosine kinase (c-Kit) -23. In CThis systematic review will focus on the efficacy and safety of apatinib for the treatment of mCRC in patients who have not responded to standard chemotherapies.MethodsPreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were used for this systematic review .Databases and Keywords UsedThis systematic review was conducted using research from the following databases: PubMed, PubMed Central (PMC), ScienceDirect, and Google Scholar.Medical Subject Headings (MeSH) keywords used were:  AND "apatinib" [Supplementary Concept]Keywords used for ScienceDirect and Google Scholar were “Colorectal cancer” and “Apatinib.”Inclusion CriteriaAll studies were assessed based on the following inclusion criteria: (a) papers from the past 10 years , (b) papers published in the English language, (c) papers focusing on the adult population aged ≥ 18 years, (d) papers relevant to the question, and (e) full-text papers.Exclusion CriteriaStudies were removed based on the following exclusion criteria: (a) papers discussing the pediatric population, (b) unpublished literature, (c) grey literature, and (d) abstract-only papers.Study Screening and Quality AppraisalThe first and second authors separately performed the title, abstract, and full-text screening. Any disagreements were settled by the third author at any juncture. After the final papers for this review were chosen, all of the authors named were equally active in evaluating each one for quality and gathering data for this systematic review. We compared and contrasted the data from each chosen study and retrieved information about apatinib's effectiveness , and safety (any AEs).Newcastle-Ottawa scale: A score of 0-3 is a high risk, 4-6 is moderate risk, and 7-9 is low risk. All high-risk studies were excluded, and only moderate and low-risk studies were included.Assessing the Methodological Quality of Systematic Reviews (AMSTAR) checklist: All articles satisfying ≥70% of the checklist questions were included.Scale for the Assessment of Narrative Review Articles (SANRA) checklist: All articles satisfying ≥70% of the checklist questions were included.The tools mentioned in Table ResultsA total of 4,704 results were identified from the databases mentioned above, and 4,408 results were removed because of duplicates (60 results) and automation tools (4348 results). A further 251 were excluded by screening titles and abstracts. The remaining 45 were sought for retrieval, but one could not be retrieved. In total, 44 reports were evaluated for eligibility, and 33 were removed after screening for full text, English language only papers, and quality assessment. Eleven articles were left for use in this systematic review . The PRISMA flowchart in Figure Table DiscussionEfficacy endpoints are PFS , OS (defined as the duration from the onset of treatment until death from any cause), ORR , and DCR .Efficacy of Apatinib MonotherapyWang et al. conducted a single-arm, prospective, multicenter study to investigate the efficacy of apatinib monotherapy in refractory mCRC . All 48 Similarly, in a single-arm, prospective, single-center study by Yang et al., all 14 patients received apatinib, resulting in a median PFS of six months, median OS of 10 months, ORR of 28.57%, and DCR of 71.43% . A compaThe retrospective study by Liao et al. included 53 patients, of which 27 were given apatinib, and 26 with similar clinical characteristics were subject to observation . Median In a retrospective study, Bai et al. evaluated the effect of kinase insert domain receptor (KDR) genetic variation on apatinib monotherapy in 108 mCRC patients . Median Sun et al. conducted a meta-analysis to assess the effectiveness and safety of apatinib in refractory malignancies . Out of Efficacy of Apatinib Combination TherapyLi et al. directed a single-arm, prospective, multicenter, phase II trial to appraise low-dose apatinib combined with S-1  in refractory mCRC patients . A totalThe study by Dai et al. was a retrospective cohort to evaluate the effectiveness and safety of apatinib and S-1 versus regorafenib versus fruquintinib in chemotherapy-refractory mCRC patients . The stuPan et al. conducted a prospective study to assess the efficacy and safety of a PD-1 inhibitor and apatinib versus apatinib monotherapy on mCRC patients as third-line treatment . Of the Potential Factors That Can Help Gauge the Response to Apatinib in Chemotherapy-Refractory mCRCApatinib monotherapy: Wang et al. found that the occurrence of hand-foot syndrome (HFS) during the first 28 days (p=0.007), low neutrophil-to-lymphocyte ratio (p=0.040), and early decrease in carbohydrate antigen 19-9 (p=0.011) were linked to increased PFS . Bai et Apatinib combination therapy: Pan et al. showed that patients with bevacizumab history (p=0.018) or a single metastatic site (p=0.033) had increased OS (but no difference in PFS) in the PD-1 inhibitor plus apatinib group versus the apatinib group . This inEven though numerous possible prognostic indicators for apatinib have been identified, none have found widespread usage in clinical settings . This isSafety of ApatinibThe safety profile of third-line or further-line mCRC treatments can aid clinicians in making therapy decisions and help prevent and treat possible AEs to improve quality of life . AEs werApatinib monotherapy: According to Sun et al., 84% of patients reported experiencing apatinib's AEs . HoweverApatinib combination therapy: In the study by Li et al., most AEs were grades 1-2 and were well tolerated and controlled, while 10 grade 3 AEs were observed, and the frequency of each grade 3 AE was less than 5% . AdditioOverall, the safety profile of apatinib, whether taken as monotherapy or in combination with other treatments, is acceptable, as the majority of the AEs were graded 1-2 and easily manageable.LimitationsThere are some potential limitations in our systematic review. All studies had a small sample size and were conducted in China, limiting the results' generalizability. Also, most of the studies included were single-center studies, which introduce inherent selection bias in the data. As a result, large-scale, prospective, multicenter randomized clinical trials conducted in different populations are urgently required to investigate whether apatinib is more effective as a monotherapy or combination therapy.As far as we know, this is the first systematic review to evaluate the efficacy and safety of apatinib as third-line therapy in advanced CRC patients. Most of the included studies revealed that apatinib has significant efficacy as monotherapy and combination therapy. Moreover, multiple factors identified can help gauge the response to apatinib in monotherapy or combination therapy, but the quality of evidence is low. Furthermore, apatinib has an acceptable safety profile as the AEs were predominantly graded 1-2 and could be easily managed. Therefore, apatinib is an encouraging candidate for third-line therapy in chemotherapy-refractory mCRC patients. This conclusion should be confirmed and validated by studies with larger sample sizes and prospective, multicenter randomized clinical trials worldwide to gain better insight regarding its safety and efficacy. Also, additional clinical trials are required to directly compare the efficacy and safety of apatinib with all current third-line therapies so that clinicians can assess which treatment modality is superior for chemotherapy-refractory mCRC patients.


