Atherosclerosis is a chronic multifactorial disease characterized by mainly changes of blood lipids profile and inflammation in vessel wall. The cardiovascular disease based on atherosclerosis is currently the leading cause of mortality in developed countries. Therefore, timely prevention and therapy of atherosclerosis are able to reduce the risk of the development of its clinical manifestations. Anti-atherosclerotic activity of medicinal plants mainly appears in their multiple effects such as anti-inflammatory, antioxidant, anti-atherogenic, hypotensive, lipid-lowering, anti-thrombotic. Moreover, most of medicinal plants are characterized by their pleiotropic anti-atherosclerotic action. In addition, the medicinal plants-derived pharmacological substances and/or compounds are characterized by relative safety and fewer side effects that allows considering them as one of potential anti-atherosclerotic effective agents. The direct anti-atherosclerotic effect of some medicinal plants was confirmed in clinical trials of carotid Intima-media thickness (IMT) progression during long-term medication with medicinal plants. This review attempted to determine the current status of the databases PubMed and Scopus  to investigate the medicinal plants possessing anti-atherosclerotic activity in experimental and clinical studies. Atherosclerosis is a chronic multifactorial disease characterized by dyslipidemia and inflammation. Nowadays it is one of the key reasons of cardiovascular disease that is currently the leading cause of mortality in developed countries . AtherosIn general, atherosclerosis can be also described as a type of immunological disorder, in which immune cells are activated along the inflammatory pathway and migrate into the vascular intima. After that, atherosclerotic lesion may develop in this place . Recent Currently, a strategy for the correction of lipid metabolism disorders is widely used around the world to treat atherosclerosis. But at the same time, researchers are developing methods to counteract inflammatory processes in the vessel wall at cellular level. The viability of these methods is indicated by the latest data from studies of the pathogenesis of atherosclerotic lesions. This process begins in the intima layer of large and medium arteries, especially in places of bifurcation. Vascular wall of such areas experiences increased stress due to the turbulent effects of blood flow. This causes damage to the cells of endothelial layer of intima, resulting in attracting of immune cells due to the production of adhesion molecules. . At the Thus, the activation of cascades of immune and inflammatory reactions is crucial for the progression of atherosclerotic lesions. In attempt to influence these processes, several new strategies for the treatment of atherosclerosis, based on the use of various therapeutic agents to inhibit the pro-inflammatory activation of immune cells or stimulate signals to the anti-inflammatory activity of body systems, have recently appeared. They can be used as an addition to conventional methods of treating cardiovascular diseases based on the use of lipid-lowering preparations . HoweverNowadays, there are no preparations that can be used for long-term prevention and treatment of atherosclerosis without the risk of developing pronounced side effects. This leads to the extremely high relevance of the study and use of medicinal plants for long-term anti-atherosclerotic therapy. Actually, the medical properties of various plants have been known since ancient times. A large number of herbal preparations are capable of exerting inhibitory effects in pathological immune reactions, and some of them have traditionally been used for the modulation of atherosclerosis progression. It can be explained by their relative safety, fewer side effects, and, in a sense, their greater effectiveness. Since cytokines are the main mediators in all types of inflammation, that is a significant factor at all phases of the atherosclerosis progression, the studies of the use of medicinal plants for modulation of cytokines production are very relevant in the field of atherosclerosis medication . In addiThis review reflects current views on how medicinal plants are used to reduce the risk of atherosclerosis development, their direct or indirect anti-atherosclerotic effects. English scientific literature was searched using electronic databases PubMed and Scopus by keywords “medicinal plants”, “natural products”, “atherosclerosis”, “intima-media thickness”, “cardiovascular risk”, “clinical trial” in different combinations until November, 2019, with first focus on medicinal plants with proven direct anti-atherosclerotic activity in patients with carotid atherosclerosis and natural products possessing cardioprotective effects in clinical trials, and further their anti-atherosclerotic mechanisms of action were reviewed. We will focus on medicinal plants and the products created on their base, used in modern practice meeting the principles of evidence-based medicine.Atherosclerosis is a multifactorial process, and despite the great progress in understanding the mechanisms of the development of atherosclerotic lesions in the last decades, the pathogenesis of atherosclerosis is the subject of study by a large circle of scientists around the world. Nevertheless, the key points of the pathogenesis of atherosclerosis are known, and the possible pathogenetic mechanisms of the anti-atherosclerotic effects of medicinal plants are being studied in cell cultures, animal models, and human studies. Sambucus nigra L.), violet tricolor (Viola tricolor L.), and calendula , significantly inhibits the expression of inflammatory cytokines via inhibiting IL-6 and TNF-α expression and alleviates serum atherogenic activities via unknown mechanism in ex vivo model . Glabridin possesses anti-inflammatory action by preventing TNF-α-stimulated gene expression of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via blocking JNK and NF-κB  possesses multiple anti-atherosclerotic effects. Allicor, garlic powder, inhibits inflammation signaling  . Garlic Phytoestrogens, plant-derived estrogens, can be used as an alternative estrogen replacement therapy for Cardiovascular disease (CVD) and osteoporosis prevention. Phytoestrogens, bioflavonoids characterized by similar structure to endogenous estrogens, can be found in different plants like soybean, pomegranate, spinach, etc . SoybeanCurcuma longa L.), Chinese sage or danshen , flowering plants of the barberry family (Berberidaceae family Juss.), green chireta (Andrographis paniculate Nees.), oak leaves (Quercus dentata Thunb.), garlic (Allium sativum L.), and jiaogulan (Gynostemma pentaphylla Thunb.) , cytokines (TNF-a), MCP-1) by inhibiting expression of JAK/STAT signaling pathway. Moreover, curcumin may regulate the inflammatory response by suppressing activity of iNOS, COX-2, lipoxygenase, and xanthine oxidase, and activation of NF-kB  . For exa Thunb.) . Curcumiof NF-kB .via lncRNA TUG1 up-regulating miR-26a expression (Pueraria lobate Willd.) radix is a herbal formula suppress the expression of ICAM-1 and VCAM-1 and production of MCP-1 in TNF-α stimulated human umbilical vein endothelial cells  decreased plasma LDL-cholesterol by upregulating LDLR, and apoE expression and downregulating HMGR expression  leaf extract provides anti-platelet and antithrombotic effects via blocking of platelet activation and aggregation, thromboxane B2 formation, serotonin secretion, and thrombus formation. Granule secretion and extracellular-signal-regulated kinase and Akt phosphorylation underlie the mechanism of this anti-platelet activity , which extracts possess multiple anti-atherosclerotic activities. Thus, ellagic acid promotes cholesterol removal by regulating LXR/PPAR-ABCA1 pathway , smoking, obesity, etc., explain more than 50% of the variability of atherosclerosis, so represent the most significant factor in atherosclerosis development. In this regard, cardiovascular risk factors are the most important target in the process of timely prevention and treatment of atherosclerosis.Medicinal plants have long been widely studied as anti-atherosclerotic agents; to date, sufficient data have been obtained on the effect of natural products on various traditional risk factors Table 2.Coptis chinensis Franch.) and Shen-Ling-Bai-Zhu-San  led to a significant reduction of not only HbA1c and glucose levels, but also plasma Tg, TC, LDL levels  Burm.f.], Huanglian [Coptis chinensis Franch.], Rhizoma Anemarrhenae [Anemarrhena asphodeloides Bge.], red yeast , Kugua [Momordica charantia L.], Wuweizi [Schisandra chinensis (Turcz.) Baill.], and dried ginger [Zingiber officinale Roscoe.]