Anthropometric measurements, biochemical markers, and miRNA profiles were assessed. The first indication of a relationship between urinary AGEs and c-miRNAs in the context of obesity was found. Specifically, four miRNAs, hsa-miR-10b-5p, hsa-miR-501-5p, hsa-miR-874-3p, and hsa-miR-2355-5p were significantly associated with levels of urinary AGEs. The association between AGEs, obesity, inflammation markers, and specific miRNAs highlights the complex interplay between these factors and their potential impact on cellular and tissue homeostasis. The discovery of altered c-miRNAs profiling has the potential to offer innovative methods for assessing early changes in the body’s AGE pool and allow recognition of an increased risk of disease susceptibility, routinely undetected until metabolic complications are identified.Modern dietary habits are linked to high exposure to Advanced Glycation End products (AGEs) mainly due to the dramatic increase in the consumption of highly processed foods in recent years. Body levels of these compounds vary with food intake and are almost interconnected with age and health status, formally embodying indicators of oxidative stress and inflammation in adults. However, the relationship between AGEs and health issues has not been definitively understood in children, and several pediatric investigations have produced conflicting evidence. Besides, despite extensive research, there are no universally accepted analytical techniques for measuring AGE levels in the human body, with several approaches available, each with its advantages and disadvantages. This pilot study aimed to investigate the association between urinary AGEs, measured using spectrofluorimetry-based assays, and circulating microRNAs (c-miRNAs) in a subsample ( The reaction between the free amine groups of proteins, lipids or nucleic acids and the carbonyl group of reducing sugars generates a variety of biochemical substances known as AGEs (Advanced Glycation End products). AGEs can be derived exogenously from diet or generated endogenously in the body. The formation of dietary AGEs (dAGEs) is the consequence of a series of multistep nonenzymatic reactions first described by Louis Camille Maillard in 1912 . RemarkaDespite extensive investigation linking AGEs to a wide range of clinical conditions, there are no universally accepted analytical techniques for measuring their levels in the human body; several approaches are available, each with its benefits and drawbacks . As wellMicroRNAs (miRNAs) are small noncoding RNAs with a length of 20–24 nucleotides that control gene expression post-transcriptionally . A uniquIn previous studies, we recognized specific c-miRNAs associated with obesity in a subsample of the I.Family study , among wThe study was conducted on an Italian subgroup of children/adolescents belonging to the I.Family study, an EC-funded project aiming at investigating determinants of food choice, lifestyle, and related health outcomes in European children and adolescents. A comprehensive description of the I.Family study (registration number ISRCTN62310987) has been published earlier . The stu2). Age- and sex-specific BMI z-scores were calculated according to Cole and Lobstein [A detailed description of the anthropometric measurements in the I.Family project, including intra- and inter-observer reliability, has been published elsewhere . BrieflyLobstein .® blood tubes. An earlier publication provided a thorough explanation of the sample collection and biochemical analysis methods [® Assay Systems, Meso Scale Discovery, Rockville, MD, USA).According to standard protocols, the fasting venous blood samples were collected in BD Vacutainer methods . ChemicaTaking advantage of the qPCR array technology, we previously determined c-miRNA profiles in children and adolescents of the I.Family study . MethodsChildren and adolescents collected the morning urine samples at home and brought them to the study center the same day. Parents were instructed to preserve the sample in the refrigerator at home if the time interval between collection and delivery exceeded two hours. At the study center, urine samples were stored at −80 °C on the same day of collection. A Perkin Elmer Life-Sciences LS 55 spectrofluorimeter was used to measure the urinary fluorescent AGEs. Fluorescence spectra were captured between 400 nm and 600 nm, upon excitation at 370 nm, at room temperature, using urine samples diluted 1:10 in phosphate-buffered saline [Statistical analyses were achieved by using IBM SPSS Statistics software . Analyses were performed separately for NW and OW/Ob subjects. Data collected were calculated as means and 95% confidence intervals (CIs). Associations of miRNA expression with urinary AGEs were assessed using linear regression analyses through two different models. Generated models were adjusted for covariates including age, sex, BMI z-score (model I), and covariates of the model I + hs-CRP (model II). The Benjamini–Hochberg (BH) procedure was adopted to control the false discovery rate (FDR). The level of statistical significance was set at α < 0.05.n = 10) and OW/Ob (n = 12), are reported in The anthropometric and biochemical markers of the 22 participants, divided into NW (In the current study, after plasma extraction, the candidate miRNAs were determined in individual assays by RT-qPCR. Differences in miRNA signatures with respect to anthropometric and biochemical variables were analyzed separately in NW and OW/Ob children/adolescents. Results reported in Modern dietary habits are connected with high exposure to AGEs since the consumption of high-processed foods as well as sugars and fats has dramatically risen over the past years. According to a large body of evidence, levels of these compounds in plasma, urine, and saliva vary with food intake and are nearly interconnected with age and health issues, formally embodying indicators of oxidative stress and inflammation. The relationship between AGEs, inflammation, and health status is not definitively understood in children, and various pediatric investigations have produced contradictory data. In a recent paper, we demonstrated that AGEs-linked urinary fluorescence is positively associated with markers of sub-clinical inflammation as well as C-reactive protein level in an Italian population of otherwise healthy children and adolescents , confirmIn previous studies, we showed characteristic c-miRNA profiles associated with health status in a cohort of children and adolescents of the I.Family study . In the This pilot study has some strengths and limitations. First, the main strength is the fact that this is the first research linking c-miRNAs with urinary AGE levels in healthy young people for potential biomedical applications, whereas to date only a limited number of studies have been directed at identifying miRNAs altered by AGE stimulation in cellular and animal models ,46. Of nThe contribution of AGEs to the inflammatory state and the pathogenesis of many diseases has traditionally been documented in chronic age-related inflammatory disorders . In this


Prevalence of dementia illness, causing certain morbidity and mortality globally, places burden on global public health. This study primary goal was to assess future risks of dying from severe dementia, given specific return period, within selected group of regions or nations.Traditional statistical approaches do not have benefits of effectively handling large regional dimensionality, along with nonlinear cross-correlations between various regional observations. In order to produce reliable long-term projections of excessive dementia death rate risks, this study advocates novel bio-system reliability technique, that being particularly suited for multi-regional environmental, biological, and health systems.Raw clinical data has been used as an input to the suggested population-based, bio-statistical technique using data from medical surveys and several centers.Novel spatiotemporal health system reliability methodology has been developed and applied to dementia death rates raw clinical data. Suggested methodology shown to be capable of dealing efficiently with spatiotemporal clinical observations of multi-regional nature. Accurate disease risks multi-regional spatiotemporal prediction being done, relevant confidence intervals have been presented as well.Based on available clinical survey dataset, the proposed approach may be applied in a variety of clinical public health applications. Confidence bands, given for predicted dementia-associated death rate levels with return periods of interest, have been reasonably narrow, indicating practical values of advocated prognostics. ▪ Novel spatiotemporal health system reliability methodology has been developed and applied to dementia death rates raw clinical data.▪ Accurate disease risks multi-regional spatiotemporal prediction being done.▪ Confidence bands given for predicted dementia-associated death rate levels with return periods of interest. To contribute further dementia prognostic research, authors of this study have developed novel bio-reliability technique, suitable for bio and health systems, enabling accurate future risks forecast. Naturally, the entire world’ s countries were selected, due to availability of online health observations and associated research.WHO  estimates that the number of individuals with dementia worldwide being approximately 55 million, and this number expected to reach about 80 million by 2030 and 140 million by 2050 . In geneEVT  or and statistical lifespan data modeling being widely used in bio-engineering, public health and medicine. There have been numerous recent publications supporting and criticizing upper boundaries distribution of life expectancy , 21. ForFor general reliability studies, not necessarily limited to bio and public health systems –29. In –32 authohttps://ourworldindata.org/causes-of-death). The bio-system under examination here can be thought of as a multi-degree of freedom (MDOF) dynamic bio-system, with highly inter-correlated regional components/dimensions.Clinical incidence data for dementia in 195 global nations between 1990 and 2019 has been obtained from a public source,  dynamic bio-system, consisting of its critical system components mentclass2pt{minimNow the non-decreasing synthetic vector troduced –45.In both neurology and mathematical biology, the focus has been on the prediction of dementia-like conditions. Public health dynamics being well-known for its highly non-linear, multidimensional, spatially cross-correlated dynamic bio-system properties, that being challenging to analyse. Different methods have been used in earlier research to mimic dementia death rates. This section uses a novel approach to raw clinical dementia datasets, given as annually recorded time-series for all nations in the world to demonstrate the effectiveness of the aforementioned methodology .https://ourworldindata.org/causes-of-death). This website contains data on dementia death rates worldwide from 1990 to 2020. The component was the number of patients who died in 195 different nations throughout the world, with The strategy mentioned above being illustrated in practice in this section. The present section's statistics information was obtained from the public website, , originated from well-known Poincare plot. SODP provides an efficient QC  tool for the underlying dataset pattern and quality, based on consecutive differences within time series dataset.The 2nd-order SODP plot, based on dementia death-rate global statistics, (https://ourworldindata.org/causes-of-death). These plots are often used to identify dataset patterns and compare them with other datasets, especially when using an artificial intelligence (AI) identification method, based on entropy [Figure  entropy . For rev entropy –63. NoteTraditional biological and public health systems reliability techniques, dealing with observed raw clinical time series, do not always cope easily with bio-system’s high-dimensionality, along with nonlinear cross-correlations between different bio-system responses. The key advantage of the presented technique being its ability to analyze bio-reliability of high-dimensional nonlinear dynamic public health systems.Current study proposes novel multidimensional spatiotemporal modeling technique, and a methodological route to execute forecasting of dementia death rates. It has been explored how to set health system hazard or failure limits appropriately for each nation of interest. This study examined global death rates from dementia, reported across all nations, representing an example of a 195-dimensional (195D) bio-system, observed during three decades 1990—2020. Annual dementia-related death rates constituted multidimensional bio-system’s dynamics in real-time, and has been studied, using the novel reliability approach. The detailed theoretical justification for the suggested strategy has been provided. It should be noted that while use of either direct measurements or Monte Carlo simulations for dynamic biological or public health system’s reliability analysis being appealing, the complexity of bio-system, along with its high dimensionality necessitate development of new, accurate, yet robust techniques, that can handle limited amount of raw clinical data, and make optimal best use of what being already available. The major takeaway being that global public health bio-system being well-managed, generally speaking, if excluding countries like South Korea with alarming dementia growth rates. This study estimated all age categories risk level of 0.032% for the yearly death rate during up to 100-year return period. For ages over 65 years, dementia still poses a potential threat to global health under the current framework for national/regional health management.A general-purpose, reliable, and simple multidimensional reliability approach was the main goal of this work. The approach described in this study has been previously confirmed by application to a broad variety of simulation models, but only for one-dimensional system responses, and, generally speaking, extremely accurate predictions were achieved. Time series responses can be measured and numerically simulated and analysed. The proposed strategy yielded reasonably narrow confidence intervals, as was demonstrated. As a result, the recommended technique may be useful for a range of reliability investigations on non-linear dynamic biological and public health bio-systems. When addressing relevant age and gender dependencies, prognostics methodology, advocated in this study has wide applicability range, meaning that any specific age ang gender group can be well studied, using advocated methodology. As mentioned, the recommended technique has a wide range of potential applications in public health, thus by no means does the provided dementia example restrict the potential applications of new methodology.