Consolidation with fibrosis measured using DL-based analysis was independently associated with poor survival. The lesion extent measured using DL-based analysis showed a negative correlation with the pulmonary function test results and prognosis.We investigated the feasibility of a new deep-learning (DL)-based lung analysis method for the evaluation of interstitial lung disease (ILD) by comparing it with evaluation using the traditional computer-aided diagnosis (CAD) system and patients’ clinical outcomes. We prospectively included 104 patients (84 with and 20 without ILD). An expert radiologist defined regions of interest in the typical areas of normal, ground-glass opacity, consolidation, consolidation with fibrosis (traction bronchiectasis), honeycombing, reticulation, traction bronchiectasis, and emphysema, and compared them with the CAD and DL-based analysis results. Next, we measured the extent of ILD lesions with the CAD and DL-based analysis and compared them. Finally, we compared the lesion extent on computed tomography (CT) images, as measured with the DL-based analysis, with pulmonary function tests results and patients’ overall survival. Pearson’s correlation analysis revealed a significant correlation between DL-based analysis and CAD results. Forced vital capacity was significantly correlated with DL-based analysis (r = 0.789,  Interstitial lung diseases (ILDs) are varied and heterogenous diseases . RecentlComputer-based quantification of CT images based on computer-aided diagnosis (CAD) can provide an objective and reproducible measure of the lesion extent of ILD. However, the traditional CAD system cannot differentiate consolidation with fibrosis (traction bronchiectasis) from that without fibrosis. Quantification with fully manual tracing and CAD with manual corrections are the existing solutions to this problem. Specifically, a manual tracing method by an experienced chest radiologist may be the best approach for ILD classification and volumetry. However, these existing techniques are time-consuming, and they are impractical for clinical settings .Recently, artificial intelligence-based methods have been applied for CT evaluation of ILD segmentation and diagnosis ,7,8,9. TThe present study aimed to quantitatively and qualitatively evaluate the effects of DL-based analysis on ILD characterization by comparing it to the traditional quantitative measures, i.e., visual evaluation by a radiologist and evaluation using a CAD system. Furthermore, we investigated the association between the quantitative results of the DL-based analysis and the disease severity and prognosis in ILD patients.This study consisted of two steps, i.e., (1) the development of the DL-based analysis model  and (2) a clinical study of DL-based analysis.The study design is shown in The review board of our institution approved the study protocol. Written informed consent was prospectively obtained from all the patients who underwent CT examinations to evaluate ILD or other pulmonary diseases between June 2016 and August 2018 .For the step-1 preclinical study, we used CT images of 110 patients with ILD who were not included in the subsequent clinical study  Figure .For the step-2 clinical study, we enrolled 104 patients whose characteristics are shown in Eighty-four ILD patients  included 40 idiopathic pulmonary fibrosis (IPF) patients and 44 non-IPF ILD patients. ILD was diagnosed by multidisciplinary discussion according to the criteria established by the latest international consensus guidelines ,21. TwenThin-section non-contrast CT images were obtained during inspiration with the patient in a supine position using 320- or 64-row multi-detector CT scanners . The scanning parameters were 0.5-mm collimation, 0.5-sec gantry rotation speed, tube voltage of 120-kVp, and tube current of 250–300 mA (automatic exposure control). CT images were reconstructed with a slice thickness of 0.5 mm using an iterative reconstruction algorithm .The ILD classification and lesion extent on CT images were estimated using the CAD system and DL-based analysis method.CAD system CAD), emphysema (ECAD), ground-glass opacity (GCAD), consolidation (CCAD), reticulation (RCAD), and honeycombing including traction bronchiectasis (HCAD). The total fibrotic lesions (FibCAD) were calculated as the sum of RCAD and HCAD.The GHNC system  is a traditional CAD software that divides the lung into six categories based on the CT attenuation values and values on the differential images ,23,24,25DL-based analysis (QZIP-ILD)DL), emphysema (EDL), ground-glass opacity (GDL), consolidation (CDL), consolidation with fibrosis (traction bronchiectasis) (CFDL), reticulation (RDL), honeycomb (HDL), and traction bronchiectasis (TDL). We calculated the total fibrotic lesions (FibDL) as the sum of CFDL, RDL, HDL, and TDL, corresponding to FibCAD.The DL-based ILD analysis system  is a research software, and its development details  are described in the DL-based analysis was developed to classify the lung regions into eight categories, including two more categories (consolidation with fibrosis and traction bronchiectasis) than the CAD system. The classification of the lung lesions based on the two methods is summarized in 3) of five different lung CT imaging feature categories  measured using the CAD system and DL-based analysis. The agreement on the measured volume of each CT imaging feature category between the CAD and DL-based analysis was evaluated.The original number of categories of the CAD system (six categories) and DL-based analysis (eight categories) differed from each other. Therefore, we compared the volumes  on the CT images of the 104 patients (3 to 7 ROIs per patient), including the region of normal, emphysema, GGO, consolidation, consolidation with fibrosis, reticulation, honeycomb, and traction bronchiectasis. We chose a 3-mm diameter ROI because the size was sufficiently large to avoid missing characteristic imaging features and not so large that it would be affected by other structures surrounding the ROI. We measured the proportion of pixel numbers for each ROI and calculated the accuracy. We also evaluated the relationship between the segmentation results of the DL-based analysis and CAD methods, which were displayed as a chord diagram using the Power BI analysis tool .DL, GDL, CDL, CFDL, RDL, HDL, TDL, EDL, and FibDL (CFDL+RDL + HDL + TDL) categories and that of the whole lung volume, as measured with DL-based analysis, with the pulmonary function test results , forced expiratory volume in 1 s (FEV1), and total lung capacity (TLC)).We compared the lung volumes of the NWe compared the DL-based analysis parameters and characteristics (age and sex) of the 104 patients with survival time.p-value < 0.05 was considered statistically significant.SPSS Statistics version 28  was used for the data analysis. All numerical data are reported as mean ± standard deviation. Bland-Altman plots were used to evaluate the agreement of lesion volumes between the CAD system and DL-based analysis. We also used Pearson’s correlation coefficients to compare the lesion volumes as measured with the CAD and DL-based methods. Survival time was analyzed from the date CT scanning was performed