}, involving patients with type 2 diabetes, not only reduced HbA1c and normalized the lipid profile of blood plasma, but also led to weight loss  and LDL in postmenopausal women with hypercholesterolemia after 12 months of daily intake of 1 g of the drug in a randomized placebo-controlled trial . A randoL levels . Anotherght loss .Garlic powder is characterized by significant effects on many risk factors of atherosclerosis. In a randomized placebo-controlled trial performed by Zeb F. et al., the weight loss of the subjects was demonstrated . In thisPhytoestrogens are characterized by lipid-lowering and hypotensive effects. Villa P et al. in their pilot randomized trial involving ninety women in menopausal transition showed that administration of phytoestrogen substances in addition to vitamins and passionflower herbal preparation during 6 months led to TC decrease in blood plasma . Eight-wTurmeric also has lipid, hs-CRP, BMI, and glucose lowering effects observing during treatment of type 2 diabetes. Curcumin, a natural polyphenol from turmeric was tested in a randomized, double-blind, placebo-controlled trial on patients with diabetes who consumed 1,5 g curcumin daily for 10 weeks. Adibian M et al. have found significant hs-CRP and Tg-lowering effects . Adab Z In the placebo-controlled clinical study of the effect of 1-year licorice root extract consumption on cardiovascular risk factors, beneficial results were demonstrated, namely, the significant reduction of TC and LDL levels as well as hypotensive activity .The intima-media thickness of common carotid arteries is often used as a direct quantitative characteristic of atherosclerosis in clinical studies of the effectiveness of anti-atherosclerotic preparations. Currently, a number of medicinal plants have been studied using ultrasound scanning of the carotid arteries, that allows evaluating not only the indirect anti-atherosclerotic effect of these natural products by conversion of cardiovascular risk factors, but also studying their effect on carotid atherosclerosis development. Salvia miltiorrhiza Bge.) and gegen radix (Pueraria lobate Willd.), that is often used for cardiovascular protection, caused the reduction of cIMT by –0.012mm after 1-year administration in 165 postmenopausal women (Polygonum cuspidatum Siebold & Zucc.) and hawthorn fruits (CrataegusTourn.ex L.) also demonstrates a significant reduction of cIMT after 6 months of follow-up , has therapeutic potential for the prevention of cardiovascular disease in postmenopausal women and in the perimenopausal period. The significant reduction of annual rate of cIMT progression was demonstrated in 2-year double-blinded placebo-controlled study in postmenopausal women – 0.006 vs. 0.011 mm/year in placebo group (p < 0.001) (Glycine max (L.) Merr.] is one of the richest sources of phytoestrogens so it's widely used for therapy of climacteric syndrome and it's also successfully used for cardiovascular protection in women after menopause  to inhibit the formation of new atherosclerotic lesions and slow down the development of existing ones. The data of some studies  indicate< 0.001) . Soybeanenopause . In the enopause . It was enopause .ex vivo models as was described above, has been conducted. Based on them, an optimal dosage regimen of the preparation was developed to achieve a stable anti-inflammatory effect. In patients with subclinical atherosclerosis, a clinical study was designed to evaluate anti-atherosclerotic properties of Inflaminat. As a criterion for assessing the development of atherosclerotic lesions was also used the cIMT indicator. As it turned out, Inflaminat possesses direct anti-atherosclerotic activity since significantly reduces of the cIMT progression during 2-years of administration. It was demonstrated that annual rate of cIMT progression was +0.006 mm/year in Inflaminat-treated group and +0.022 mm/year in placebo group (p=0.045) (Glycyrrhiza glabra L.) consumption on cIMT dynamics was examined in 94 participants aged 41–80 years. It was demonstrated that cIMT reducted by - 0.008 mm in licorice-treated group and increased by +0.003 mm in placebo group  . Among obo group . In clinbo group .Based on this evidence in our knowledge prevention and treatment of atherosclerosis with medicinal plants has certain limitations. The most important fact is that natural products have multiple therapeutic effects, and it will be almost impossible to know which exact nature of the mechanism of action has led to a beneficial effect. This is especially true for natural complexes in which plants can potentiate and/or attenuate the effects of each other due to various multiple mechanisms of action. Almost all studies have a sufficient number of limitations, very few of them are registered, so it is difficult to assess the main outcome indicators and adverse reaction. Most researchers report that there are no side effects, but protocol requirements for recording any side effects are usually not given; moreover, possible interactions with prescription preparations practically are not describe. Therefore, given the importance of long-term prevention of atherosclerosis and reduction of cardiovascular risk, it is recommended to use the medicinal plants possessing pleiotropic anti-atherosclerotic effects in experimental studies those have shown atheroprotective activity in registered clinical trials.https://clinicaltrials.gov/ . This research was also supported within the framework of the grant provided by CSP Ministry of the Health Russian Federation, and by the IPAC RAS State Targets Project # 0090-2019-0005” for Gjumrakch Aliev. This work partially was also supported by the Russian Academic Excellence Project “5-100” for the Sechenov University, Moscow, Russia (for Gjumrakch Aliev and Vadim V. Tarasov).GA was employed by GALLY International Biomedical Research LLC.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Prevotella copri (increased) and Prevotella histicola (depleted), as well as Gram-positive Bifidobacterium dentium (increased) and Bifidobacterium bifidum (depleted). In total, 21 auto-antigens were predicted to be related to RA, and five of them were previously reported to be associated with RA with experimental evidence. Furthermore, we identified 94 potential adhesive virulence factors including 24 microbial ABC transporters. While eukaryotic ABC transporters are key RA diagnosis markers and drug targets, we identified, for the first-time, RA-associated microbial ABC transporters and provided a novel hypothesis of RA pathogenesis. Our study showed that RM, by broadening the scope of RV, is a novel and effective strategy to study from bacterial level to molecular level factors and gain further insight into how these factors possibly contribute to the development of microbial alterations under specific diseases.Alterations in the gut microbiome have been associated with various human diseases. Most existing gut microbiome studies stopped at the stage of identifying microbial alterations between diseased or healthy conditions. As inspired by reverse vaccinology (RV), we developed a new strategy called Reverse Microbiomics (RM) that turns this process around: based on the identified microbial alternations, reverse-predicting the molecular mechanisms underlying the disease and microbial alternations. Our RM methodology starts by identifying significantly altered microbiota profiles, performing bioinformatics analysis on the proteomes of the microbiota identified, and finally predicting potential virulence or protective factors relevant to a microbiome-associated disease. As a use case study, this reverse methodology was applied to study the molecular pathogenesis of rheumatoid arthritis (RA), a common autoimmune and inflammatory disease. Those bacteria differentially associated with RA were first identified and annotated from published data and then modeled and classified using the Ontology of Host-Microbiome Interactions (OHMI). Our study identified 14 species increased and 9 species depleted in the gut microbiota of RA patients. Vaxign was used to comparatively analyze 15 genome sequences of the two pairs of species: Gram-negative  Microbiota are now widely recognized as the key player in maintaining host health. They have a profound impact on human diseases, including obesity , diabeteRheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory diseases, characterized by inflammation in the connecting or supporting structures of the body . RA is tPrevotella copri and Prevotella histicola have been found to be associated with RA  microbial organisms can be cultured in a laboratory . Next-geMost current microbiota and dysbiosis studies ended at the stage of identifying new microbes differentially enriched (increased) or depleted (decreased) in dysbiotic patients compared to healthy controls. Such studies are useful in uncovering microbial profiles in microbiome-associated diseases. However, given more microbiome profiles identified, it has become urgent, and yet a big challenge, to further study the underlying gene-level pathogenesis mechanisms that contribute to the diseases, which would lead to preventative and therapeutic measures against diseases. To address the challenge of efficiently identifying the underlying molecular mechanisms of microbiome-related diseases, we propose a Reverse Microbiomics (RM) strategy.Neisseria meningitidis serogroup B (MenB) (Streptococcus pneumoniae (Bacillus anthracis (The proposed RM strategy is inspired by Reverse Vaccinology (RV), which is an emerging vaccine development methodology that predicts vaccine targets by bioinformatics analysis of pathogen genomes . RV faciB (MenB) , Streptoeumoniae , and Bacnthracis . The Vaxnthracis . We haventhracis . AnticipPrevotella copri and Prevotella histicola, and Gram-positive Bifidobacterium dentium and Bifidobacterium bifidum). After analyzing 15 genome sequences of these two gut bacteria pairs, we successfully predicted and evaluated many auto-antigens and potential virulence factors that are likely to be associated with RA.In this study, we describe the development of the RM strategy and apply this strategy to the systematic identification of microbial gene factors contributing to the pathogenicity of RA. We found 23 gut bacteria