Background: Long non-coding RNAs (lncRNAs) play an important role in the immune regulation of gastric cancer (GC). However, the clinical application value of immune-related lncRNAs has not been fully developed. It is of great significance to overcome the challenges of prognostic prediction and classification of gastric cancer patients based on the current study.Methods: In this study, the R package ImmLnc was used to obtain immune-related lncRNAs of The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) project, and univariate Cox regression analysis was performed to find prognostic immune-related lncRNAs. A total of 117 combinations based on 10 algorithms were integrated to determine the immune-related lncRNA prognostic model (ILPM). According to the ILPM, the least absolute shrinkage and selection operator (LASSO) regression was employed to find the major lncRNAs and develop the risk model. ssGSEA, CIBERSORT algorithm, the R package maftools, pRRophetic, and clusterProfiler were employed for measuring the proportion of immune cells among risk groups, genomic mutation difference, drug sensitivity analysis, and pathway enrichment score.Results: A total of 321 immune-related lncRNAs were found, and there were 26 prognostic immune-related lncRNAs. According to the ILPM, 18 of 26 lncRNAs were selected and the risk score (RS) developed by the 18-lncRNA signature had good strength in the TCGA training set and Gene Expression Omnibus (GEO) validation datasets. Patients were divided into high- and low-risk groups according to the median RS, and the low-risk group had a better prognosis, tumor immune microenvironment, and tumor signature enrichment score and a higher metabolism, frequency of genomic mutations, proportion of immune cell infiltration, and antitumor drug resistance. Furthermore, 86 differentially expressed genes (DEGs) between high- and low-risk groups were mainly enriched in immune-related pathways.Conclusion: The ILPM developed based on 26 prognostic immune-related lncRNAs can help in predicting the prognosis of patients suffering from gastric cancer. Precision medicine can be effectively carried out by dividing patients into high- and low-risk groups according to the RS. Helicobacter pylori (Gastric cancer (GC) is a common tumor of the gastric mucosa. In 2020, GC ranked fifth and fourth in terms of cancer incidence and mortality worldwide, respectively . Nearly r pylori . Currentr pylori . The Amer pylori . Recentlr pylori . Programr pylori . Hence, GC is a disease with high heterogeneity between and within tumors. How to find the ideal biomarker is a question worthy of study. Therefore, a multigene panel, especially messenger RNAs (mRNAs) or microRNAs (miRNAs), based on microarray and RNA‐seq databases such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), was used to develop a prognostic gene signature by bioinformatics technology . HoweverIn this study, we obtained immune-related lncRNAs for gastric cancer based on the ImmLnc method and integrated multiple machine learning algorithms to construct a prognostic model for gastric cancer patients. The prognostic model outperformed other clinical features in both the training and validation sets. Patient subtypes based on prognostic risk scores differ in a variety of characteristics, including immune cell infiltration, drug sensitivity, and mutational characteristics. This study may help in improving the clinical prognosis and precise treatment of gastric cancer patients.via the R package Affy. We used the following steps for processing: 1) the samples without clinical data were removed; 2) the samples with no survival time, less than 0 days, or no survival status were removed; 3) the probe name was converted to the gene name; 4) the samples with multiple genes corresponding to one probe were removed; and 5) the mean value of multiple identical gene expression values was taken as the expression value of the gene. Following the gene annotations from the GENECODE , 17,450 protein-coding genes and 15,900 lncRNAs were included in the TCGA-STAD. Meanwhile, the gene symbols of GPL570 have annotated 17,912 protein-coding genes and 2415 lncRNAs.Here, we downloaded the RNA-seq raw read count, mutation data, and clinical data on stomach adenocarcinoma (STAD) from The Cancer Genome Atlas (TCGA) database. The read count was converted to transcripts per kilobase million (TPM) using the R package GenomicFeatures and further log-2 conversion. We kept the clinical information on age, grade, pathologic M stage, pathologic N stage, pathologic T stage, gender, and AJCC stage. Only samples with clinical information were retained. At the same time, microarray expression profile data and clinical information for two additional gastric cancer datasets GSE57303 and GSE62254 were all extracted from the Affymetrix GPL570 platform (Human Genome U133 Plus 2.0 Array) and were downloaded from the Gene Expression Omnibus (GEO) database. The raw data (.cel files) on GSE57303 and GSE62254 were processed by the robust multi-array average (RMA) algorithm p < 0.05) prognostic immune-related lncRNAs for prognosis.ImmLnc was used in this study as an effective algorithm to identify immune-related lncRNAs based on immune-related pathways. The basic idea of the algorithm is as follows: 1) tumor purity was evaluated by the ESTIMATE algorithm; 2) partial correlation coefficients of mRNAs and lncRNAs were calculated by removing the influence of tumor purity; and 3) all mRNAs associated with a specific lncRNA were ranked according to the correlation coefficient, and the sorted gene list was analyzed for gene set enrichment analysis (GSEA). A default threshold of lncRES scores >0.995 and FDR <0.05 was used to screen immune-related lncRNAs. Based on immune-related lncRNAs, we carried out a univariate Cox regression analysis of immune-related lncRNAs with the coxph function of R package survival to find Here, we integrate 117 algorithm combinations from 10 machine learning algorithms to develop an ILPM with high accuracy and robust performance. The 10 algorithms are random survival forest (RSF), elastic network (Enet), Lasso, Ridge, stepwise Cox, CoxBoost, partial least squares regression for Cox (plsRcox), supervised principal components (SuperPC), generalized boosted regression modeling (GBM), and survival support vector machine , respectively. After that, the 117 algorithm combinations were performed in the training dataset (TCGA-STAD) and two validation datasets (GSE57303 and GSE62254). In every model, Harrell’s concordance index (C-index) was calculated both in the training and validation datasets. We selected the model with the highest average C-index as the ILPM. The risk score of each gastric cancer sample was obtained by the ILPM, and the samples were divided into high- and low-risk groups according to the median.The CIBERSORT algorithm of the R package IOBR was used according to the expression profile of the TCGA-STAD dataset for measuring the proportion of immune infiltrating cells. The CIBERSORT algorithm is a method used to characterize the composition of cells based on the gene expression profile of complex tissues. We used the leukocyte characteristic gene matrix LM22 composed of 547 genes to differentiate 22 immune cell types, including myeloid subsets, plasma cells, naive and memory B cells, natural killer (NK) cells, and seven T-cell types. CIBERSORT, in combination with the LM22 characteristic matrix, was employed for estimating the proportion of 22 cell phenotypes in the sample. The sum of the proportions of all immune cell types in each sample was equal to 1. Meanwhile, the single-sample gene set enrichment analysis (ssGSEA) algorithm of the R package GSVA was employed for computing the 28 immune cells in the TCGA-STAD dataset.50 value) of 138 medications in the Genomics of Drug Sensitivity in Cancer (GDSC) database. The IC50 value was used to determine how sensitive lung adenocarcinoma patients were to medication treatment. The Wilcoxon test examined the variations in IC50 values between high- and low-risk groups, and medications with significant variations between the two groups were discovered.A waterfall diagram was drawn using the R Package maftools to depict the variation distribution of genes between high- and low-risk groups. The R package pRRophetic and model gene expression data were employed to predict the sensitivity  between high- and low-risk groups were used for further study. Gene Ontology (GO) analysis is a common method for large-scale functional enrichment studies, including biological process (BP), molecular function (MF), and cellular component (CC). The Kyoto Encyclopedia of Genes and Genomes (KEGG) is a widely used database of information about genomes, biological