to the date of death or censoring. Univariate and multivariate Cox regression analyses were used to determine variables related to survival. A All CT data were successfully segmented using both the CAD system and DL-based analysis. Representative images are shown in A manual operation was not required with the DL-based analysis because the system was designed to detect lung contours and classify and measure lesions automatically; the CAD system required a manual operation to detect the lung contours in all patients. The mean time required to prepare for and complete the manual operation of the CAD lung analysis (tracing lung contours) was 17.3 ± 3.9 min per case. In some patients, consolidation with or without traction bronchiectasis in the peripheral zone was missed owing to manual correction errors .CAD) and honeycombing (HCAD). Some perivascular areas were misjudged as GGO , normal lung , and consolidation  volumes. Conversely, the calculated volume of total fibrotic lesions was significantly lower  with the DL-based analysis than with the CAD method.One expert radiologist defined 549 ROIs on 104 CT scans, including normal, emphysema, consolidation, fibrosis, GGO, honeycomb, reticulation, and traction bronchiectasis, and compared the output results using DL-based analysis and the CAD system. The accuracy for each lesion and for the normal lung area according to the DL-based analysis and CAD system was 0.922–1.000 and 0.529–0.995, respectively . The relDL volume was inversely correlated with TLC , FVC , and DLCO .DL. Univariate analysis showed that age  and CFDL  were statistically significant, while sex  was not statistically significant. Multivariable analysis, including age and CFDL, revealed that age  and CFDL  were independently associated with shorter survival.Of the 104 patients, 16 died during the study period. The median follow-up time was 3.3 years. Univariate and multivariate Cox regression analyses were performed to identify the prognostic factors. DL) and consolidation with bronchiectasis (CFDL). The lesion extent measured with DL-based analysis correlated well with FVC, and multivariate Cox regression analysis showed that CFDL was independently associated with a worse prognosis. We consider consolidation with bronchiectasis, i.e., CFDL, a critical index correlating with patients’ prognosis in ILD.In the present study, DL-based analysis appropriately classified typical ILD lesions, in agreement with the classification provided by the expert chest radiologist. The DL-based analysis allows for automatic measurement, rendering it free from operator-dependent errors and variability, which is clinically helpful. Furthermore, DL-based analysis can quantify consolidation by distinguishing between the presence and absence of bronchiectasis. The lesions segmented into consolidation by CAD system were segmented into two patterns by DL-based analysis: consolidation without bronchiectasis  ,28. We aThe present study had several limitations. First, the results were obtained from a small number of patients recruited from a single center, and our study lacked a power analysis. This was not a case-control study, but a feasibility study of new analytic technique, i.e., a DL-based analysis model for the quantitative and qualitative evaluation of ILD. In addition, the number of cases available for this study was limited because it was a single-center prospective study and because a large number of cases had to be used as training data for the DL analysis development. In addition, we did not evaluate CT images from scanners of different vendors or those with various reconstruction methods. Furthermore, the DL-based analysis developed for this study is not currently capable of detecting pulmonary nodules. As the detection of lung cancer in patients with ILD is important for each patient’s prognosis, the system may need to be used in combination with other artificial intelligence-based methods for detecting pulmonary nodules. Despite these limitations, we believe that our study results demonstrate that the DL-based analysis is clinically appropriate for the evaluation of ILD. The usefulness of the DL-based analysis presented here should be verified in greater detail in future studies.In conclusion and recommendation, QZIP-ILD, our newly developed DL-based analysis model, can accurately and automatically detect, characterize, and quantify the extent of ILD. The DL-based analysis can distinguish between consolidation with and without fibrosis, which could not be achieved by previously reported systems. The quantitative results of DL-based analysis correlated with pulmonary function tests, and consolidation with fibrosis was associated with patient prognosis. We regard ILD evaluation with the newly developed DL-based analysis model as clinically applicable, leading to the appropriate management of ILD patients.2. Labeling was performed by a radiologist with 30 years of experience in chest imaging.The following steps were taken to develop the DL-based analysis model  . The firNext, we used this dataset for training. The training model was based on a three-dimensional (3D) convolutional neural network for semantic segmentation and had a structure similar to that of a 3D U-Net, as shown in For training, the dataset was divided into three groups such that the eight labels were evenly distributed. The total areas of the labels in each group are listed in


N = 1,655; Bias-based aggression at school in the form of homophobic name-calling is quite prevalent among early adolescents. Homophobic name-calling is associated with low academic performance, higher risky sexual behaviors, and substance abuse, among other adverse outcomes. This longitudinal study examined risk and protective factors across multiple domains of the social ecology  and levels of analysis (within- and between-person) associated with homophobic name-calling perpetration and victimization. Students from four middle schools in the U.S. Midwest ( Homophobic name-calling is a common form of bias-based aggression at school. Homophobic name-calling is understood as a form of gender-based harassment, consisting of pejorative labels  or denigrating phrases  aimed at youth perceived to be gay, lesbian, bisexual, queer, or gender nonconforming . It is aAs a form of bias-based aggression, homophobic name-calling shares both similarities and differences with traditional bullying . While bBeing the target of homophobic name-calling is often associated with poor mental health symptoms, such as higher incidence of anxiety, depression, and suicide-related behaviors among adolescents . It has The social-ecological correlates of homophobic name-calling can be found among peers, family, the school, and the community, which are all embedded within the broader society and can influence homophobic attitudes and behaviors at school . The socIndividual domain characteristics associated with homophobic name-calling are gender, age, traditional masculinity attitudes, social dominance orientation, empathy, and impulsivity . StudiesSimilarly, studies have found that homophobic name-calling perpetration serves to establish and maintain social dominance hierarchies within and between adolescent