species that played an important role in the disease of RA. We selected four of these species through our ontology-based comparative analysis that were grouped into two pairs  were included in the next analysis. The annotated differentially regulated bacteria, taxonomy ID, rank, location, PMID, and description information were collected in a pre-defined Excel file.RA related microbiome literature was searched on PubMed with the keywords “microbiome,” “microbiota,” and “Rheumatoid arthritis.” Each up- or down-regulated bacterium to be included in the study required that the bacterial alteration in the RA-associated microbiome must be concluded from the original peer-reviewed experiment-based research paper(s). Review articles were also used as sources for original research papers. Experimental assays identifying differential bacterial profiles included traditional culture-based approaches, 16S rRNA sequencing, and metagenomic sequencing. The meta-analysis identified enriched (increased) or depleted (decreased) microbe in RA patients compared to healthy controls. Only those enriched (increased) or depleted (decreased) microbe in RA patients compared to healthy controls with significant statistics . The Ontofox tool  was thenPrevotella copri (enriched) vs. Prevotella histicola (depleted); (ii) and Bifidobacterium dentium (enriched) vs. Bifidobacterium bifidum (depleted). The genome sequences of these four species were retrieved from the NCBI database. In addition, the information of these genomes, including strain names, NCBI BioProject numbers, NCBI BioSample numbers, and protein size, were also retrieved and summarized in Excel. All completed and annotated genomes with their NCBI BioProject numbers were used for Vaxign dynamic analysis. Given the BioProject numbers, Vaxign automatically retrieved the protein sequences of the chromosome and any possible plasmid(s) of these bacteria. For each protein, the Vaxign pipeline was used to compute various features, including subcellular localization, conservation among different strains, exclusion from non-pathogenic strains, and homology with human proteins  of enriched or depleted bacteria were found to be differentially regulated, only those bacteria altered at the species level were considered for the next step analysis due to the feasibility of identifying genomes matching these species. To make the prediction more specific, we selected pairs of bacterial species, and each pair consisted of enriched and depleted bacteria. With these selection criteria, we finally chose two pairs of representative bacterial species for further comparative genomics analysis, including (i) proteins . The defVaxign-ML was used to calculate and rank the corresponding protective antigenicity (protegenicity) scores of potentially pathogenic bacterial antigens . Vaxign-http://www.ontobee.org/. The Ontofox tool for taxonomy subclass extraction is available at http://ontofox.hegroup.org/. The Protégé-OWL editor for ontology visualization and editing can be downloaded from https://protege.stanford.edu/. The Vaxign program for comparative genome analysis is available at http://www.violinet.org/vaxign. The Vaxign-ML machine learning tool is available at http://www.violinet.org/vaxign/vaxign-ml. The Docker standalone Vaxign-ML is available at https://hub.docker.com/r/e4ong1031/vaxign-ml. The source code of the Vaxign-ML is available at https://github.com/VIOLINet/Vaxign-ML-docker .The COG protein function assignment was performed using the EggNOG 4.5 server . The first pairs were the P. copri and P. histicola, which were enriched and depleted in RA patients, respectively. P. copri has been known to play an important role in influencing the pathogenesis of RA  from the NCBI database (We hypothesized that specific pathogenic virulence factors were commonly found in the pathogenic (enriched) strains, which were also rarely found in probiotic (depleted) strains in the microbiome-associated diseases. To demonstrate the usage of the RM strategy, we selected two pairs of representative bacterial species , extracellular, or unknown. Among these 152 proteins, nine proteins were potential auto-antigen, while 143 proteins had no homology to human proteins. Adhesins are critical for pathogens to invade host cells. Therefore, a second filter was applied to select proteins with adhesin probabilities ≥ 0.51. Out of the nine potential auto-antigen, three proteins were predicted to be adhesins. On the other hand, among the 143 no human homology proteins, 77 were predicted to be adhesins.In the group of d genome . Out of Prevotella, P. copri DSM 1820 was used as a seed genome, and the same workflow described in the previous paragraph was applied (In the group of  applied . From thP. copri and B. dentium) had homology to human proteins through the RM strategy  transporter protein family proteins, 21 hypothetical proteins, 7 LPXTG-motif cell wall anchor domain proteins, 4 glycosyl hydrolase family proteins, 7 DNA-binding proteins, 3 cell wall-binding repeat proteins, 2 receptor family ligand-binding proteins, and 26 other proteins . Among tPrevotella copri, in which 14 proteins were predicted to have protegenicity scores of over 90% , which focuses on metagenomics shotgun sequencing and identification of the associations between microbiomes and diseases . Being “Another method similar to RM is the reverse ecology, which aims to use a systematic approach to study microbiome ecology and the interactions among different microbes and the environment in a particular microbiome niche. Several network-based reverse ecology approaches, including NetSeed , NetCoopOntology plays an important role in the standard representation of various data, metadata, and knowledge. The Ontology of Host-Microbiome Interactions (OHMI) developed by our group was used to systematically represent these diseases and microbes associated with rheumatic diseases . OHMI prKlebsiella pneumoniae, Proteus mirabilis, and Lyme disease spirochete Borrelia burgdorferi carry antigens that cross-react with human antigens  which play important pathological roles in RA . The predictive results were also insightful. Given the complexity of each use case presentation, this paper only reported only the RA use case as a proof-of-concept study, and we plan to report the other two use cases in the future. Meanwhile, the RM approach is generically applicable for researchers to test their own use cases.B. bifidum and B. dentium) and a pair of Gram-negative bacteria (P. copri and P. histicola) were selected and analyzed using the reverse comparative genome sequence analysis. Our study predicted 21 auto-antigens and 94 non-human homologous proteins, which were likely associated with RA formation. Many of these predictions were verified from published literature reports, and new hypotheses could be generated. The RM strategy presented here is also applicable to other microbiome-associated diseases. Overall, the RM strategy facilitates our understanding of diseases involving intricate host-microbiome interactions from bacterial level association to molecular level mechanism prediction.To address the important need for the identification of bacterial alteration and explore molecular mechanisms involved in disease development, we developed the new Reverse Microbiomics (RM) strategy. We applied the RM strategy to predict pathogenic auto-antigens and virulence factors associated with rheumatoid arthritis (RA) in the dysbiotic gut microbiota. The RM strategy includes the literature mining and annotation, ontology classification of mined results, and reverse informatics analysis inspired by reverse vaccinology. The reverse informatics analysis applies comparative genomics methods to identify new microbial gene factors contributing to the disease pathogenesis. Our strategy was used to study rheumatoid arthritis (RA). A total of 15 genomes from a pair of Gram-positive bacteria (All datasets generated for this study are included in the article/HW performed RA knowledge extraction, ontology representation, data analysis, and result interpretation. EO performed Vaxign data analysis. JK provided inflammatory disease and microbiome consultation and result interpretation. DS provided pharmacology and microbiome consultation and result interpretation. YH contributed to project design, ontology development, and data analysis. HW and YH contributed to the manuscript preparation and discussion. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Body mass-independent parameters might be more appropriate for assessing cardiometabolic abnormalities than weight-dependent indices in Asians who have relatively high visceral adiposity but low body fat. Dual-energy X-ray absorptiometry (DXA)-measured trunk-to-peripheral fat ratio is one such body mass-independent index. However, there are no reports on relationships between DXA-measured regional fat ratio and cardiometabolic risk factors targeting elderly Asian men.We analyzed cross-sectional data of 597 elderly men who participated in the baseline survey of the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study, a community-based single-center prospective cohort study conducted in Japan. Whole-body fat and regional fat were measured with a DXA scanner. Trunk-to-appendicular fat ratio (TAR) was calculated as trunk fat divided by appendicular fat (sum of arm and leg fat), and trunk-to-leg fat ratio (TLR) as trunk fat divided by leg fat.N = 347) were significantly larger than those who did not use such medication  (P < 0.05). After adjusting for potential confounding factors including whole-body fat, both TAR and TLR were significantly associated with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, fasting serum insulin, and the insulin resistance index in the non-user group and non-overweight men in the non-user group (N = 199).Both TAR and TLR in the group of men who used ≥ 1 medication for hypertension, dyslipidemia, or diabetes (“user group”; The trunk-to-peripheral fat ratio was associated with cardiometabolic risk factors independently of whole-body fat mass. Parameters of the fat ratio may be useful for assessing cardiometabolic risk factors, particularly in underweight to normal-weight populations. Some individuals are not obese or overweight according to standard weight tables, but have metabolic abnormalities that are characteristically associated with obesity . Such meWaist-to-hip ratio (WHR), a conventional weight-independent parameter and an index of abdominal fat distribution , was sugAssociations between DXA-measured truncal fat proportion and cardiometabolic risk factors have also been reported for Europeans –14 and NThe present study aimed to investigate the relationship between DXA-measured trunk-to-peripheral fat ratio and cardiometabolic risk factors in community-dwelling elderly Japanese men using baseline data from the second Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study.The FORMEN study is a large-scale community-based single-center prospective cohort study which aims to determine risk factors for osteoporotic fractures, prevent frailty, increase the number of healthy life years, and enhance the functioning and quality of life of elderly men in Nara Prefecture, Japan. Participants at the baseline survey were aged ≥ 65 years, lived at home, were able to walk without assistance from another person, and were able to provide self-reported information and written informed consent. The baseline survey of the first cohort of the FORMEN study was conducted from June 2007 to October 2008; details of the first cohort have been described elsewhere . In the Whole-body and regional fat mass were measured with a single DXA scanner  mounted on a mobile examination car in the same way as described previously , 18. The2). Overweight and underweight participants were identified using BMI cut-offs of 25 kg/m2 and 18.5 kg/m2, respectively. Systolic blood pressure and diastolic blood pressure were measured using an automatic oscillometric sphygmomanometer  with an appropriate cuff size based on the upper arm circumference of each participant. Participants were relaxed and seated with legs uncrossed at an appropriate ambient temperature. Measurements were performed with the right arm supported at the level of the heart after resting for 5 min. The mean value of two readings was used for analysis.Body weight, height, and waist circumference were measured in light clothing with no shoes. BMI was calculated as weight divided by height squared  and physical activity. Participants were asked to bring current prescriptions of medications to the baseline visit, and the nurses recorded the names and doses of the medications. Food frequency questionnaire (FFQ) for dietary intake of nutrients in Japan  was use2) was calculated using the Modification of Diet in Renal Disease Study modified for Japanese individuals by the Japanese Society of Nephrology as follows: eGFR = 194 × serum creatinine−1.094 × age−0.287 [Blood samples were obtained by vein puncture after an overnight fast for conventional biochemical tests. Levels of triglyceride (mg/dl) were determined by the enzymatic method (glycerol phosphate oxidase with glycerol blank) ; high-density lipoprotein  cholesterol by the Sekisui HDL direct method ; low-density lipoprotein  cholesterol by the Sekisui LDL direct method ; total cholesterol (mg/dl) by the ultraviolet method with cholesterol dehydrogenase ; fasting plasma glucose (mg/dl) by the ultraviolet method with hexokinase ; Hemoglobin A1c  by the latex aggregation immunoassay ; fasting serum insulin (μU/ml) by the chemiluminescent enzyme immunoassay ; aspartate aminotransferase (U/l) by the Japan Society of Clinical Chemistry recommended method ; alanine aminotransferase (U/l) by the Japan Society of Clinical Chemistry recommended method ; and creatinine (mg/dl) by the enzymatic method . To estimate insulin resistance, homeostasis model assessment-insulin resistance (HOMA-IR) was calculated using fasting plasma glucose and fasting serum insulin . Estimatge−0.287 .t test or Mann-Whitney U test. Correlations among cardiometabolic variables, potential confounders, and TAR/TLR were evaluated using Pearson’s correlation coefficients. Associations between TAR/TLR and cardiometabolic variables in the non-user or user group were evaluated using multiple regression analysis after adjusting for age, height, MET-minutes/week, current smoking, alcohol intake, energy intake, NaCl intake, and whole-body fat.All statistical analyses were performed with SPSS Statistics Desktop for Japan, Version 22 . Frequency distributions for the biochemical tests were determined. We confirmed that levels of biochemical markers were distributed log-normally. Therefore, these values were logarithmically converted before statistical analyses, analyzed, and expressed as geometric means. Medication status might affect cardiometabolic variables. Thus, subjects were stratified by mediation status to evaluate the association between TAR/TLR and cardiometabolic variables. Comparisons between users of hypertension, dyslipidemia, or diabetes medication (“user group”) and those who did not use such medication (“non-user group”) were performed using the unpaired Table N = 250), both TAR and TLR were significantly correlated with LDL cholesterol, HDL cholesterol, triglyceride, hemoglobin A1c, fasting serum insulin, fasting plasma glucose, and HOMA-IR. Similarly, both TAR and TLR in non-overweight men of the non-user group (N = 199) were significantly correlated with LDL cholesterol, HDL cholesterol, triglyceride, fasting serum insulin, and HOMA-IR. Both TAR and TLR also showed significant positive correlations with whole-body fat in the non-user group and non-overweight men of the non-user group.Table Table Table The present cross-sectional study showed significant associations between trunk-to-peripheral fat ratio and cardiometabolic variables  in elderly Japanese men who did not use hypertension, dyslipidemia, or diabetes medication. These associations remained significant even after whole-body fat was accounted for, indicating that trunk-to-peripheral fat ratio, independently of overall fat mass, was associated with cardiometabolic variables. In addition, these associations were also observed among non-overweight participants. These results indicate that a large volume of body fat may not be a prerequisite for the development of cardiometabolic abnormalities, and weight-independent indices (non-weight-reliant indices) such as regional fat ratios may provide additional information for the evaluation of health risks.A previous cross-sectional study from a representative Japanese female population (the JPOS study) reported that TAR was significantly correlated with LDL cholesterol, HDL cholesterol, and hemoglobin A1c levels and that the relationships between fat ratio and cardiometabolic variables were independent of relationships between fat volume and cardiometabolic variables . Our preAlthough BMI is the most common parameter related to adiposity for all age groups, it reflects total fat mass rather than body fat distribution. On the other hand, WHR is a weight-independent index which more accurately describes abdominal fat distribution than BMI , 26, 27.Although the pathophysiological background underlying the associations between trunk-to-peripheral fat ratio and cardiometabolic variables was not explored in the present study, the associations might be attributed to differences between visceral and subcutaneous adipose tissue. Subcutaneous adipose tissue acts as a “protective metabolic sink,” metabolizing and storing excess free fatty acids and storing the bulk of body energy . When thThis study has several strengths. First, DXA can be used to determine the bone and soft tissue composition of the whole body and subregions such as the arms, legs, and the trunk and is a simple and safe technique that can be used for children and the old and frail . FurtherThere are also some limitations worth noting. First, participants were not a random sample, but rather volunteers living in a certain region of Japan, and thus may not be representative of the entire Japanese population. Older adults who volunteer and engage in more volunteer activities have been reported to be more likely to have higher levels of well-being, including self-rated health, functional dependency, and depressive symptomatology . IndividThe trunk-to-peripheral fat ratio, a body mass-independent index, was associated with cardiometabolic variables in elderly Japanese men. Moreover, these associations were also observed among non-overweight men and were independent of associations between whole-body fat and cardiometabolic variables. Fat ratio parameters may be useful for assessing cardiometabolic risk factors, particularly in underweight to normal-weight populations. The trunk-to-peripheral fat ratio may also allow for the characterization of MONW individuals who are very common in Asian populations.