pathways, diseases, and drugs. We used the R package clusterProfiler for GO annotation analysis of DEGs. The entry screening criteria included a p-value of <0.05, and the FDR value (q.vue) < 0.25 was considered statistically significant; p-values were corrected by the Benjamini–Hochberg (BH) method. Gene set enrichment analysis (GSEA) is a computational method to analyze whether a particular gene set is statistically different between two biological states. It is commonly used to estimate changes in the pathway and biological process activities in expression dataset samples. In this study, the clusterProfiler package was used for the enrichment analysis of DEGs. The parameters used in the GSEA were as follows: the number of genes contained in each gene set was at least 10, and the number of genes contained in each gene set was at most 500. The p-value correction method used was the Benjamini–Hochberg (BH) method. Downloaded from MSigDB database. The “c2. Cp. Kegg. 7.5.1. Symbols. gmt” and “c5. Go. 7.5.1. Symbols. gmt” were downloaded from MSigDB database as a reference gene set.Differentially expressed genes (DEGs)  is a non-parametric unsupervised analytical method, which is mainly evaluated by transforming the expression matrix of genes among different samples into the expression matrix of genes among samples. Transcriptome gene set enrichment results were analyzed to assess whether different metabolic pathways are enriched between different samples. To study the biological process variation between high- and low-risk groups, we used the R package “GSVA” to conduct gene set variation analysis based on the TCGA-STAD gene expression profile dataset. The reference gene set “h.all.v2022.1. Hs.symbols.gmt” which downloaded from MSigDB database was used to compute dataset every sample enrichment of reference genes in each set of scores, GSVA scores between high- and low-risk group, and p ≤ 0.05, * indicates p ≤ 0.05, ** indicates p ≤ 0.01, *** indicates p ≤ 0.001, and ****indicates p ≤ 0.0001. Among them, p < 0.05 was significant, and the difference was statistically significant. The receiver operating characteristic curve (ROC) was implemented via the pROC package. The time-dependent area under the ROC curve (AUC) for survival variables was proved by the timeROC package. The Kaplan–Meier survival analysis and univariate and multivariate analyses with Cox proportional hazard regression for overall survival (OS) and disease-free survival (DFS) were carried out using R packages survivalROC and survminer. All the statistical analyses were performed in R 4.1.1 software.The Wilcoxon test was used in significance labeling for comparing the differences between the two groups of samples, and the Kruskal–Wallis test helped in comparing the differences between multiple groups of samples. Here, ns indicates The workflow of this study is shown in p-value of MIR181A2HG is the smallest, indicating that it has the best prediction effect. The MIR181A2HG gene is a member of the MIR181A2 host gene, which is located in the nucleus and expressed in most tissues of the human body  for each patient was calculated based on the Lasso algorithm for 18 lncRNA coefficients. All patients were divided into high- and low-risk groups according to the optimal cut-off value defined in the R package survminer. Afterward, we assessed the impact of the model scores developed by the 18 lncRNA signatures on the overall survival of the training dataset. The outcomes are illustrated in p < 0.0001, showing that there were major variations in the prognosis of the two groups. According to the developed ILPM, the ROC curve of the prognostic signature was drawn, as illustrated in First of all, according to the expression profile data on the 321 immune-related lncRNAs from TCGA-STAD, we identified 26 prognostic lncRNAs by the univariate Cox regression analysis . Then, wman body . As an i limited , so MIR1p < 0.05) to predict patient prognosis and found that the combined model could better predict the prognosis , tumor metabolism, and the tumor itself, which were collected by the R package IOBR. Of the 114 metabolism signatures collected, 64  were sigImmune cells were the key categories of non-tumor components in the tumor microenvironment, and they had been postulated to be useful for tumor diagnosis and evaluating the prognosis. In this study, according to the signature genes of 28 immune cells, we calculated the percentage of infiltrated immune cells based on ssGSEA. Between the high- and low-risk groups, 16 of the 28 immune cells were significant differences , for exa50 value of 138 drugs in the Genomics of Drug Sensitivity in Cancer (GDSC) database was predicted, of which 18 drugs had significant differences between high-risk and low-risk groups, which is displayed in According to the expression profile data from TCGA-STAD, the sensitivity ICHere, we performed differential expression analysis to identify differentially expressed genes between high- and low-risk groups. For comparison, according to RS, there were 53 upregulated and 33 downregulated genes in the high-risk group. Heatmaps showed 86 DEGs between high- and low-risk groups , and thep < 0.05)  .Due to the high incidence of gastric cancer, there is an urgent need to identify effective biomarkers to predict patient prognosis . The traBased on this, we integrated prognostic immune-related lncRNAs to construct a prediction model to predict the prognosis of patients and conduct a classification study of patients. The ImmLnc algorithm was applied to identify immune-related lncRNAs. According to the lncRNA expression profile of the TCGA-STAD training dataset, 117 combinations were developed by 10 machine learning algorithms. Further evaluation in two GEO datasets indicated that the ILPM, the optimal model, was the combination of stepwise Cox regression (direction = forward). In terms of predicting OS, the ILPM showed good performance in both TCGA and GEO datasets. In different datasets, the ROC AUC and C-index values were higher in terms of RS, according to the ILPM, compared with other clinical variables , which revealed good potential clinical application value. The IPLM enables us to make more accurate predictions and classifications of patients’ prognoses, which is of great significance in clinical application and solves the problem that traditional classification cannot distinguish patients with the same AJCC stage. Compared with the existing prediction models, such as those by Afterward, all patients with RS were calculated based on the ILPM, and according to the median of RS, all patients were divided into high- and low-risk groups. Patients in the high-risk group had a worse prognosis and a lower percentage of immune cell infiltration, which is consistent with previous studies showing that cancer cells evade the immune system by having a smaller percentage of immune cells. However, the frequency of mutations was lower in high-risk patients, and in general, the frequency of mutations was higher in patients with poor prognoses, suggesting that our classification is not suitable for studies that predict immunotherapy response based on tumor mutational burden (TMB) . On the At the same time, patients in the high-risk group were more sensitive to 18 GDSC drugs . These drugs fight tumors in different ways, for example, ABT.263 (navitoclax), AG.014699 (rucaparib), AMG 706 (motesanib), AP.24534 (ponatinib), AZD.0530 (saracatinib), BX-795, CCT007093, elesclomol, IPA.3, Nutlin-3a (rebemadlin), Osi-906 (linsitinib), Pd-0332991, and Vx-702 were acting as inhibitors of different signaling pathways to fight tumors. In particular, AG.014699 and AZD.0530 were first-generation inhibitors , and AP.Our analysis of DEG enrichment between the high- and low-risk groups found that DEGs are mainly enriched in certain parts, like the immune response-regulating cell surface receptor signaling pathway, immune response-activating cell surface receptor signaling pathway, immunoglobulin receptor binding, and other immune-related pathways. Descriptions of the differences between the high- and low-risk groups of patients are mainly based on the regulation of immune-related pathways, and these pathways affect the patient’s immune cells and tumor immune microenvironment. High- and low-risk groups of TME verified the results, and the numerous differences between the 50 cancer-related hallmark pathway GSVAs were further highlighted.In conclusion, based on immune-related lncRNAs, signatures constructed by a variety of machine learning algorithms have effective and stable efficacy in prognostic prediction and classification of patients, the ILPM is an effective and convenient tool for personalized treatment and the clinical diagnosis of GC patients.