peer groups through the promotion of heteronormative gender roles . Social N = 190) social networks, impulsivity was strongly associated with higher engagement in homophobic name-calling over time  . Both diParental monitoring and surveillance have been found to influence adolescents’ involvement in bullying and other forms of youth aggression. Studies found bullying and other aggressive behavior tends to occur when parents are absent or when youth are not provided sufficient supervision . Within Family social support is the level of recognition, approval, and care that youth receive from family members and has been correlated with bullying and other types of aggression involvement. Experiencing parental rejection and inadequate support from family members has been associated with bullying perpetration . Other sA recent review of protective factors associated with homophobic name-calling and its consequences highlighted that few individual and family characteristics have been examined . SpecifiRelying on close non-family others such as friends, romantic partners, or individuals considered “found family” or “chosen family” for support is a common experience among LGBTQ youth . FurtherPeer social support could also play a protective role against homophobic name-calling victimization among heterosexual youth by providing support for youth being targeted by perpetrators. However, peer networks have previously been identified as a context that promotes homophobic name-calling perpetration among adolescents . The homSchool belonging is commonly described as students’ sense of being accepted, valued, included, and encouraged by peers and other school community members . FeelingIn addition, social support from trusted non-family adults has been identified as a robust protective moderating element in the pathway from victimization to mental health issues among LGBTQ youth cross-culturally . For traSchool climate is heavily impacted by the larger community in which schools are embedded . ExposurThe extant literature reveals a combination of risk and protective factors associated with homophobic name-calling at multiple domains of the social-ecological model. However, most studies have employed cross-sectional designs, which can only inform between-person differences, but not variation within a person over time. Furthermore, the few longitudinal studies on homophobic name-calling among adolescents have yet to include within-person variability, thus confounding within- and between-person sources of variability. Also, no study to date has simultaneously examined a comprehensive set of social-ecological domains with a risk and protective factors framework . To addrWhile between-person variation informs overall homophobic name-calling trends, examining within-person variation is critical to understanding how time-specific contextual factors in the social-ecological model are associated with concurrent levels of homophobic name-calling. To illustrate the interpretation and importance of this statistical technique, consider the findings from We hypothesize that the following protective factors will be significantly associated with a lower incidence of homophobic name-calling perpetration and victimization at both the within- and between-person levels of analysis: (H1) individual domain empathy; (H2) family social support; (H3) parental monitoring; (H4) school belonging; (H5) social support from adults at school; and (H6) social support from peers. In addition, we hypothesize that the following risk factors will be associated with higher homophobic name-calling perpetration and victimization at both the within- and between-person levels of analysis: (H7) individual domain impulsivity; (H8) family violence; and (H9) neighborhood violence. Finally, we hypothesize significant associations between the following risk factors and higher homophobic name-calling perpetration (not victimization): (H10) social dominance; and (H11) traditional masculinity.N = 1655) were surveyed four times . Data were collected every semester in middle school to capture temporal associations among risk and protective factors of multiple forms of violence. New students were enrolled at each wave, and students may not have been surveyed at some waves because of moving to another school or being chronically absent. Students in this data set had to have data at Wave 1. Response rates ranged from 92% to 95% at each wave. At baseline, students were in fifth (4.0%), sixth (34.1%), seventh (34.2%), and eighth (27.7%) grade. Participants’ average age was 12.75 years (range 10–16), 49.5% were female, 47.9% African American, 36.1% White, 3.3% Hispanic, 1.6% Asian/Pacific Islander, and 10.8% other , age (open-ended), grade, race/ethnicity , and highest parental education , and sexual orientation . Full descriptions of measures are available in Supplemental Table 1.Participants completed demographic questions on The 10-item Homophobic Content Agent Target Scale was used to assess homophobic name-calling perpetration and victimization , 2007. APerceptions of individual domain factors that were assessed: (a) impulsivity, four items, ωs = .76 to .81 (Perceptions of family domain factors that were assessed: (a) family conflict and hostility, three items, ωs = .81 to .83 (Perceptions of school and neighborhood domain factors included: (a) exposure to community violence, five items, ωs = .92 across all waves  and included participants’ perceptions of individual, family, school, neighborhood, and peer domain factors. 6 to .81 ; (b) emp6 to .81 ; (c) tra6 to .81 ; and (d)6 to .81 . Percept1 to .83 ; (b) par1 to .83 ; and (c)1 to .83 . Perceptll waves ; (b) socll waves ; and (c)ll waves . Percept4 to .87 .A longitudinal latent growth model was used to examine trajectories of homophobic name-calling perpetration and homophobic name-calling victimization among middle school students across four waves of data conditioned on both time-variant (within-person) and time-invariant (between-person) predictors. The intraclass correlations for homophobic perpetration (HP) was .52, indicating that 52% of the total variation reported perpetration was variation between students, whereas 48% was variation within a student across time. Similarly, the intraclass correlation for HV was .59. With a substantial proportion of the total variation attributable to both within- and between-person components, explaining the variation in the outcomes necessitates including in the model both within-person variables that vary across time for the same individual and between-persons variables that are stable across time for a given individual and highlight differences between persons. To do so, we fit a taxonomy of unconditional and conditional growth models. First, an unconditional model (Model 1) established plausible rates of change for HP and HV. The model included random linear and quadratic slopes, meaning a separate linear and quadratic slope was estimated for each student.We then tested our hypotheses by examining groups of conditional growth models for each social ecological domain . A separate model for each domain was fit (Models 2–7) followed by a final competing model that included predictors