Genomics & Informatics has recently been archived in a GitHub repository. The full-text publications of volumes 10 through 17 are also directly downloadable from PubMed Central (PMC) as XML files. During the Biomedical Linked Annotation Hackathon 6 (BLAH6), we experimented with converting, annotating, and updating 301 PMC full-text articles of Genomics & Informatics using PubAnnotation, a system that provides a convenient way to add PMC publications based on PMCID. Thus, this review aims to provide a tutorial overview of practicing the iterative task of named entity recognition with the PubAnnotation/PubDictionaries/TextAE ecosystem. We also describe developing a conversion tool between the Genia tagger output and the JSON format of PubAnnotation during the hackathon.The prototype version of the full-text corpus of  Genomics & Informatics is the official journal of the Korea Genome Organization. The prototype version of the full-text corpus of Genomics & Informatics (GNI version 1.0) has recently been archived in a GitHub repository [Genomics & Informatics are growing, we needed a persistent and sharable repository to annotate and to upload the PMC articles of Genomics & Informatics.pository . FurtherGenomics & Informatics, making a custom dictionary using PubDictionaries, and uploading the annotation results into PubAnnotation. PubDictionaries is a public repository of dictionaries and PubAnnotation is a public repository of text annotations; these resources are primarily developed and maintained by the Database Center for Life Science (DBCLS), Japan [During the Biomedical Linked Annotation Hackathon 6 (BLAH6), we experimented with annotating the PMC articles of ), Japan ,4. PubAn), Japan .Genomics & Informatics corpus [Thus, the purpose of this interdisciplinary tutorial review is to share our experiences of using the PubAnnotation ecosystem and writing a conversion script to apply to the s corpus ,7. We prhttps://github.com/Ewha-Bio/Genomics-Informatics-Corpus/tree/master/code/BLAH; https://github.com/Ewha-Bio/Genomics-Informatics-Corpus/tree/master/XML).The conversion code between the Genia tagger output and JSON files and the indexed XML files for Genomics & Informatics during BLAH6 are both available through GitHub , initially to upload the Genomics & Informatics corpus. PubAnnotation provides a convenient way to add, annotate, and edit PMC publications based on PMCID. We specified the PMCID and uploaded the text files of Genomics & Informatics. In total, 301 documents were imported into the project.During BLAH6, we created a PubAnnotation pilot project, called BLAH6-GNI-Corpus  tags, chunk tags, and named entity tags. The tagger is specifically tuned for biomedical texts such as MEDLINE abstracts. The last tag is a semantic-level tag to classify named entities in the text into pre-defined categories such as proteins, DNAs, RNAs, cell lines, and cell types. For named-entity tags, B/I/O notation was used, wherein the B/I/O terminology refers to the beginning of the phrase (B), internal to the phrase (I), and outside of the phrase (O).The desired result of a dictionary-based text annotation task would be an index of the dictionary entities corresponding to the referenced target texts. PubAnnotation’s text sequencer turns a document into a sequence of characters, so that positions in the document can be specified unambiguously by character offsets. For this reason, a conversion tool between the Genia tagger output and the JSON import/export format of PubAnnotation was written in Python during BLAH6. As shown in A facility of visualization and manual editing is one of the primary aspects of making the PubAnnotation ecosystem adoptable by end-users. A user can easily add a new entry or delete an entry, in a try-and-revise manner."span":{"begin":89, "end":95} denotes an entity T1 "id":"T1" of which the type is Protein.In Once an annotation file is prepared, TextAE can be used for manual editing of NER , as in Fhttp://pubannotation.org/annotators/BLAH6-GNI-ANNOTATOR).In this tutorial review, we presented our experiences of conducting and agile text mining. During BLAH6, we created two separate PubAnnotation projects (BLAH6-GNI-Corpus and BLAH6-GNI-Corpus2), a dictionary (BLAH6-GNI-Dictionary), and an annotator (BLAH6-GNI-Annotator). A total of 12,908 labels were registered in the PubAnnotation ecosystem (While developing a conversion tool during BLAH6, indexing and calculating spans was a non-trivial task, as PubAnnotation utilizes character-based indexing; enforcement of a fixed tokenization of the text is technically expensive.Some minor suggestions relate to the user interface. In some menus, it was not fully obvious for a first-time user of the system what was clickable. We also had to create two separate projects, simply to utilize PubAnnotation’s text sequencer.We assume that there are many categories of users with different levels of experience and familiarity with PubAnnotation, ranging from pure natural language processing specialists to biomedical research end users. We hope that some additional features will be added to the PubAnnotation ecosystem, to provide diversified access to different groups of users, who have different needs regarding workflow and information density.


Thyroid cancers (TC) have increasingly been detected following advances in diagnostic methods. Risk stratification guided by refined information becomes a crucial step toward the goal of personalized medicine. The diagnosis of TC mainly relies on imaging analysis, but visual examination may not reveal much information and not enable comprehensive analysis. Artificial intelligence (AI) is a technology used to extract and quantify key image information by simulating complex human functions. This latent, precise information contributes to stratify TC on the distinct risk and drives tailored management to transit from the surface (population-based) to a point . In this review, we started with several challenges regarding personalized care in TC, for example, inconsistent rating ability of ultrasound physicians, uncertainty in cytopathological diagnosis, difficulty in discriminating follicular neoplasms, and inaccurate prognostication. We then analyzed and summarized the advances of AI to extract and analyze morphological, textural, and molecular features to reveal the ground truth of TC. Consequently, their combination with AI technology will make individual medical strategies possible. Thyroid cancers (TC) have emerged in popularity over the past decades, with indolent TC accounting for the majority –3. For aArtificial intelligence (AI) is a series of technologies combined to mimic human interaction Figure 1In this review, we aimed to summarize the use of AI for extracting and analyzing morphological, textural, and molecular features to reveal detailed information and personalize therapies for TC patients Figure 2TN with several typical ultrasound features implies an increased risk of malignancy, such as solid composition, hypoechogenicity, irregular margin, microcalcification, and taller-than-wide shape. However, these properties can neither confirm nor exclude the diagnosis of TC . The obsWildman-Tobriner et al.  developeA meta-analysis suggested that a taller-than-wide shape displays TN’s variation in space and orientation growth, and it is defined as the most suggestive feature for malignancy . TextureFNA is a primary preoperative examination to evaluate TN. Its report system, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), is a state-of-the-art and category-based method for clinicians’ decision-making. While TBSRTC includes six diagnostic categories on the estimated risk of malignancy (ROM) Table 2,PTC, the most common TC (>80%), arises from abnormal growth of thyroid epithelial cells , 38. In The major difference between FC and FA is the occurrence of capsular or vascular invasion . PreoperFor patients with ITN, repeat FNA or lobectomy might be performed because management guidelines are more flexible , 73. ForBRAF mutations  and tumor nest  . The morThe morphological feature is the final station of biological behavior and genetic variation of TN. The morphological performance supported by AI might be beneficial for the accurate diagnosis of TN. Wang et al.  successfMorphologically, FV-PTC is a mixed entity for typical PTC nuclear features and entirely or almost entirely follicular growth patterns. FV-PTC includes two major subtypes: encapsulated (EFV-PTC) and non-encapsulated or infiltrative variants (IFV-PTC) . The forAs FV-PTC’s definition stated, the coexistence of papillary and variable follicular structures is so common in cancer nests that we hold a positive view about more transitional or intermediate categories between the cPTC and FV-PTC. Undoubtedly, the clearer the learning exemplars, the easier it is to learn for the AI model because it receives fewer error messages . For greThe American Thyroid Association risk stratification system and the American Joint Committee on Cancer TNM staging system are used to guide postoperative treatment and predict post-treatment outcomes, which incorporate several parameters including age, ETE, anatomic location, number, and size of metastatic lymph nodes, aggressive variants, vascular invasion, and distant metastasis. Nonetheless, these systems fail to routinely recommend a genetic determination to guide individual management , 93. ZhaThe future development of personalized medicine in TC still faces several challenges like inconsistent rating ability of US physicians, uncertainty in cytopathological diagnosis, difficulty in discriminating follicular lesions, and inaccurate prognostication. AI’s application has improved the efficiency and accuracy of diagnosis and treatment in other tumors –96. A grL-RL: study design, literature review, article writing, and revision. BD: literature review. H-QL: literature review. CC: study design, article revision. All authors contributed to the article and approved the submitted version.This research was supported by the grants from the Fundamental Research Funds for the Central Universities (2042019kf0229) and the Science and Technology Major Project of Hubei Province (Next-Generation AI Technologies) (2019AEA170).