Plants synthesize volatile organic compounds (VOCs) that function as signaling molecules. These VOCs are essential in plant defense against herbivores and insects and play a vital role in plant interaction with biotic and abiotic elements in the environment. Moreover, the composition of VOCs of consumable fruits and grains defines aroma and flavor, thereby considerably deciding consumers’ preferences towards them. In general, the set of biosynthesized volatiles is called volatilome, and analysis of such volatilomes using gas chromatography-mass spectrometry (GC-MS)-based targeted and untargeted approaches is usually referred to as volatilomics. The field of volatilomics is continuously growing and evolving with rapid development in analytical and data processing methods. Hence, capturing recent advances and applications in volatilomics is becoming valuable in advancing interdisciplinary research in plant sciences. The goal of this Research Topic was to collect recent research highlights about the application of volatilomics, both targeted and untargeted in different research areas of plant and agricultural sciences. Under this Research Topic, seven research articles are published that highlight the recent applications of GC-MS-based volatilomics in screening breeding lines/cultivars, understanding the effect of growing conditions on aroma-based fruit quality to optimize quality preferences and unraveling volatiles-based plant-plant communication, including the potential of volatilomics in identifying novel antibacterial and insect repellent volatile compounds.Jo et al. used a GC-MS-based untargeted volatilomics approach to differentiate 20 representative cucumber lines from various geographical locations such as Korea, Europe, and Thailand. In this study, authors demonstrated that the analysis of volatiles from the flesh of cucumber breeding lines provides a more distinct metabolite pattern than that obtained from the peel of these lines. In addition, it was shown that key cucumber VOCs such as 2-hexenal, 2,4-nonadienal, and 2,6-nonadienal are relatively low in Korean cucumber lines which makes them less flavor intense. Similarly, Deng et al. used an optimized GC-MS headspace method for leaf volatilome fingerprinting of 42 citrus cultivars and showed the utility of the volatilomics tool in citrus species identification, including chemotaxonomic studies. The key VOCs that contributed to distinguishing these citrus cultivars include thymol derivatives , which are usually involved in defense response. Moreover, it was reported that (Z)-3-hexen-1-ol contributing to green aroma had a role in distinguishing orange and mandarian groups of citrus cultivars. Quan et al. employed two-dimensional gas chromatography quadrupole time of flight mass spectrometry (GC×GC-QTOF-MS) to investigate the volatilomes of four cultivars of Chinese rose. Analysis of a total of 122 volatiles showed significant quantitative variation of VOCs among the different cultivars. Rosa Crimson Glory contained high concentrations of phenyl acetate, rose oxide, trans-rose oxide, phenylethyl alcohol, and 1,3,5-trimethoxybenzene, which are all described as flowery and rose-like descriptors. Ros Blue River and Rosa Funkuhr both had significant amounts of 3,5-dimethoxytoluene and phenylethyl alcohol, respectively.Rapid screening of breeding lines/cultivars is crucial for accelerating breeding programs, including efficient selection of genotypes with desired quality traits such as aroma. Volatilomics is found to be valuable in the rapid characterization of genotypes based on the composition of VOCs. E)-2-hexanal contribute to a fresh aroma, which decreases during ripening. Although the aroma is genotype-dependent, the perceived aroma of agricultural products is strongly affected by growing and environmental conditions  in improving fruit quality. The authors demonstrated that drainage ratios could improve fruit quality by minimizing the accumulation of VOCs linked to over-ripening such as hexanal and ethyl hexanoate.Aroma-active VOCs are used in defining fruit quality. For example, in strawberries, furanones contribute to a sweet aroma that increases during ripening, while aldehydes such as hexanal and  on maize growth and reproduction. The study showed that defensive responses in maize leaves against herbivores such as common armyworms were induced due to the exposure to weed volatiles. Moreover, maize seedlings exposed to goldenrod-specific or mixed volatiles produced more leaves and tillers than control plants. Interestingly, maize seedlings treated with volatiles generated from the damaged weeds increased the number of female ears and sugar content in kernels. The study also observed an elevated salicylic acid content in seedlings upon volatiles exposure.It is known that VOCs mediate plant-plant as well as plant-pathogen and -herbivore interactions. Research interest in understanding the role of VOCs in plant-plant “communication” and the perception of volatiles has increased substantially . SakuraiPatel et al. demonstrated antibacterial  and insect (bed bug) repellent activities of essential oils from novel cultivars of catnip (Nepeta cataria L. cv. CR9) and oregano (Origanum vulgare L. cv. Pierre) that are rich in the terpenes nepetalactone and carvacrol, respectively. Similarly, Gomes et al. studied the effect of successive harvesting on the essential oil composition of catnip cultivars using GC-MS. It was found that agronomic practices can significantly affect the accumulation of VOCs, mainly arthropod-repellent iridoid terpenes, in catnip genotypes. In a nutshell, these articles highlight the significance of volatilomics in developing novel plant-based antibacterial and insect repellents for agricultural pest and pathogen management.Plant essential oils that contain complex mixtures of low-molecular-weight, highly volatile compounds have been proven to be promising biopesticides . AnalysiDK: Writing – original draft, Writing – review & editing. JL: Writing – review & editing. NS: Writing – review & editing.


In 2015, a series of randomized trials led to the widespread acceptance of mechanical thrombectomy (MT) as a treatment for patients with acute ischemic stroke. Particularly, MT for large vessel occlusion (LVO) under specific pre-treatment conditions is now considered the standard of care  is one of the actively discussed conditions. Reports indicate that ICAD accounts for 6%  to 29.6%The challenges in treating ICAD-related LVO are 2-fold. Firstly, diagnosing ICAD based on the initial imaging is often technically impossible due to the lack of contrast filling in the target lesion. As a result, interventionalists need to make a decision once partial recanalization of the target lesion is achieved although differentiating between ICAD-related occlusion and occlusion caused by hard clot or arterial dissection can also be challenging. Secondly, ICAD-related occlusions are known to be associated with a higher rate of post-treatment re-occlusion . TherefoNumerous non-controlled studies have been conducted to address these issues; however, the optimal timing to shift from MT to PTA/PTAS during the procedure remains unclear. The number of thrombectomy attempts made can provide more convincing evidence of unsuccessful reperfusion/underlying ICAD, but it also raises concerns about intimal damage due to endothelial denudation, vessel perforations or stretching/torsions.Deng et al. conducted a retrospective subgroup analysis of the Angel-ACT registry to evaluate the efficacy and safety of PTAS for ICAD-related acute LVO. Of the 1,793 patients enrolled in the Angel-ACT group, 475 patients who met the inclusion criteria were included in the study. The patients were divided into three groups based on treatment methods: (1) Early Rescue Therapy Group: Patients underwent PTA/PTAS after one or no MT attempt, (2) No Rescue Therapy Group: Patients treated only with MT, and (3) Late Rescue Therapy Group: Patients underwent PTA/PTAS after two or more MT attempts.In this Research Topic of Frontiers of Neurology, p = 0.01] or Late Rescue Therapy group . There was no difference in the risk of symptomatic intracranial hemorrhage between the groups.After propensity score matching, the Early Rescue Therapy group showed better functional outcomes (mRS 0–1) at 90 days compared to the No Rescue Therapy group [adjusted odds ratio (aOR), 0.55, The authors concluded that once ICAD-related LVO is suspected, early decision-making to perform rescue therapy improves the efficacy of treatment without increasing the risk of post-procedural complications. The relatively poor clinical outcome in the Late Rescue Therapy group, which underwent MT attempts of twice or greater before transitioning to PTA/PTAS, was accounted for by (1) the lower reperfusion rate that can lead to prolonged procedure time and (2) more intimal damage causing vasospasm and intraluminal thrombosis.This article provides a valuable contribution to the field of neuro-interventional practice by addressing another predicament that interventionalists have to face from time to time. The study provided another evidence that early decision making of shifting the procedure from simple MT to the rescue therapy improves the treatment outcomes of patient with ICAD-related-LVO.The results above is also consistent with a recently performed large-scale study, the SAINT (Stenting and Angioplasty in Neurothrombectomy) study, which is a multicenter retrospective study evaluating the efficacy of rescue intracranial stenting for failed thrombectomy .Cai et al., the article is titled “Rescue intracranial stenting for acute ischemic stroke after mechanical thrombectomy failure: a systematic review, meta-analysis, and trial sequential analysis.” The authors conducted a meta-analysis and trial sequential analysis of 15 clinical studies  evaluating the efficacy and safety of rescue stenting for the failed MT. Compared to non-stenting approaches, rescue stenting was associated with better modified Rankin Scale (mRS) scores (0–2), a lower 90-day mortality rate, without increasing the risk of symptomatic intracranial hemorrhage. The trial sequential analysis also confirmed sufficient sample size and statistical power of the meta-analysis concerning mRS scores. Authors concluded that the study supported the use of rescue stenting as an effective and safe treatment for patients with acute ischemic stroke after a failed MT.In our Research Topic, there is another article that delves into the same subject. Authored by As we witness the growing body of positive clinical data regarding the effectiveness of rescue therapy for IACD-related-LVO, it is logical to consider a randomized clinical trial (RCT) as the subsequent phase to gain more clarity on the treatment's clinical advantages. Nevertheless, it is important to exercise caution due to the historical track record of PTA/PTAS for “symptomatic ICAD”, which has been discouraging , 6. ReceThe overall efficacy of rescue therapy for failed thrombectomy cases has been improving over the past several years, partially due to the improvement of the peri-procedural antiplatelet therapy. For instance, an increasing number of studies have reported the benefits of utilizing intra-arterial (IA) injection of short-acting IIb/IIIa inhibitors, such as Tirofiban, as a rescue treatment for failed thrombectomy . FurtherCurrently, there are ongoing developments for the ICAD treatment with the introduction of new-generation endovascular stents specifically designed for this condition, including drug-eluting stent systems. Encouraging results have emerged from several clinical studies conducted in China . On the IY: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing—original draft, Writing—review and editing. JC: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing—review and editing.


Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral abnormalities accompanied by impairments in various personality domains. AD has an intricate pathophysiology that is believed to be initiated by oxidative stress, leading to the deposition of amyloid-β (Aβ), tau hyperphosphorylation, neuroinflammation, and neurodegeneration  are interconnected through intracellular and extracellular loops  , which serves as the rate-limiting enzyme for converting the amino acid tyrosine into dopamine  , the mesocorticolimbic (MCL), and the tuberoinfundibular. While the role of dopaminergic modulation in cognition is not fully understood, dopamine in the striatum, midbrain, limbic system, and PFC is believed to be involved in memory and cognition through the NS and MCL pathways , a prototype of a non-specific DAT inhibitor that also acts on NET and serotonin transporter in the striatum  modafinil analogs. Although both amphetamine and methamphetamine are non-specific, having more affinity NET receptors, they are potent inhibitors of DAT methyl)thiazole), S,S-CE158 (5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole), and S-MK-26 ((S)-5-(((B(3-chlorophenyl)methyl)sulphinyl)methyl)thiazole) do not exert any effect on the reward pathway, making them less likely to cause addiction, abuse or withdrawal symptoms compared to the parent drug and other non-specific counterparts methyl)-2-cyclopropylthiazole)) and CE-111 (4-(benzhydrylsulfinylmethyl)-2-methyl-thiazole), acting as DAT-specific inhibitors along with dopamine receptor modulators, have shown potential as better alternatives to modafinil-derived analogs by having multiple targets in the dysfunctional dopaminergic system (Saroja et al., Studies found that the MCL pathway is affected more than the NS pathway in AD (Koeppe et al., Presently, no drug is approved to treat the dopaminergic system-related cognitive deficits in AD. However, recent studies on DAT inhibitors demonstrate its potential to be an efficacious target, with the newly discovered DILAP possessing the ability to restore cognitive deficits by ameliorating AD neuropathology. The DILAP binds to DAT causing translocation of the latter to the lysosomal membrane in order to increase the lysosomal biogenesis and subsequent dissolution of amyloid plaque by a mechanism not understood yet. The exact mechanism of action of DILAP to improve cognition is yet to be elucidate, however, it is suggested to be linked with the attenuation of amyloid burden. Moreover, a study on an AD mouse model showed promising effects of Nilotinib, a tyrosine kinase inhibitor that reduces Aβ levels, prevents structural damage and degeneration of dopaminergic neurons in the VTA, and restores VTA-hippocampal loop function, thereby reducing dopamine-related cognitive impairments (Barbera et al., AS: Conceptualization, Methodology, Writing – original draft. MY: Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – review & editing. FA: Writing – review & editing. JK: Writing – review & editing. ST: Writing – review & editing.


Application of ‘treat-to-target’ (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE.An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals’ views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus.The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life ; and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated.These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society. Childhood-onset systemic lupus erythematosus  is a multisystem chronic autoimmune/inflammatory disease. When compared with patients with adult-onset disease, children and adolescents with SLE have higher disease activity and medication burden, more widespread and severe organ manifestations, and higher incidence of renal, cardiovascular and neuropsychiatric involvement than adult-onset SLE (aSLE).A treat-to-target approach (T2T) is increasingly adopted in chronic diseases, whereby treatment is adjusted or escalated until a specific predefined goal or ‘target’ is achieved, consequently improving disease outcomes. T2T is part of routine clinical care in rheumatoid arthritis, hypertension and diabetes, underpinned by studies demonstrating improvements in long-term outcomes.Internationally agreed principles and recommendations for T2T have laid the foundation for T2T in aSLE,Here, an international Task Force was convened to determine if T2T overarching principles and recommendations, summarised here as ‘points-to-consider,’ could be formulated for cSLE, to inform development of future target-based approaches.The methodology was closely aligned with previous T2T initiatives.Task Force members were invited through the Paediatric Rheumatology European Society (PReS), the Childhood Arthritis and Rheumatology Research Alliance (CARRA), the UK JSLE Study Group, and the UK British Association for Paediatric Nephrology. Self-nominated members were selected according to the following criteria: (A) consultant/specialist in paediatric rheumatology (≥5 years), recognised nationally/international as cSLE expert; (B) treated >10 patients with cSLE over the last 2 years; (C) lead/represent national/international cSLE organisation/group; (D) representative of a subspecialist group(s) that is integral to the care of patients with cSLE ; or (E) expertise in leading T2T initiatives in SLE or related conditions. The final Task Force committee was chosen based on the applicants’ expertise, balancing representation of the different professional organisations, geographical distribution across all five continents, and availability to participate in all steps of the consensus process.The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative published recommendations for the diagnosis and management of cSLE in 2017, based on systematic literature searches performed in 2013,Provisional overarching principles and points-to-consider for T2T in cSLE were formulated by the steering committee, considering literature on: (A) targeted therapeutic approaches in cSLE and aSLE; (B) the SHARE recommendationsA virtual consensus meeting (November 2021) was attended by 18 cSLE T2T Task Force members , with representation from West/East Europe, Africa, Australia, Asia, North and South America. The meeting was chaired by MWB, facilitated by EMDS (both non-voting members). Two patients (NM and LB) and one parent (JA) attended, representing the views of patients/families (non-voting members).Modified nominal group technique (NGT)The literature review revealed that no randomised controlled trials had evaluated T2T in cSLE or aSLE. ASLE recommendations for T2T were published in 2014, including four principles and 11 recommendations, supporting targeting of remission, prevention of flares and damage, addressing factors that impact on HRQOL, minimising corticosteroid treatment, recognition of lupus nephritis (LN) and antiphospholipid syndrome (APS) and assessment/treatment of comorbidities.JIA is the the most common paediatric rheumatic disease, with recent evidence supporting use of T2T approach in polyarticular JIA,The Task Force agreed four overarching principles be considered when implementing cSLE T2T points-to-consider .In-keeping with SHAREThese goals are achieved through control of disease activity, minimising comorbidities and drug toxicity, optimising function, mental well-being, growth, development, education and social participation.Overarching principle 2 includes two statements emphasising that T2T should aim to improve long-term outcomes  and that a multifaceted approach is required; controlling disease activity, managing comorbidities, drug toxicity, improving function, mental well-being, growth, development, education, and social participation. cSLE morbidity relates in part to treatment, in-particular high dose or chronic use of glucocorticoids which although aimed at reducing the risk of disease flare, carries the associated risk of long-term steroid-induced damage.This overarching principle acknowledged the different clinical phenotypes of cSLE, which must be recognised if the optimal target and treatment strategies are to be selected for an individual patient. It also underlines the need for collaboration between different medical specialists, allied healthcare professionals and nurses to support children and adolescents to reach their targets.Maintenance of the target and ‘tight control’ underpin the T2T approach.The Task Force agreed on 14 points-to-consider, the details of which are presented in Remission is proposed as the ultimate treatment target. However, defining cSLE-specific remission was beyond the scope of the current initiative. To inform development of paediatric target definitions, 93% of the Task Force agreed that overall targets are most appropriate (rather than ‘organ-specific’ targets), recognising that it is unusual for one organ to be involved and treated in isolation in cSLE.Two previous studies investigated the achievability of aSLE-defined clinical remission (CR) on/off treatment in cSLE, using definitions from the 2017 Definition of Remission in SLE Framework.c>0.05).In UK patients, achievement of CR on-treatment was associated with significantly reduced hazards of severe flare  and new damage . Achievement of CR off-treatment was associated with further reduction in the hazards of severe flare (HR 0.13 (95% CI 0.09 to 0.20), 95% CI 0.15,0.24) and new damage . Statistically, there was no significant difference between the hazards of severe flare when the aSLE definition of LLDASWhile remission is the ultimate target, this often is unattainable for patients; particularly those with long-standing disease, an aggressive disease course, pre-existing damage, or where drug toxicity is encountered. In such patients, shared decision making was viewed as key to deciding whether low disease activity would be an appropriate initial target. The patient representatives agreed that low disease activity should be recognised as an alternative target, as having only the target of remission could lead to a sense of failure for some patients.In the UK and the Netherlands, a higher proportion of cSLE patients reached the aSLE LLDAS definitioncSLE flares often result in the addition of a short course of high-dose glucocorticoid treatment and/or initiation or intensification of immunosuppressives. Optimisation of immunosuppressant treatment should be systematically pursued, through adequate weight-based drug dosing, assessment of adherence, quantification of drug levels (where possible) to mitigate the difficult balance between treating with glucocorticoids to reduce disease flare versus the risk of steroid-induced damage.No cSLE studies have specifically looked at the risk of flare in patients with clinically inactive disease and persistent (or on-going) low complement and/or elevated anti-ds-DNA antibody titres. In cSLE, patients