across all social domains (Model 8).The within-person predictors were person-mean centered to examine how individuals deviate from their own “typical” levels (within-person average). The between-person predictors were grand-mean centered to examine average differences between people. The centering strategies separate within- and between-person variance, thereby making within- and between-person representations of the predictors orthogonal to each other . As suchSupplemental Table 2.Descriptive statistics across time are presented in Homophobic name-calling and other forms of bias-based aggression are quite prevalent among youth. Often occurring among friends, this form of homophobic aggression during early adolescence is strongly inﬂuenced by peers and rooted in gender and masculinity . Over 90The social-ecological factors which influence homophobic name-calling victimization and perpetration can be found beyond the individual domain, and include peers, family, the school, and the community. Within the individual domain, impulsivity had significant positive associations with homophobic name-calling perpetration and victimization at both within- and between-person levels of variability. These results suggest that impulsivity is a significant risk factor for homophobic name-calling involvement, a finding that is consistent with previous literature . Highly Similarly, social dominance was a risk factor for higher homophobic name-calling perpetration, but not victimization. Traditional masculinity was also significantly associated with higher homophobic name-calling perpetration only at the between-person level, and higher homophobic name-calling victimization at both the within- and between-person levels. These associations offer support for previous work, suggesting that students may use social dominance to assert their masculinity and are therefore more likely to be perpetrators . In addiConsistent with the literature, results indicated that family violence was a risk factor for higher homophobic name-calling perpetration and victimization both between person- and within-person . These aContrary to our hypothesis, family social support emerged as a risk factor, with a significant positive association for homophobic name-calling perpetration at the between-person level, but not within-person. Similarly, a significant positive association between family social support and homophobic name-calling victimization emerged at the within-level but only in the competing model. These findings are inconsistent with the literature that has found that youth engaging in bullying perpetration or experiencing victimization typically have lower family support . FindingFinally, exposure to neighborhood violence was also a risk factor associated with higher levels of homophobic name-calling perpetration and victimization at both the within- and between-person levels. It is possible that students who live in neighborhoods with higher rates of violence also attend schools where homophobic name-calling is more likely to occur, and violence witnessed in these neighborhoods may translate to the adoption of views supportive of homophobic attitudes. For example, researchers have found bidirectional associations between school and neighborhood violence where both contexts influence each other . HoweverWithin the individual domain, significant associations were found between higher empathy and lower homophobic name-calling perpetration at both the within-person and between-person levels. These results support previous literature underscoring empathy as a protective factor of homophobic name-calling perpetration . EmpathyHowever, contradictory results emerged for empathy and homophobic name-calling victimization at the within- and between-person levels, where higher empathy within-person was associated with lower homophobic name-calling victimization but at the between-person level it was associated with higher homophobic name-calling victimization. It is possible that students who are perceived as more empathetic by their peers (between-person) may be more likely to be targets of homophobic name-calling due to negative perceptions of empathy as a weakness or feminine trait. Conversely, empathy may still be protective at times when individuals are experiencing higher empathy compared with their own typical levels due to yet unexplored mechanisms. In addition, our measure of empathy did not distinguish between the multiple dimensions of affective versus cognitive empathy which have been shown to function differently in traditional bullying and cyberbullying; therefore, further examination is needed to interpret the associations uncovered in the present study .Within the family domain, results indicated that higher parental monitoring was protective and associated with lower homophobic name-calling perpetration and victimization at both the within- and between-person levels. The results are consistent with the literature, where adequate supervision from parents can buffer against bullying behaviors through peer selection , and parents who monitor their children can actively reduce opportunities to engage in bullying behaviors such as homophobic name-calling .When considering the peer domain, peer social support was examined as a protective factor for homophobic name-calling involvement. Significant negative associations were found between peer social support and homophobic name-calling perpetration and victimization at the within-person level. At times when individuals were experiencing higher levels of peer social support , they were also less likely to engage in HP and experience victimization. Contradicting these relationships, the associations between peer social support and both homophobic name-calling perpetration and victimization were not significant at the between-person levels in the peer model, but they became significant and positive when all variables were entered in the competing model. Because homophobic name-calling is inherently social in nature, students who have more peers overall  may be more likely to engage in these behaviors due to having greater opportunities to interact with peers. However, at times when the student has greater social support than what they typically experience, this may still be protective. These findings illustrate the need to disentangle within- and between-person relationships when examining interpersonal factors such as social support from peers.Within the school-domain, school belonging and social support from adults at school were examined as protective factors for homophobic name-calling perpetration and victimization. School belonging was protective for homophobic name-calling perpetration and victimization both within- and between-person levels of analysis. These results support a growing body of evidence suggesting a protective effect of school belonging on several aggressive behaviors . In addiSeveral limitations of this study should be noted. The sample for this study was collected from one U.S. Midwest city, which limits the generalizability of the findings. In addition, all measures were self-report, which could potentially yield biased results. However, all measures used in this study had a