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Children of immigrants are often considered to be at increased risk of mental health problems due to families' immigration-related stress and perceived discrimination and prejudice from the host country. However, many studies found them to have better developmental outcomes than children with native-born parents in the U.S. This study aims to unfold this paradoxical phenomenon using data from a population-based cohort of children born in large U.S. cities. Specifically, we investigated differences in mental health outcomes between children of immigrants and those with native-born parents, stratified by children's race-ethnicity. We also explored the mediating role of child maltreatment risk in the association of parental nativity status and race-ethnicity with children's mental health. Our findings supported the immigrant paradox, with better self-reported and parent-reported internalizing and externalizing outcomes in Hispanic and Black children of immigrants than their same race-ethnicity peers and White children of native-born. Such immigrant-native variations were partially explained by parents' physically and psychologically abusive behaviors. Hispanic and Black children with immigrant parents were less likely to be physically or psychologically abused than their peers of native-born at ages 4–5, which translated into mental health advantages of children of immigrants at age 9. Our findings shed light on future research to further clarify the mechanism underlying different parenting practices between same race-ethnicity immigrants and native-born families so that culturally responsive interventions can be developed to safeguard racial-ethnic minority children's mental health. In the United States (U.S.), immigration has played an essential role in shaping and reshaping the racial-ethnic diversity of children and adolescents. In 2018, ~18 million 26%) children and adolescents under the age of 18 lived with at least one foreign-born parent  . Childre% childreAmong the large body of studies documenting the immigrant paradox, there has been an inconsistent operationalization of the paradox. Previous research often compared children of immigrants with their White counterparts with native-born parents to document the paradox . Such apStudies of racial-ethnic minority often suggest that Black and Hispanic children, regardless of immigration background, experience more behavioral problems and mental health challenges than their White counterparts , 11. A sHowever, when distinguishing Hispanic and Black children by parental nativity status, the evidence is less straightforward. Among Hispanic children of immigrants, some research has identified that the protective effect of nativity on behavioral outcomes tend to decrease as individuals spend longer time in the United States , 7. A stBlack children and families have often been treated as a homogeneous group. Only a handful of studies examined the potential differences between immigrant and native-born Black families. A study with a nationally representative sample of children found that Black children of immigrants of age 4 compared favorably to their Black peers of native-born in terms of social behaviors in the classroom such as cooperating with other children and aggression . HoweverWhile documenting the immigrant paradox by race-ethnicity is informative, research is also needed to identify the mechanism underlying the relations between parental nativity status and mental health outcomes among Hispanic and Black children. Parenting plays an important role in determining children's behavioral outcome and mental health functioning . ResearcEvidence has shown that immigrant Hispanic parents are less likely to use physical punishment and emotional aggression toward their young children than native-born Hispanic parents –27. SomeBlack children, in general, are overrepresented among child abuse and neglect victims compared to Whites , 31. OneTaken together, children of immigrants are a heterogeneous group with vastly different social and cultural experiences. Such variety, as a determinant of parenting practices and child maltreatment risk, may complicate our understanding of the immigrant paradox. To unfold the immigrant paradox in children's mental health outcomes, it is critical to acknowledge the diversity among children of immigrants in terms of race-ethnicity and investigate the underlying mechanisms of the mental health disparities. Using a populated-based sample of U.S. families, this study investigates: (1) to what extent do mental health outcomes differ between children of immigrants and their peers of native-born across different racial and ethnic groups ; and (2) whether child maltreatment risk, operationalized as parents' physically abusive, psychologically abusive, and neglectful behaviors, can explain racial and ethnic differences in mental health outcomes. Based on theoretical expectations and existing empirical research, we hypothesize that, across all racial-ethnic groups, children of immigrants will have more favorable mental health outcomes than their White peers of native-born and their same race-ethnicity peers of native-born. Moreover, maltreatment risk may explain the differences; that is, children of immigrants will be less likely to experience maltreatment  than their counterparts of native-born and thus have better mental health outcomes.We used data from the Fragile Families and Child Wellbeing Study (FFCWS), a longitudinal study of a diverse cohort of children born between 1998 and 2000 . The FFCAt baseline, the full sample included 3,711 non-marital births and 1,187 births to married parents . Due to Parents' nativity status was determined by their answers to a question regarding whether the parent was born in the United States at childbirth. Children were coded as “children of immigrants” if they had at least one foreign-born parent and were coded as “children of native-born” if both parents were born in the United States. Race-ethnicity was categorized as non-Hispanic White, non-Hispanic Black, and Hispanic based on mothers' race-ethnicity due to a large proportion of unmarried mothers in the sample. Children who did not belong to those categories  were grouped as “other” by the FFCWS. We did not include the “other” group in our analyses due to the limited racial-ethnic information. Finally, six mutually exclusive groups  were identified to capture the intersection of parental nativity status and race-ethnicity.We operationalized mental health outcomes with internalizing and externalizing behaviors, two of the most critical mental health domains for children , 6. BothZ-score with a mean of 0 and a standard deviation of 1 to represent each child's internalizing and externalizing score relative to peers . The correlations between parent- and child-reported mental health outcomes were 0.12 for internalizing behaviors and 0.26 for externalizing behaviors, suggesting distinct information reported from the difference sources.For both parent- and youth-reported internalizing and externalizing behavior questions, a three-point Likert-scale was used to rate whether primary caregivers or the child felt “not true,” “sometimes or somewhat true,” or “very true” with each of the items. The responses were summed so that higher scores represent more unfavorable behaviors. In the study sample, Cronbach's alpha was 0.79 and 0.89 for parent-reported internalizing and externalizing scales, and 0.78 and 0.76 for youth-reported internalizing and externalizing scales, respectively, suggesting good reliability . We furtIn addition to the internalizing and externalizing scores collected at age 9, we used parent-reported scores collected at age 5 in our analyses  as control variables. Those scales also had good reliability for internalizing and externalizing behaviors . The FFCWS did not collect data on child-reported internalizing and externalizing behaviors at age 5.Z-scores for physical assault, psychological aggression, and neglect, with a mean of 0 and a standard deviation of 1. We then calculated averaged scores at ages 3 and 5. The Cronbach's alpha for physical assault, psychological aggression, and neglect subscales at ages 3 and 5 were around 0.60.We examined childhood maltreatment risk based on primary caregivers' report on their physically abusive, psychologically abusive, and neglectful parenting behaviors toward the focal child based on items from the Parent-Child Conflict Tactics Scale . The phyWe considered a rich set of child and family characteristics as control variables that may influence the relationship between race-ethnicity, parental nativity status, child maltreatment, and children's mental health outcomes as identified in prior work such as by Berger . With thMplus to account for missing values in our study  estimation in ur study .Mplus 7.4. As shown in We used Structural Equation Modeling (SEM) to examine mediational models in r = 0.73, p < 0.001), following prior research , about 21% had at least one parent who was born outside of the United States. Among children of native-born, about 26% were non-Hispanic White, 55% were non-Hispanic Black, and 19% were Hispanic. Of the children of immigrants, about 11% were non-Hispanic White, 18% were non-Hispanic Black, and 71% were Hispanic. We found that children of immigrants were less likely to have a low birth weight and more likely to live in a married family, while more likely to have worse family socioeconomic status than their peers of native-born. Our results indicate that children of immigrants had a lower risk of physical assault and psychological aggression, comparable neglect score, better parent-reported externalizing, and better self-reported internalizing and externalizing behavior scores than their peers of native-born.b = −0.11, p < 0.001) and externalizing  scores compared to White children of native-born. However, Black children of native-born had higher (worse) self-reported internalizing  and externalizing  scores compared to the White children of native-born. Hispanic children of native born had better parent-reported externalizing scores  than White children of native-born. Hispanic children of immigrants had better parent-reported externalizing scores  and self-reported externalizing scores  than their White peers of native-born.Results in b = 0.25, p < 0.001) than White children of native-born. Hispanic children of immigrants had a significantly lower risk of physical assault  relative to White children of native-born. The risk of experiencing physical assault, in turn, was positively associated with levels of parent- and self-reported internalizing and externalizing behaviors.Regarding indirect relationships, as shown in Results in b = −0.38, p < 0.001; b = −0.48, p < 0.001, respectively). Such differences contributed to more favorable mental health scores for Black children of immigrants compared to their peers of native-born. Results in b = −0.29, p < 0.001) and psychological aggression . Such results suggest that Black and Hispanic children of immigrants were less likely to suffer from maltreatment, which contributed to better mental health outcomes than their peers of native-born with same race-ethnicity.We further examined whether racial and ethnic minority children of immigrants, namely non-Hispanic Black and Hispanic children, had a lower maltreatment risk and thus better mental health outcomes relative to their peers of native-born. To unfold the immigrant paradox in children's mental health outcomes, this study investigated factors that can potentially explain mental health disparities based on race-ethnicity and parental nativity status. Specifically, we examined the role of child maltreatment risk  in mediating the associations of parental nativity status and race-ethnicity with children's internalizing and externalizing outcomes. Our findings supported an immigrant paradox in children's mental health outcomes, suggesting that children of immigrants generally had more favorable self-reported and parent-reported internalizing and externalizing scores than both White children of native-born and their same race-ethnicity peers of native-born. Such native-immigrant variations were partially explained by parents' physically and psychologically abusive behaviors. More specifically, Hispanic and Black children of immigrants were less likely to be physically or psychologically abused than their same race-ethnicity peers of native-born at ages 4–5, and thus had better internalizing and externalizing outcomes at age 9. We discuss our findings separately for Hispanic and non-Hispanic Black children below considering the unique cultural characteristics with each group.familismo values closeness and interconnectedness among extended family members, which includes a sense of responsibility to care for family members, particularly for young children (Our findings suggest that having mothers living in and acculturating to the U.S. culture may be associated with increased risk of maltreatment and, in turn, mental health difficulties among Hispanic children of native-born compared to their peers of immigrants. Such results are consistent with existing studies suggesting that first- and second-generation Hispanic children show better mental health outcomes than their peers of U.S.