have a higher rate of both anti-dsDNA positivity and low C3 levels than in aSLE,Damage in cSLEIn cSLE, HRQOL correlates with fatigue, pain, anxiety and depressive symptoms, with disease activity scores being a poor predictor of impaired HRQOL.LN is a major cause of morbidity in cSLE, a common form of damage,No RCTs have compared different durations of maintenance LN immunomodulatory therapy, and observational data are limited.The Task Force debated extensively whether this point-to-consider should only apply to class III/IV LN or class III, IV and/or V. Class V LN has been included as it is frequently concomitant with class III/IV LN, histological transition from class V to class III/IV LN has been observed,The Task Force advised that glucocorticoid withdrawal should be gradual, balanced against disease severity and organ involvement. A recent aSLE study comparing maintenance low-dose prednisolone (5 mg/day) versus complete withdrawal, in patients with clinically quiescent disease, showed low-dose maintenance prednisone to be superior in terms of time to first flare , occurrence of mild/moderate flares (RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and moderate/severe flares (RR 0.1 (95% CI 0.1 to 0.9), p=0.013).Based on currently available data it is not possible to define a ‘safe low dose’ of maintenance glucocorticoid for cSLE, and further studies are required to investigate this issue  of remission which maintains sufficient homology with adult-onset SLE (aSLE) remission target definitions to promote life-course collaborative studies between the paediatric and adult rheumatology communities.Validation of paediatric specific definition(s) of remission in international cohorts and prospective studies.Prospective randomised clinical trial comparing targeted versus standard care in cSLE.Longitudinal clinical studies investigating the longer-term outcomes of targeted treatment in cSLE.Defining the most effective means of ensuring meaningful shared decision making within routine clinical care environment.Development of a paediatric specific definition of Low Disease Activity which maintains sufficient homology with aSLE remission target definitions to promote life-course collaborative studies between the paediatric and adult rheumatology communities.Compare outcomes associated with attainment of paediatric specific definitions of remission and low-disease activity in cSLE.Further validation of flare definitions and flare assessment tools.Prospective studies to investigate early intensive therapy and the principle of induction/maintenance in non-renal lupus, as a means of preventing flares.Undertake analyses within existing longitudinal cohorts and prospective clinical studies, looking at risk of flare in patients with clinically quiescent disease and persistent low complement and/or elevated anti-ds-DNA antibody titres.Undertake further analyses within existing longitudinal cohorts and prospective clinical studies, assessing early accrual of damage as a predictor for subsequent damage accrual and mortality (as in aSLE).A study specifically assessing whether damage prevention leads to improvements in HRQOL.Prospective studies to investigate early intensive therapy and the principle of induction/maintenance in non-renal lupus, as a means of preventing damage accrual.Further studies of non-inflammatory factors influencing health related quality of life in cSLE.Development and validation of a set of key patient-reported outcomes that capture factors influencing health related quality of life, including fatigue, pain, mental health, educational challenges, and medication side effects.Development of multidisciplinary interventions that could be used in parallel to a T2T approach in cSLE, to address parallel patient targets, eg. fatigue, pain, mental health, educational challenges and medication side effects.Further assessment of haematuria and/or leukocyturia as a prompt for consideration of renal biopsy (as compared tocompared with persistent mild proteinuria and/or impaired glomerular filtration rate).Undertake analyses within existing longitudinal cohort to assess if delay in renal biopsy (and therefore diagnosis of Lupus Nephritis) is associated with development of end-stage renal disease in cSLE.Prospective clinical studies comparing different durations of maintenance immunomodulatory therapy for different lupus nephritis classes.Undertake analyses within existing longitudinal cohort and prospective studies to assess rates of histological transition from class V to class III/IV lupus nephritis in cSLE patients undergoing a repeat renal biopsy (performed either per protocol or during an lupus nephritis flare).Undertake analyses within existing longitudinal cohorts and prospective clinical studies to assess for a dose-related association between glucocorticoid exposure and damage accrual, and whether a ‘safe’ lower dose of glucocorticoid can be identified.Prospective clinical studies comparing high-dose versus low-dose intravenous methylprednisolone treatment regimens in terms of efficacy, side effects and damage accrual.Studies on glucocorticoid withdrawal, comparing flare rates in cSLE patients with clinically quiescent disease on maintenance low-dose prednisolone versus patients where glucocorticoids have been withdrawn.Studies to better define which patients would benefit from treatment aimed at primary prevention of thrombosis.Therapeutic studies in cSLE antiphospholipid syndrome with different immunosuppressives/immunomodulators.Therapeutic studies in cSLE antiphospholipid syndrome to provide evidence for different anticoagulation and anti-aggregation regimens.Studies assessing the feasibility of discontinuing anticoagulant therapy following immunomodulation, where the production of antiphospholipid antibodies has been suppressed.Further studies to assess if hydroxychloroquine must be recommended or not in every patient with cSLE.Further studies investigating the assessment of serum hydroxychloroquine drug level monitoring.Studies assessing long-term toxicity/side effect associated with hydroxychloroquine in cSLE.Development and validation of a structured assessment to longitudinally assess for comorbidities in cSLE, for used within routine clinical practice.Develop standardised interventional approaches to address comorbidities once they have been identified.Determine the optimal frequency of target assessment and treatment escalation.Prospective clinical studies assessing the impact of varying percentages of follow-up time in target (low disease activity and remission), and how this impacts on flare rates and new damage accrual.Studies assessing approach to withdrawal of therapy when remission has been achieved.APS is rare in cSLE. In 2004, the international Ped-APS registry identified 121 cases across a multinational study, 41% in association with cSLE or ‘lupus-like’ disease.The Task Force discussed this point-to-consider extensively, particularly related to prevention of APS related morbidity. They noted the detailed SHARE recommendations for APS, and supported screening for antiphospholipid antibodies  in all cSLE patients in accordance with the SHARE recommendations.Antimalarial treatment is considered a quality indicator in North America,The aSLE T2T recommendationsThe Task Force recognised the importance of prevention, assessment and control of cSLE-associated comorbidities including hypertension, hypercholesterolaemia, insulin resistance/diabetes, antiphospholipid antibody related morbidity, bone health/osteopenia/osteoporosis, prevention of infection through adequate vaccination, assessment and provision of support for mental health, delivered through a multidisciplinary team where possible. The high prevalence of depression, anxiety,Of particular importance, many disease-related factors increase cardiovascular disease risk in cSLE  adding to treatment related issues , and lifestyle/traditional factors .The Task Force noted the frequency of assessments in cSLE should be guided by organ manifestations, level of disease activity, disease duration, stage of treatment and any patient characteristics associated with potentially poor outcome. The Task Force stressed that dependent on these factors, weekly, monthly, up to 3-monthly assessment by a cSLE specialist centre may be indicated, in keeping with SHARE.Evidence supporting this point-to-consider comes from the UK JSLE Cohort Study,The Task Force discussions and structured literature review highlighted important issues that remain elusive in relation to evidence informing a future T2T based approach for cSLE. The Task Force therefore developed a research agenda, shown in The International cSLE T2T Task Force has developed overarching principles and points-to-consider, which have been endorsed by PReS, representing the first step towards developing a T2T approach for cSLE. These are based on published evidence available to date, derived after two rounds of Delphi surveys and extensive discussions using a modified NGT approach, with excellent agreement between a broad range of international experts. The overarching principles and points-to-consider are intended for experienced clinicians aimed at improving patient care, and are not intended to replace clinical judgement, knowledge, and experience. Patient preferences, shared decision making and equity (or otherwise) of access to care and resources should be taken into consideration at the individual patient level. Development of full principles and recommendations for T2T in cSLE is anticipated, following investigation of the research agenda items detailed above.The three essential elements of T2T are: (1) a target; (2) a means of measuring whether the target has been achieved and (3) having appropriate interventions to achieve the target. There are many ways to treat cSLE, and T2T does not recommend specific treatments to achieve the goals outlined. In cSLE, recent studies involving UK and Dutch cSLE cohorts have demonstrated that aSLE-derived targets (LLDAS/CR) are attainable in cSLE,Therapeutic options for cSLE remain limited, with only one biologic (belimumab)Among the outstanding research priorities , two areThe importance of including patients’/caregivers’ views in the development of these T2T overarching principles and points-to-consider was crucial and pivotal in many of the Task Force discussions.T2T overarching principles and points-to-consider for cSLE have been developed by an international Task Force, including paediatric rheumatologists, nephrologists, adult rheumatologists and patients/caregivers, endorsed by PReS. Building on published evidence available to date, excellent levels of agreement were achieved. These overarching principles and points-to-consider form a key initial step towards developing a T2T approach and establishing its role within cSLE patient care.