high degree of internal consistency and validity. Another limitation is that the study assessed sexual orientation only at Wave 1 because the school district received complaints about this question from parents and only 0.5% of the sample reported identifying as anything other than heterosexual. Finally, the sample used in this study was predominantly White and African American, which limits the generalizability of these findings to students of other races or ethnicities.Despite these limitations, the current study is a significant contribution to the literature on homophobic name-calling and bias-based aggression because it incorporates multiple domains of the social-ecological framework in a longitudinal design and includes both risk and protective factors while at the same time accounting for within- and between-person differences. The results illustrated a complex and comprehensive picture of the lives of youth who participate in these behaviors and provide potential avenues for intervention and further scientific inquiry. Schools with violence prevention efforts must look at the neighborhood domain and the family as key partners and allies for prevention while also paying attention to students’ social emotional competencies to address risk and protective factors at the individual domain. Specifically, prevention programs should target empathy, impulsivity, and aim to reduce the risk factors of social dominance and traditional masculinity through psycho-educational interventions. Another important area of application is increasing school belonging and social support from peers and adults as these domains emerged as protective factors for homophobic name-calling.Due to the evidence in this article, the same construct manifested differently when accounting for intra-individual changes (within-person) rather than just differences between people. Therefore, we recommend future research to employ a similar approach to better understand how homophobic name-calling develops over time. Future research on homophobic name-calling should consider expanding on the gendered nature of this phenomenon by focusing on heteronormative gender roles that promote both homophobic name-calling perpetration and victimization. In addition, future studies should include transgender and other gender nonconforming individuals in their analysis as well as students at the intersections of gender, sexual identity, and race. These types of studies can further our understanding of homophobic name-calling by capturing how students negotiate their marginalized identities in different contexts and how heterosexism, racism, and transphobia influence bias-based aggression, both in-person and online.Click here for additional data file.Supplemental material, sj-docx-1-jea-10.1177_02724316211002271 for Social-Ecological Predictors of Homophobic Name-Calling Perpetration and Victimization Among Early Adolescents by Alberto Valido, Gabriel J. Merrin, Dorothy L. Espelage, Luz E. Robinson, Kyle Nickodem, Katherine M. Ingram, America J. El Sheikh, Cagil Torgal and Javari Fairclough in The Journal of Early AdolescenceClick here for additional data file.Supplemental material, sj-xlsx-2-jea-10.1177_02724316211002271 for Social-Ecological Predictors of Homophobic Name-Calling Perpetration and Victimization Among Early Adolescents by Alberto Valido, Gabriel J. Merrin, Dorothy L. Espelage, Luz E. Robinson, Kyle Nickodem, Katherine M. Ingram, America J. El Sheikh, Cagil Torgal and Javari Fairclough in The Journal of Early Adolescence


Computable models as a fundamental candidate for traditional biological experiments have been applied in inferring lncRNA–disease association (LDA) for many years, without time-consuming and laborious limitations. However, sparsity inherently existing in known heterogeneous bio-data is an obstacle to computable models to improve prediction accuracy further. Therefore, a new computational model composed of multiple mechanisms for lncRNA–disease association (MM-LDA) prediction was proposed, based on the fusion of the graph attention network (GAT) and inductive matrix completion (IMC). MM-LDA has two key steps to improve prediction accuracy: first, a multiple-operator aggregation was designed in the n-heads attention mechanism of the GAT. With this step, features of lncRNA nodes and disease nodes were enhanced. Second, IMC was introduced into the enhanced node features obtained in the first step, and then the LDA network was reconstructed to solve the cold start problem when data deficiency of the entire row or column happened in a known association matrix. Our MM-LDA achieved the following progress: first, using the Adam optimizer that adaptively adjusted the model learning rate could increase the convergent speed and not fall into local optima as well. Second, more excellent predictive ability was achieved against other similar models . Third, a 6.45% lower time cost was consumed against the advanced model GAMCLDA. In short, our MM-LDA achieved a more comprehensive prediction performance in terms of prediction accuracy and time cost. Long non-coding RNA, named for its transcription length of over 200 nucleotides, has received extensive attention from biological researchers . With thAs biological experiments are time-consuming and laborious, numerous computational models are mostly used to replace biological experiments in real life to identify disease-related associations and provide efficient and more accurate candidates for biological experiments in recent years . CurrentThe first category of methods is based on constructing biological similarity networks. Label propagation algorithms are used commonly in association-related prediction , especiaThe second category of methods utilizes machine learning with a classifier to identify pathogenic lncRNAs. The third category of methods is based on disease-related genes, for example, mRNA, miRNA, and protein information. Models belonging to the aforementioned two categories all rely on the known LDA, whose number with experimental verification is relatively small. Therefore, researchers have to explore new ideas to infer the potential associations with using third-party data, also known as genetic information. Utilizing deep learning technology has gradually become a research hotspot to make up for the deficiencies in the abovementioned three categories. The graph that can abstract the relationship between entities is widely used as a data structure . Wu et aKnown lncRNA–disease association: After removing repeated and redundant lncRNAs (diseases) in the original dataset lncRNA disease V2.0 , a proceFor formal description later, the number of lncRNAs and diseases involved in this dataset  was denoted by Disease–disease semantic similarity network: Directed acyclic graph (DAG) was utilized to calculate the semantic similarity between diseases . The semribution , and it If two diseases have more overlaps in DAG, it implies greater similarity between them . MatrixLncRNA–lncRNA functional similarity network: Functionally similar lncRNAs are often associated with diseases in similar phenotypes . To calcMatrix Gaussian interaction spectrum kernel similarity network: As an efficient and useful