-born parents from comparable socioeconomic backgrounds , 13. Onechildren . Recent children , 29.The immigrant paradox in children's mental health was also explored among non-Hispanic Black children in this study. Compared with Black children of native-born, Black children of immigrants had better parent- and youth-reported internalizing and externalizing outcomes. Compared to studies on Hispanic immigrants, research in the “Black immigrant paradox” is noticeably lacking. In particular, there is little evidence on the mental health advantages among Black children of immigrants. Some research suggested that although immigrant and native-born Black families may experience comparable socioeconomic disparities and racial discrimination, immigrant cultural traits such as family cohesion and positive parenting could serve as a buffer against those adverse conditions for Black immigrant parents , 17. OurAdditionally, we found that Black children of native-born reported themselves to have the most internalizing and externalizing difficulties among all groups, which is consistent with existing evidence suggesting the disproportionate burden of mental health disorders among Black children , 49. HowAlthough our findings suggest the potential protective role of parental cultural values in immigrant families, it is unclear how gaining American cultural values could contribute to the immigrant paradox in children's mental health. Evidence on the role of the U.S. culture has been mixed. On the one hand, the U.S. culture can be protective because it does not endorse authoritarian beliefs and practices as much as in other cultures; such less restrictive parenting style may contribute to lower risk of physical punishment . On the Several caveats apply to the findings presented in this study. First, we were not able to include other racial-ethnic groups such as Asian, Native American, and children with mixed-racial backgrounds in our analyses due to the unavailability of such data. National data suggested that the number of newly arrived Asian immigrants have surpassed Hispanic immigrants since 2010 . HoweverDespite the limitations, this study's results provide substantial evidence on the immigrant paradox in children's mental health among Black and Hispanic children and the underlying mechanisms through child maltreatment risks. The relatively better mental health outcomes among immigrant children do not suggest that they need less mental health prevention and treatment services. Instead, children of immigrants that need mental health services are found to be less likely to receive treatment than their peers of native-born due to a wide range of structural and sociopolitical obstacles, such as poverty, lack of insurance, language, and cultural barriers, and insufficient availability of mental health services in immigrant neighborhoods . The U.Shttps://fragilefamilies.princeton.edu/data-and-documentation/public-data-documentation.Publicly available datasets were analyzed in this study. This data can be found here: Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LZ contributed to the study design and performed the data analysis. All authors, including LZ, AB, and WL interpreted the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Fluoropyrimidine (FP) is used to treat a wide range of cancers; however, it is associated with drug-induced vascular toxicity, as well as angina pectoris and coronary spasm. FP has been administered for many years, although the incidence, mechanisms, and appropriate methods for managing its associated cardiovascular toxicities have not been clarified, and the management of these complications has not been standardized. This lack of evidence is not limited to FP. Many trials of anticancer agents have been conducted, excluding patients with heart diseases. Hence, there is a paucity of epidemiological data on cardiovascular adverse events caused by anticancer agents. There have been remarkable improvements in cancer treatment in recent years, with consequent improvements in prognosis. In this context, new cardiovascular toxicities related to new drugs have emerged. We are now compelled to respond to cardiovascular adverse events despite the lack of evidence regarding optimal management. The result has been establishment and rapid maturation of the new academic field of cardio-oncology. Despite the relative lack of evidence, we must review small pieces of evidence that have accumulated to date and make the utmost efforts to provide patients with effective evidence-based medical care. Simultaneously, we urgently need randomized clinical trials to build strong evidence. According to the WHO, cancer incidence is predicted to increase by about 70% over the next 20 years . While sIn particular, cardiovascular diseases such as angina pectoris and heart failure significantly alter overall morbidity and mortality. The need for appropriate interventions for cardiovascular diseases in cancer patients and cancer survivors has given rise to the medical specialty of cardio-oncology .Anthracycline, an important anticancer agent with a long track record, and trastuzumab, used for breast and gastric cancers, cause cardiotoxicity . Many otFP is an antimetabolite agent used to treat solid tumors such as colon, breast, and head and neck cancers. It possesses a structure similar to that of substrates and enzymes required for DNA replication. Subsequent to cellular uptake, FP becomes active by each and exerts its antitumor effects by inhibiting DNA and RNA synthesis. 5-FU possesses a structure in which a hydrogen at position 5 of the pyrimidine ring is substituted by fluorine. This drug was generated because uracil is readily taken up into tumor cell DNA. 5-FU is metabolized to 5-fluorodeoxyuridylate, suppressing DNA synthesis by inhibiting thymidylate synthase. 5-FU is also converted to 5-fluorouridine triphosphate, which is incorporated into RNA and inhibits RNA synthesis . CapecitCardiovascular adverse events associated with FP, especially with FU, include angina with coronary artery spasm and ischemic heart disease secondary to coronary artery thrombosis. In addition to ischemic heart diseases, there have been reports of direct myocardial damage, including more serious cardiovascular toxicity –9. 5-FU In this review, we present an updated overview of FP-induced cardiovascular toxicity, its mechanisms, pathophysiology, and available treatment options.Incidence of FP-related cardiovascular toxicity ranges from 1 to 19% , and morIn a review of 377 cases of FP-related cardiotoxicity, while only 14% of patients had a history of heart disease, 37% were found to have known risk factors for heart diseases , of whicConcomitant use of FP with cisplatin and leucovorin increased the incidence of 5-FU-related cardiovascular toxicity , 24. The5-FU is considered a radiosensitizer in patients receiving radiation therapy and concomitant chemoradiotherapy; there have been reports of possible involvement of 5-FU in the development of cardiovascular complications by accelerating small vessel thrombosis , 30.The incidence of cardiovascular toxicity attributable to 5-FU may depend on the administration route. Cardiovascular toxicity occurs more commonly when administered by continuous intravenous infusion over many hours , 34, 44.Several factors have been identified as major issues regarding FP-related cardiovascular toxicity. It is difficult to summarize data from the large number of published reports. The definitions of FP-related cardiovascular toxicity of each report are often based on different criteria; many are case reports; many others lack accurate data in line with current methods, i.e., combination therapy with other cardiotoxic anticancer agents rather than FP monotherapy .The most common symptom related to 5-FU-induced angina is chest pain. There are also reports of palpitation, shortness of breath, and pleural pain. Symptoms appear at rest or on exertion . PatientThere is no difference between 5-FU-induced cardiovascular toxicities and those caused by capecitabine . Angina FP-related cardiovascular toxicity usually develops during the first cycle of administration , 41, 54,No diagnostic methods have been established by which FP-related cardiovascular toxicity can be specifically diagnosed. To correlate cardiovascular events with FP treatment, causal relationships should be clarified based on clinical course, e.g., increased incidence of cardiovascular events occurring during treatment with FP and reproducibility of cardiovascular events upon re-administration of FP.Biomarkers are commonly used in cardiovascular clinical practice, including those that indicate myocardial injury, such as troponins T and I, creatine kinase myocardial band, and those that indicate cardiac load, such as B-type natriuretic peptide. These biomarkers are not highly sensitive to FP-related cardiovascular toxicity. Nevertheless, as cardiovascular toxicity develops, levels of these biomarkers increase abnormally , 52, 55.Jensen et al. examined biomarkers related to the coagulation system following FP administration. They measured thrombus-related biomarkers in patients with colorectal cancer, focusing on vascular endothelial damage by FP and subsequent thrombus formation. The authors found significant increases in D-dimer and von Willebrand factor (wWF) levels, while levels of coagulation factors II, VII, and X significantly decreased . DespiteOther potential biomarkers of FP-related cardiovascular toxicity include heart-type fatty acid-binding protein  and angiECG abnormalities are not highly sensitive for detecting abnormalities due to FP-related cardiovascular toxicity; nevertheless, supraventricular arrhythmias including arterial fibrillation , ventricHolter-ECG is useful for detecting 5-FU-related cardiovascular toxicity, especially ST-T wave abnormalities and arrhythmias , 27, 35.Echocardiography is not highly sensitive for detecting abnormalities caused by FP-related cardiovascular toxicity; nevertheless, echocardiogram can detect diffuse or focal left ventricular hypokinesis or decreased ejection fraction (EF) caused by FP. Wacker et al. found decreased EF in 10.5% of patients with symptomatic acute FP-related cardiovascular toxicity . NeverthIn the context of ST-T abnormalities and detection of cardiac enzymes such as troponin, it is necessary to exclude coronary artery lesions. The high negative predictive value of coronary computed