Colonoscopy is a commonly performed procedure, but most patients will not actually be found with colorectal cancer. Subsequent face-to-face consultations to explain post-colonoscopy findings are common despite the time and cost-saving benefits of teleconsultation, especially in a post-COVID-19 era. This exploratory retrospective study examined the proportion of post-colonoscopy follow-up consultations that could have been converted to teleconsultation within a tertiary hospital in Singapore.A retrospective cohort of all patients who underwent colonoscopy in the institution from July to September 2019 was identified. All follow-up face-to-face consultations related to the index colonoscopy from the scope date to 6 months post-colonoscopy were traced. Clinical data relevant to the index colonoscopy and these consultations were extracted from electronic medical records.n = 643, 74.9%) were scheduled for at least one post-colonoscopy visit − a total of 884 face-to-face clinical visits. The final sample was 682 (77.1%) face-to-face post-colonoscopy visits that did not involve any procedures performed or indicated the need for any subsequent follow-up.The cohort consisted of 859 patients . Of these, 15 (1.7%) had colorectal cancer, but the majority (If such “unnecessary” post-colonoscopy consultations exist within our institution, then similar situations possibly occur elsewhere. As COVID-19 continues to periodically tax healthcare systems worldwide, preservation of resources will remain integral alongside quality standards of routine patient care. There is a need for detailed analyses and modeling to hypothesize potential savings by also considering the start-up and maintenance costs of switching to a teleconsultation-dominated system. Colonoscopy is a frequently performed lower gastrointestinal procedure in the management of colorectal cancer (CRC). While most patients undergoing colonoscopy will not actually have CRC, there will typically be a subsequent face-to-face consultation to explain post-colonoscopy findings.Due to the COVID-19 pandemic, adoption of teleconsultation has especially been accelerated to ensure continuity of care while reducing unnecessary contact among patients . Other bWe identified a retrospective cohort of all patients who underwent colonoscopy in our institution from July to September 2019. The timeframe was selected to predate the onset of the COVID-19 pandemic in Singapore. Ethical approval was obtained from the National Healthcare Group's Domain Specific Review Board (DSRB Ref: 2021/00936) in accordance with the Declaration of Helsinki. As the study utilized retrospective institutional data, written informed consent from participants was not required in accordance with local/national guidelines.Using the institutional electronic medical records system, we traced all follow-up face-to-face consultations related to the index colonoscopy from the scope date to 6 months post-colonoscopy. Relevant data were extracted using a standardized data collection form, comprising the following indicators: colonoscopy diagnosis, number of clinical visits post-colonoscopy, dates of visit, purpose of visit, procedures performed, persistence of pre-colonoscopy symptoms, and the presence of new patient-reported complaints.n = 643, 74.9%) were scheduled for, and attended, at least one post-colonoscopy consultation − which accounted for a total of 884 face-to-face clinical visits.The cohort consisted of 859 patients . All patients were native to our institution . Of these patients, 15 (1.7%) had CRC, but the majority of patients (Further stratification demonstrated that only 200 of the 859 patients (23.3%) in our cohort had their index colonoscopy performed for screening purposes . Of these, 138 patients (69.0%) received a face-to-face follow-up consultation, but persistence of pre-colonoscopy symptoms and/or highlighting of new complaints was only present in 12 of these visits (8.7%). None of the 138 patients required any procedures performed in their follow-up visits.To estimate the number of follow-up consultations that could have potentially been converted to teleconsultation, we applied the following eligibility criteria. First, we excluded all visits in which a subsequent procedure/operation  was performed, resulting in 817 (92.4%) visits being retained in the analysis. We then excluded the 94 (10.6%) visits in which pre-colonoscopy symptoms were recorded to have persisted. Finally, we excluded the 41 (4.6%) visits in which patients highlighted a new complaint. The final sample was therefore 682 (77.1%) “routine” post-colonoscopy visits that did not involve any intervention or procedure performed nor indicated the need for any subsequent follow-up visits, in a physical face-to-face setting  or indirect  costs for what is likely an inconsequential clinical visit. Healthcare institutions are also likely to incur unnecessary costs as more clinical and administrative manpower is needed to logistically facilitate a face-to-face consultation. As COVID-19 continues to periodically tax healthcare systems worldwide, the need for preservation of resources will remain integral, even as quality standards of routine patient care must be maintained.We caveat that in contrast to scholarly discussion surrounding the recently published NordICC trial, our data should not be taken as a commentary on the benefits of colonoscopy , 8. NonePatients' perceptions, barriers, and facilitators toward teleconsultation must also be known prior to widespread implementation, but healthcare costs continue to rise unsustainably in many high developmental index countries, including Singapore . We urgeThe authors would like to thank Si-Ying Fong and Yong Kang Chua for their support in data acquisition and extraction. They did not receive compensation for their contribution to this work.Ethical approval was obtained from the National Healthcare Group's Domain Specific Review Board (DSRB Ref: 2021/00936) in accordance with the Declaration of Helsinki. As the study utilized retrospective institutional data, written informed consent from participants was not required in accordance with local/national guidelines.The authors have no conflicts of interest to declare.This study was supported by the National Medical Research Council Singapore's Health Services Research Grant (HSRGMS20nov-0002) and the National University Health System's Family Medicine/Primary Care/Health Services Research Seed Grant (NUHSRO/2021/064/RO5+6/FMPCHSRG-Mar21/02). The funders had no role in the conceptualization, design, data acquisition and analysis, manuscript preparation, or decision to publish the research. The authors have no other relevant financial or nonfinancial interests to disclose.Jerrald Lau, Ning-Qi Pang, and Ker-Kan Tan conceptualized the study. Chermaine Ang collected the data. Jerrald Lau and Chermaine Ang performed data curation. Jerrald Lau and Ning-Qi Pang performed statistical analysis of the data. Jerrald Lau drafted the initial manuscript. Ker-Kan Tan provided resources and formal supervision. All the authors critically reviewed and revised the manuscript.All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.


Shame is considered central in body dysmorphic disorder (BDD) and empiricalaccounts highlight the link between shame and BDD symptoms as well as commonnegative psychosocial effects of the disorder, yet there is a lack ofinterventions addressing shame in this context. In the past decade, Acceptanceand commitment therapy (ACT) and interventions that foster self-compassion haveshown promise for reducing the negative effects of shame in a range of clinicalproblems. The aim of the present study was to develop and evaluate an acceptanceand compassion-based treatment specifically targeting shame in BDD. Using arandomized nonconcurrent multiple baseline design, the 12-session intervention,ACT with Compassion (ACTwC), was examined in a psychiatric outpatient sample offive adults diagnosed with BDD. The daily ratings showed marked reductions inBDD-behaviors and self-criticism at posttreatment for four of five participants,while three participants demonstrated decreases in body shame compared tobaseline. Improvements were maintained at 6-months follow-up. The interventionalso led to reliable long-term improvements in general shame, overallBDD-symptoms, depressive symptoms, and quality of life for four of fiveparticipants. All treatment responders showed significant gains in psychologicalflexibility and self-compassion. Participants reported high credibility andsatisfaction with the treatment. These preliminary results suggest that ACTwCmay be a promising approach to treating shame in BDD, worthy of furtherinvestigation. Body dysmorphic disorder (BDD), characterized by a preoccupation with a perceivedflaw in appearance , is a deOne way to improve treatment outcomes for BDD may be to target shame, an emotionconsidered central in this disorder . A growiShame refers to the affective experience of perceiving the self as intrinsicallyflawed and socially undesirable . It invoAccumulating research points to considerable negative effects of shame in BDD. Shamecontributes significantly to increased overall BDD-symptoms and commonlyco-occurring negative psychosocial consequences, such as limited functioning,hopelessness, depression, and suicidal thoughts , 2017. CEven though research shows a link between shame and severe adverse outcomes in BDD,there are yet no evaluations of interventions specifically targeting shame in thisdisorder. One reason for this is perhaps that CBT, the most establishedpsychological treatment method for BDD, is focused on treating maladaptivecognitions and diagnosis-specific symptoms, rather than shame. However, whentreating people who are highly shame-prone and self-critical, theorists suggeststhat shame needs to be directly targeted in treatment .In the past decade, evidence has emerged supporting the use of interventionsdeveloped in more recent “third-wave therapies” building on the CBT tradition, forconditions where shame is a prominent feature. Treatment approaches such asAcceptance and commitment therapy (ACT) and Compassion focused therapy (CFT), haveshown potential to reduce shame and associated problems in a range of clinicalconditions; for example, binge eating disorder , eatingACT is proposed to be an effective approach for reducing negative effects of shamedue to the treatment’s potential to decrease experiential avoidance and increasepsychological flexibility, including weakening the influence of self-criticalthoughts . ExperieAnother promising approach for alleviating detrimental effects of shame andself-criticism is to build self-compassion .Self-cod = 1.93, p .001),reliable increases in psychological flexibility and quality of life, and a 79%treatment response rate.Based on advances in the research field on shame and previous research on BDD, wehave developed a psychological treatment intervention targeting shame in BDD. Themanualized treatment, ACT with Compassion (ACTwC) for BDD, integrates ACT withelements from CFT and knowledge on BDD. ACTwC for BDD, is designed to target shameand self-criticism and increase psychological flexibility and self-compassion withthe overarching goal of increasing quality of life in patients suffering from BDD.An earlier version of this treatment that did not include elements focused oncompassion and shame (ACT for BDD) was tested in a group therapy format with 21patients with BDD . InitialThe purpose of the present study was to evaluate the effect and feasibility of apsychological treatment intervention directly targeting shame in BDD. In this earlystage of evaluating a new treatment approach to BDD, our objectives were toinvestigate; (a) preliminary effectiveness and (b) patient’s acceptance of andsatisfaction with the treatment. Using a multiple baseline design, the treatment’seffect on the primary outcomes of body shame, self-criticism, and BDD behaviors, wasevaluated. Secondary outcomes were overall symptoms of BDD, depression, quality oflife, self-compassion, and psychological flexibility. Treatment feasibility wasevaluated by investigating patient’s perceived credibility and expectancy as well assatisfaction with the intervention. We aimed to evaluate the feasibility of thetreatment in a real-world context and therefore chose to conduct the study in apsychiatric outpatient clinic.Participants were recruited and treated at a psychiatric outpatient clinic inStockholm, Sweden, specialized in treatment for OCD-spectrum disorders. Fiveindividuals with BDD as their primary diagnosis, assessed by a