method in biological information classification, the Gaussian kernel function  has beenSimilarly, matrix Integrated similarity network: Since not all diseases involved could calculate the semantic similarity due to the inherent sparsity in the dataset, an integrated similarity network Similarly, matrix Finally, a multi-source heterogeneous network as a diagonal matrix was constructed, preparing for the following calculation in the model:N-heads attention with multiple-operator aggregation: The original GAT utilizes attention scores to adaptively aggregate information from neighbor nodes during node updating and learns the representation of nodes on the graph by assigning different weights to its neighbor nodes. N-heads attention could stabilize the process of self-attention, with erations . HoweverAttention-based feature training: Any element in the feature vector matrix In order to make the attention score within the interval of , the softmax function was used for normalizationGNN-based feature aggregation: In order to enhance node features further, based on a nonlinear graph neural network (GNN), a multiple-operator that aggregated the features coming from the attention-based feature training layer was designed:via the n-heads attention mechanism formed the final feature matrix Inductive matrix completion: Known LDA was represented as a low-rank matrix in original matrix completion which recovers missing elements only with less sampling data . HoweverModel optimization: Optimization of MM-LDA mainly focused on parameter training by minimizing the loss function. During parameter training, improper selection of learning rates will cause abnormal loss function. A large learning rate will lead to the non-convergence of the loss function. Otherwise, a small learning rate will make the model trap into local optimization. Therefore, the Adam optimizer  that comEvaluation metrics: All known LDAs were randomly divided into five groups with which 5-fold cross-validation was carried out to evaluate the predictive performance of our model. Successively selecting one group in five (as negative samples) with a group of unknown lncRNA–disease pairs in the same size (as negative samples) made up the test samples. The remaining four groups in five and the remaining unknown lncRNA–disease pairs were used to train the model. A total of five model evaluation metrics were defined by setting different thresholds, including true positive rate (TPR), false positive rate (FPR), and recall rate. Model performance was measured by an area under the ROC curve (AUC) and an area under the PR curve (AUPR). In order to avoid the influence of grouping randomly, each experiment was repeated 10 times. Finally, an AUC value and AUPR value were calculated according to the average value of the results from the 10 repeated experiments.Parameter selection: Parameters used in our model could impact the predictive performance in the process of model training. Therefore, this section discussed the selection process of these three parameters in detail.Number of attention heads: According to the literature , the numWeight decay parameter: According to the previous training, with the number of heads in a fixed value of 6 and the number of neurons in fixed value of 8, the influence of the weight decay parameter Number of neurons: With the number of heads in a fixed value of 6 and the weight decay parameter in fixed value of 5E-2, the influence of the number of neurons on predictive performance was discussed by choosing the value within the set of . After implementing 5-fold cross-validation, the results shown in Based on the previously mentioned discussion, by setting the number of heads in a fixed value of 6, the weight decay parameter • GAT-NG: A prediction model was constructed without kernel similarity of the Gaussian interaction spectrum as the kernel part.• GAT-GIMC: A prediction model was constructed only based on a standard multiple-heads graph attention network.• GAT-GMC: A prediction model was constructed only based on standard matrix completion.Ablation experiments: In order to evaluate the role of each kernel part in MM-LDA, such as multiple-operator aggregation in n-heads attention, IMC in lncRNA–disease association reconstruction, three ablation experiments that were used to compare with our MM-LDA were set up:For each ablation experiment, 5-fold cross-validation was repeated 10 times, and the average values of the results are shown in From the results shown, MM-LDA obtained 5.65%, 3.3%, and 3.1% higher AUC values than GAT-NG, GAT-GMC, and GAT-GIMC, respectively. Furthermore, MM-LDA obtained 14.62%, 9.6%, and 13% higher AUPR values than GAT-NG, GAT-GMC, and GAT-GIMC, respectively. Therefore, it proved that the three kernel parts  of MM-LDA could significantly improve the predictive performance.Comparison with other models: SDLDA , DMFLDA From the results shown, we could easily find that MM-LDA obtained the best AUC value that is 5.9%, 6.05%, and 11.05% higher than that of GAMCLDA, SDLDA, and DMFLDA, respectively. In addition, MM-LDA also obtained the best AUPR value that is 2.9%, 32.4%, and 49.5% higher than that of GAMCLDA, SDLDA, and DMFLDA, respectively. Though the running time of MM-LDA is 7.82% and 5.08% longer than that of SDLDA and DMFLDA, MM-LDA achieved the highest cost-effective prediction performance comprehensively.In order to further verify the independent prediction performance of MM-LDA, gastric cancer was selected as the target for the case study. All known associations relating to gastric cancer composed the training set, and unknown associations composed the testing set. Then, gastric cancer-related lncRNAs identified by MM-LDA were sorted by scores. The top 10 lncRNAs with the highest scores were selected to validate the predictive performance of MM-LDA, with the evidence coming from relevant literature and database, as shown in In In this study, a new lncRNA–disease association prediction model, namely, MM-LDA, combining the graph attention network and inductive matrix completion technology was established. MM-LDA designed a multiple-operator aggregation in n-heads attention to enhance the features of nodes. The enhanced features were input into the whole process of induction matrix completion, and the original association matrix was reconstructed by completing the missing elements of the matrix. The results from 5-fold cross-validation showed that MM-LDA obtained the best AUC value and AUPR value compared with the other three state-of-the-art computational models. Comparing with GAMCLDA, 6.45% of training time was saved. In general, MM-LDA deserves to be recommended as the highest cost-effective prediction model. However, there are still some aspects that need to be further improved and studied. First, more biological information relating to lncRNAs and diseases should be effectively integrated. Second, MM-LDA did not predict the associations relating to new lncRNAs and isolated diseases because we could not capture the features of new lncRNAs and isolated diseases without known associations. Third, we should continue to optimize the aggregators by considering the research progress of association prediction in other fields.


Developing clean and renewable ocean wave energy is a top priority and an effective way to achieve carbon neutrality. Triboelectric nanogenerators (TENGs) have emerged as promising green and clean energy-harvesting devices. To harvest low-frequency wave energy efficiently, much effort has been made on the modification of the contact surface, which leads to a higher fabrication cost. In this work, we designed a novel “Lucky-Bag” core (LBC) for spherical TENGs with a low-cost and easy fabricating process. The nanofiber/silicone hybrid porous outer layer of the LBC can switch freely from plane to surface and improve the output performance of both the plane and spherical TENGs. Several factors, such as the input frequency, direction, and resistive load, together with the thickness were systematically investigated; the unique porous soft-contact structure increased the triboelectric contact area, and the working mechanism was studied by using the COMSOL software. The experimental results showed that the peak-to-peak open-circuit voltage (V Harnessing natural forces to provide energy to humans is as old as the first sailing ship, driving people to urgently search for new energy sources in our environment. For decades, renewable and clean energy technologies have provided a rapidly increasing share of the energy used in the whole world. Although solar power, wind power, water power, and other technical fields have seen substantial cost declines, climate change is dramatically impacting the long-term sustainability of these ambient energy collection technologies . The oceSince first being reported in 2012, triboelectric nanogenerators (TENGs) have shown great potential for macro-scale wave energy harvesting with outstanding characteristics, including high energy conversion efficiency, an ultrahigh output voltage, abundant material sources, etc. ,8. AmongTFE ball ,siliconeTFE ball , PDMS baTFE ball  and etc.TFE ball . Wang fiTFE ball . Cheng erability . Brieflyrability ,23. The Among a wide range of triboelectric polymers , silicone rubber and cellulose nanofiber are widely used in high-performance TENGs ,25,26. T surface . The celed TENGs . Additioed TENGs  construced TENGs , such ased TENGs , UV irraed TENGs , nanopared TENGs ,33 etc. Herein, we report a novel “Luck-Bag” prototype of an optimized soft-contact structure driven by a nanofiber-enhanced spherical TENG (NS-TENG). The porous surface uses nanocrystal-cellulose (CNC)-based silicone film and commercial Kapton as the tribo-layers and aluminum foil as the electrodes. The hollow core coating silicone replaces the traditional hard/soft ball with a porous CNC/silicone layer. The porous elastic layer enlarges the contact area and results in a three-times enhancement in the performance. Under the 2 Hz x-y cross-motion triggering, the NS-TENG can deliver a peak power of 9.1 mW and a short-circuit current of 23.5 sciencek.com). The commercial CNCs with a cellulose Ismooth-on.com). The hollow acrylic sphere and Al electrode were bought from a local hardware store. All the other reagents were used as received without treatment.The cellulose nanocrystals were obtained from ScienceK  was added to the silicone bases (Ecoflex/PDMS) using a magnetic stirrer at room temperature. The concentration of CNCs varied from 5 wt% to 20 wt% with an interval of 5 wt%, and obvious agglomeration was observed when the amount of CNCs used was over 15 wt%. Thus, in subsequent experiments, mixtures loaded with 15 wt% of nanocellulose additive were prepared. After being mixed evenly with the curing component, the liquid CNC/polymer precursor was poured into a rectangular groove mold and cured with fine granulated sugar at a ratio of 35:1. Subsequently, we performed a drying procedure in an air-circulating oven at 90 °C for 30 min. This step is conducive to the complete penetration of the PDMS mixture into the gap of the nanoparticlesand fully exhausts the air bubbles. A water bath was then used to remove the sugar template and obtain the rectangular nanofiber-enhanced silicone porous (NSP) film. Finally, the plane TENG was assembled by using a polyimide (PI) film as a collector and copper-plated electrodes on both sides of the printed circuit board sheet as the electrode disks (5 mm in thickness). Two lead wires were connected, respectively, to the two sets of electrodes.The “Luck-Bag” vibration core (LBC) was prepared through a straightforward process by one-step warping of the NSP film, specifically, taking an NSP film and folding the outer layer to the middle in a circle to make a round wrapper. Top with a hollow acrylic ball (6 cm in diameter) of filling, and bring the sides up to cover the filling like a petal around the hollow ball. Tie the open side with a self-locking strip to make a pouch, and seal the hole with liquid silicone via curing progress. Finally, the “Luck-Bag” vibration cores of different coating films were prepared with PDMS, porous PDMS, Ecoflex, and porous Ecoflex, denoted as PDMS@LBC, P-PDMS@LBC, Eco@LBC, and P-Eco@LBC. The spherical TENG was assembled by using a transparent acrylic spherical shell, Kapton film, and an aluminum electrode, as shown in The current, transferred charges, and capacitor voltage were measured by an electrometer (Keithley 6514). The open-circuit voltage was measured using an electrostatic voltmeter (Trek 347). A step motor imposed the displacement with adjustable speed by a pulse drive circuit. A universal material testing machine that uses a stretch control mode with a stretch strain rate of 100% minThe nanofiber-enhanced spherical triboelectric nanogenerator (NS-TENG) consists of a CNC/ecoflex-layer-coated vibration core and two semi-spherical shells with Al electrodes and dielectric Kapton layers on their inner surfaces. As shown in The Fourier transform infrared (FTIR) spectra were used to evaluate changes in the molecular structure and functional groups of the original and the nanofiber-enhanced silicone rubber a. It can to PDMS c. As sho to PDMS d,e, poreAmong various solid point-contact models, the most beneficial way to improve the outputs is typically by increasing the movement displacement and frequency in a single direction ,20. Howe outputs . NotablyThe capacitor-charging characteristics of the NS-TENG were analyzed by using a circuit consisting of a bridge rectifier and various capacitors, as shown in The electric outputs were mainly related to the contact frequency and triboelectric area for the rolling-friction-based TENG. The vital distinction in the contact modes between the NS-TENG and typical TENGs provides insight into the low-frequency output performance. The hard-contact between the core and shell has a high impact force, but the strain of the solid core surface is minor, as shown in In conclusion, we presented a nanofiber-enhanced spherical triboelectric nanogenerator (NS-TENG) with a soft-contact structure, which enlarges the contact area and greatly improves the output performance at a low frequency. A single NS-TENG’s peak-to-peak open-circuit voltage (V