psychiatristand/or a clinical psychologist at the clinic, participated in the study.Diagnoses were based on the obsessive–compulsive and related disorders module ofthe Structured Clinical Interview for DSM-5 , and theInclusion criteria were: (a) 18 years or older; (b) diagnosis of BDD according toDSM-5 with BDD-symptoms of at least moderate severity (BDD-YBOCS score ≥23); and(c) elevated shame (ISS score >40). Exclusion criteria were: (a) severesuicidal ideation and intent (as defined by score >4 on item 9 of MADRS-S),(b) lifetime diagnoses of bipolar disorder, (c) psychosis, (d) autism spectrumdisorder or (e) a severe personality disorder , (f) current substance dependence, (g) psychotropicmedication changes within 12 weeks prior to treatment, (h) completed CBT for BDDwithin 12 months, or (i) concurrent psychotherapy. Participants who were on astable dose of psychotropic drugs were asked to not make changes to theirpharmacological treatment during the study period. Participant characteristicsare presented in Seven consecutive participants meeting inclusion and not exclusion criteria wereinvited to take part in the study. One participant was withdrawn from the studybefore initiating treatment due to increased suicidality requiring a higherlevel of care at an inpatient clinic. Another patient dropped out early duringtreatment when face-to-face sessions at the clinic changed to video sessions dueto Covid-19. The two non-completers did not have sufficient data to be includedin the final analyses, leaving a sample of five treatment completers.Non-completers did not differ distinctly from completers in terms ofdemographics, initial symptom severity, comorbidity, type of BDD concerns or BDDbehaviors.To investigate the effectiveness of the intervention for reducing body shame,self-criticism, and BDD-behaviors, a randomized, nonconcurrent, multiplebaseline across participants design was used .ConsistFollowing enrollment, participants were randomized to baseline assessment phasesof different lengths, between 2 and 6 weeks, using randomly drawn sealedenvelopes. Participants completed daily self-report measures via a secureInternet-based platform throughout the baseline and subsequent 12-sessiontreatment phase and at 6-months follow-ups. In addition to the daily measures,standardized outcome measures were used to evaluate the secondary outcomes atbaseline, mid-treatment, posttreatment, and at 6-month follow-up.A second aim was to investigate feasibility of this new treatment approach toBDD. We assessed credibility of treatment and patient’s expectancy forimprovement (after the third session) and satisfaction with the treatment (aftertreatment completion).Prior to data collection, the study was registered and approved by the regionalethics committee (Registration number 2018/2374-31).Structured Clinical Interview for DSM 5—Research Version (SCID-5-RV),module G . The sum of each participants’ daily BDD-behaviors ispresented in the results section.Along with the BDD-behaviors, participants were asked to rate theirdegree of (1) body shame  and (2) self-criticism .The Yale-Brown Obsessive Compulsive Scale Modified for BDD  with the full 26-itemSelf-Compassion Scale  and correlates(r = .87) with the Beck Depression Inventory,indicating acceptable convergent validity  was adapted for a BDD populationfrom the Body Image-Acceptance and Action Questionnaire  is an investigator created 12-item measure of willingness toaccept undesirable thoughts and feelings associated with one’sappearance, while acting in a way that is congruent with values andgoals. All items are reverse scored and are summed to produce a totalscore. Higher scores indicate greater psychological flexibility. Thescale .The treatment, ACTwC, was designed to target shame and self-criticism andincrease self-compassion, psychological flexibility, and quality of life inpatients suffering from BDD. A manual to guide each treatment session wasdeveloped based on integrating research on BDD with theory and techniques fromACT and compassion-focused therapies ; buildingskills in present-centered, nonjudgmental awareness, especially of one’s ownsuffering ; experiential exercises; training in acknowledging, eliciting, andregulating previously avoided emotions of shame ; practicing self-compassion in response toshame and self-criticism and promotion of value-guided actions in dailylife.Treatment was delivered by three clinical psychologists with previous experiencein treating BDD patients. The first author, with expertise in BDD treatment,developed the treatment manual in collaboration with experts in ACT, treated twoof the patients and also supervised the other two therapists weekly. Beforedelivering treatment, the therapists received approximately 3 hours of trainingin the manual. All treatment sessions were audio-recorded for weekly supervisionand therapist adherence to the treatment manual. Sessions were divided into10 minute modules that were chosen randomly for adherence checks. Adherence tothe session content and structure as well as therapist adherence to ACT andcompassion principles were evaluated by the treatment developer using apredefined adherence manual (available on request). Adherence level was rated aseither sufficient, or not sufficient. The majority of the modules (90%) wasjudged as having been conducted in a sufficient manner.Data analyses were conducted according to established guidelines for single-caseexperimental designs, with visual inspection of plotted data as the primarymethod . The weeFor the standardized outcome measures, 95% confidence intervals (CIs) werecalculated for each participant’s change scores to evaluate the reliability ofthe change from pre- to posttreatment and change from pretreatment to 6-monthfollow-up. For each outcome measure, a standard error of the difference (Sdiff)was calculated, following the method developed by treatment response and symptom remissionfrom baseline to posttreatment and 6-months follow-up. We used the establishedcriteria of a BDD-YBOCS reduction ≥30% to define treatment response and a scoreof ≤16 as cut-off for symptom remission .At the initial assessment, all five participants met the criteria for BDDaccording to DSM 5, with scores on the BDD-YBOCS indicating moderate to severeBDD symptom severity (p < .01) for allfive participants between baseline and the intervention phase.Visual inspection of baseline data  indicateOverall BDD symptoms reliably decreased for four of five participants  with atVisual inspection indicates that self-criticism was stable or worsened duringbaseline for all participants . Across Scores on the self-judgment subscale of the SCS-SF decreased from pre- toposttreatment for all participants with 11% to 44% . Gains wThe daily records of body shame showed large fluctuations from day-to-day duringall phases, including baseline phase . HoweverM = 69.0,SD = 7.9, range 58–78). Notably, at mid treatment shamescores had further increased for three of the patients. However, followingtreatment, shame had reliably decreased for three of five participants and at6 months follow-up four of the participants showed significant reductions inshame scores (25%–66%) compared to pretreatment . Four of the five participants reportedreliable and large decreases in depressive symptoms between pre- andposttreatment . After treatment, scores of quality of life had significantly andstrongly improved for P1, P2, and P5 (with 167%–301%), and all participantsexcept P7 had scores comparable to non-clinical samples in previous studies for P1, P2, andP5 during treatment. For P4, scores were unchanged at posttreatment but hadsignificantly improved at follow-up. On the contrary, P7 reported an increase incognitive fusion posttreatment.M = 8, range 7–10) and reported high expectancy oftreatment efficacy for their problems .After psychoeducation phase, all participants rated ACTwC for BDD as credible, is keyto reduce negative effects of inner experiences. In fact, the real goal in ACT is topromote psychological flexibility and value-guided action in the presence of painfulemotions, rather than reducing emotions themselves. However, when psychologicalflexibility in response to difficult thoughts and feelings increases, usually theemotions are also perceived as less burdensome and tend to decrease, which mayexplain the long-term reductions in shame.Even though the treatment was designed to target shame, it also had a large effect onpatient’s BDD-behaviors, providing some preliminary support for the proposition byFurthermore, the secondary outcomes showed large and reliable treatment effects onBDD-symptoms for most participants. At posttreatment, four of the five participantscould be classified as treatment responders, reflecting clinically meaningfulreduction on the BDD-YBOCS according to the predefined criterion, and as achievingsymptom remission at follow up. The treatment response and symptom remission ratesgained in this study is excellent compared to what is typically found in clinicaltrials of BDD. In comparison, a study by In addition, the four responders in the present study made large and reliableimprovements in quality of life and depressive symptoms. They went frommoderate-severe depression at pretreatment to mild or subclinical symptoms aftertreatment, and from low quality of life to levels comparable to non-clinical samplesin previous studies . All gaiCongruent with expectations, the treatment also had a significant effect on theproposed treatment processes. Most participants demonstrated increases inpsychological flexibility and self-compassion after treatment, suggesting that theintervention strengthened these abilities. Additional research is needed to evaluatethe impact of these proposed treatment processes. Future studies should investigatethe mediating or moderating potential of these processes on the effects of shame inBDD.The second objective of the present study was to evaluate the feasibility of this newtreatment approach to BDD. Most participants reported high levels of satisfactionwith the intervention and stated that it met almost all their needs. They all foundthe treatment to be highly credible. Hence, the second aim was supported, indicatingthat ACTwC was acceptable to people with BDD and elevated shame, and feasible to bedelivered in a psychiatric outpatient setting.Strengths of this study include the randomized multiple baseline design thatcontrolled for threats to internal validity, such as the passage of time andrepeated assessments. Further, the daily assessment method has the advantage that itis sensitive to change and fluctuations in mood and behaviors. Additional strengthswere the real-world setting and the large improvements across patients withconsiderable symptoms and low quality of life. Moreover, we used three differenttherapists who after moderate training were able to deliver treatment adequately,providing some initial evidence that the intervention can be successfully deliveredin a real-world context.Single-case experimental designs  are suitable for initialevaluation of psychological treatments . With thAnother limitation of the study is the relatively unknown reliability and validity ofthe daily assessments of body shame and self-criticism. The daily measures consistedof single item questions that required participants to be able to understand theseconstructs. Identifying and discriminating self-conscious emotions can be difficult. To addrIn conclusion, the results from this pilot study suggest that ACT with Compassion haspotential to reduce BDD symptoms, shame, and self-criticism, and in addition,improve depressive mood and patients’ quality of life. Also, the treatment wasconsidered acceptable to the patients. Feedback and study results will be used toguide further development of the treatment protocol and future research thatexplores treatment moderators and mechanisms of change and evaluates efficacy of theintervention compared to other treatments in a larger randomized controlledtrial.Click here for additional data file.Supplemental material, sj-docx-1-bmo-10.1177_01454455221129989 for Acceptance andCompassion-Based Therapy Targeting Shame in Body Dysmorphic Disorder: A MultipleBaseline Study by Johanna Linde, Jason B. Luoma, Christian Rück, Jonas Ramneröand Tobias Lundgren in Behavior ModificationClick here for additional data file.Supplemental material, sj-docx-2-bmo-10.1177_01454455221129989 for Acceptance andCompassion-Based Therapy Targeting Shame in Body Dysmorphic Disorder: A MultipleBaseline Study by Johanna Linde, Jason B. Luoma, Christian Rück, Jonas Ramneröand Tobias Lundgren in Behavior Modification