tomography angiography (CCTA) in detecting coronary artery disease is well known. CCTA is relatively non-invasive and generally highly significant in the context of low risk patients. If a coronary artery lesion is detected using CCTA, detailed evaluation with high diagnostic significance such as catheterization is then proposed. Catheterization is indicated expediently for patients requiring further detailed examinations after CCTA for patients with heart failure, recurrent angina attacks, serious arrhythmias such as ventricular tachycardia and ventricular fibrillation, as well as for patients at high risk for coronary artery lesions such as cardiogenic shock. Coronary spasm is often involved in FP-related angina, and in many cases, coronary artery lesions are not detected or only mild stenotic lesions are detected , 57, 58.In some patients, coronary angiography only detects moderate stenotic lesions in coronary arteries, making it difficult to determine whether the chest pain is attributable to a coronary artery event. In such cases, to make a definitive correlation with coronary spasm, provocative testing using ergonovine or acetylcholine is sometimes considered. Provocative testing is invasively risky; therefore, determining its indication requires careful consideration. In patients with coronary spasm symptoms with high clinical certainty in whom significant stenosis of coronary arteries are not found, and no abnormalities of ST-T wave are detected, provocative testing should be performed after obtaining informed consent and thorough examination of the risk-benefit.The pathogenesis and mechanisms of FP-related cardiovascular toxicity development remain to be elucidated , 59••. TDPYD) are thought to be associated with common 5-FU-related drug adverse events, including bone marrow suppression and diarrhea. There are reports that DPYD mutations are involved in the development of 5-FU related cardiovascular toxicity [DPYD mutations and the development of 5-FU related cardiovascular toxicity [The enzyme first involved in 5-FU catabolism is DPD . Decreastoxicity . On the toxicity . One stutoxicity . Thus, nThe association between 5-FU dose and cardiovascular toxicity remains unclear . A studyThe most important clinical pathophysiology of FP-related cardiovascular toxicity is coronary spasm, in which vascular endothelial cell injury is thought to be markedly involved. There is a report that reversible vasoconstriction involving endothelial dysfunction occurred due to exposure of the aorta to 5-FU in an experimental model . It was Another study found that 5-FU directly damaged vascular endothelial cells and myocardial cells by blocking cell proliferation cycles . This daThere are no standard recommended drugs based on the evidence for FP-related cardiovascular toxicity. Nevertheless, discontinuation of FP and administration of nitrates and calcium antagonists are thought to significantly improve ischemic symptoms in patients in whom coronary spastic angina clearly developed during FP treatment and in those in whom myocardial ischemia was clearly detected by ECG relative to treatment . When caUridine triacetate is an oral prodrug of uridine. After uridine is taken up and converted, it reduces the uptake of 5-FU into non-cancer cells, resulting in inhibition of various adverse events, including targeted cell injury and cell death due to 5-FU overdose. Uridine triacetate has been approved by the Food and Drug Administration (FDA) as an antidote for overdose and serious acute adverse events of 5-FU or capecitabine . NeverthThere are mixed opinions regarding whether re-administration of FP to patients who have once developed FP-related cardiovascular toxicity is appropriate. In cases of FP-related cardiovascular toxicity, especially coronary spasm, recurrence of spasm is not uncommon ; the repS1 is an oral FP drug consisting of tegafur and gimeracil, which are prodrugs of fluorouracil and oteracil potassium, respectively. Although the use of S1 is not approved in the USA, it is widely used in Japan for cancers including gastric, colon, head and neck, pancreatic, and unresectable and recurrent breast cancers . There aUFT is an oral combination drug of two agents: tegafur (a prodrug of FU) and uracil (which inhibits FU degradation and increases FU concentrations). The incidence of cardiovascular toxicity is reportedly less than 1% , 85. It TAS-102 is an FDA-approved drug that has been reported to be an FP drug with low cardiotoxicity when administered in patients with colon cancer .As a treatment for FP-related cardiovascular toxicity, experimental evidence suggests that glucagon-like peptide 1 (GLP-1) may counteract 5-FU-induced decreases in the expression levels of endothelial nitric oxide synthase and SIRT-1 indicating its potential as an FP-related cardiovascular toxicity treatment. The possibility of treatment of FP-related cardiovascular toxicity with GLP-1 analogs and GLP-1 degradation inhibitors in the future has also been reported •.DPYD gene, are potential risk factors for more serious cardiovascular toxicity [Pharmacogenomic interventions are useful to elucidate the relationship between the efficacy of FP drugs and drug-related cardiovascular toxicities and to stratify cardiovascular toxicity risk. Polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, and orotate phosphoribosyltransferase, in addition to the toxicity . These f


Self-continuity, the sense that one’s personal past, present, and future selves are meaningfully connected, is unique to human beings. Self-continuity varies across individuals with higher levels conveying benefits for mental health and well-being, physical health and health-related behaviors, as well as financial planning and moral choices . From a developmental point of view, self-continuity emerges over the course of childhood, but less is known about its development in adulthood. Recent evidence indicates that higher chronological age is associated with higher perceived self-continuity among healthy adults. Studies further suggest that age effects are more pronounced for more distant time intervals but fairly symmetrical for past and future . However, prior work has predominantly relied on U.S. convenience samples raising questions about generalizability to broader population samples as well as cross-national consistency of the findings. To address these concerns, the present study examined self-continuity in the German Socio-Economic Panel . In addition to replicating the previously reported positive association between age and self-continuity  and testing for curvilinear effects, we report on the role of temporal direction (past vs. future), temporal distance , and demographic factors . The present findings add to the literature on adult age differences in self-continuity. Practical implications and directions for future research are discussed.


While relaxation-oriented interventions are more frequently employed in occupational settings, cognitive-behavioral stress management interventions reveal stronger effects on stress-related outcomes. As an effective and economic strategy, the dissemination of stress management programs via the internet is soaring, but most internet-based programs focus on relaxation or reducing perceived stress. In the present study, we examined the effects of a self-guided, cognitive-behavioral 6-week Internet-Based Stress Management (IBSM) program on perceived stress, coping skills, emotional exhaustion, depressive symptoms, and sleep quality. The IBSM consists of six modules focusing on the improvement of stress management skills such as dealing with acute stress, building up resources, or reappraising stress-facilitating cognitions. The participants have to work through the content on a weekly basis, requiring about 30 min per week followed by a transfer task lasting another 30 min. Healthy employees reporting elevated stress were recruited over the Internet and then randomly assigned to the IBSM group or a waiting list control group. A total of 134 participants completed all assessments before and after the training or waiting period. The IBSM group reported lower subjective stress levels after the program than the control group. In addition, the IBSM group exhibited improved coping skills and better sleep quality. Emotional exhaustion was reduced in both groups, while depressive symptoms did not change. These results suggest that a brief, 6-week, cognitive-behavioral internet-based stress management program improves coping skills, sleep quality, and well-being, and reduces the perceived stress of employees. Our results might encourage large-scale studies on the long-term stability and clinical efficacy of internet-based programs. The trial is registered in the German Clinical Trials Register (DRKS00014837) URL. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00014837Occupational stress management intervention programs are known to be effective in preventing stress-related health burden. Two essential mechanisms underlie this effect: (i) a reduction in perceived stress (e.g.,  Occupational stress is a widespread phenomenon. In Germany, more than 60% of all employees feel frequently or sometimes stressed . ChronicPsychological interventions to teach effective ways of handling a heavy workload by improving individual stress management skills have been proposed as a promising means of preventing the health burden caused by work-related stress .There is solid evidence that interventions based on cognitive-behavioral therapy provide particular support for persons suffering from work-stress , 10. Cogvia relaxation techniques . Concerning face-to-face stress management training programs in an occupational setting representing a wide range of different occupations, the latest meta-analysis of Richardson & Rothenstein . The effects differ according to the training content. Notably, the strongest impact on perceived stress was identified in cognitive-behavioral-oriented programs , outperforming relaxation oriented training , and multimodal programs .In healthy but stressed individuals, such interventions are directed to (i) reduce perceived stress and (ii) improve individual coping skills. Whereas some programs focus on reducing stress levels by fostering relaxation, recovery, and recreation , othershenstein  includedNowadays, online-based interventions offer a welcome and growing opportunity to offer stress management training to individuals. The general transfer of psychological interventions from face-to-face to structured self-help online training programs relies mainly on cognitive-behavioral therapy principles . The guiIn particular, self-help interventions that are Internet-based and standardized reveal several advantages over face-to-face training, including flexible and time-independent availability using multimedia content of consistent quality , 25. On d = 0.43; 95% CI, 0.31–0.54) including 26 studies with about 4,200 participants  with an internet-based training intervention specifically developed to restore depleted resources and alleviate sleeping problems. Concerning sleeping quality there is a difference in effects between online training interventions with or without guidance. Self-help programs reveal smaller effects than guided programs; on the other hand, there is an economic advantage to distributing standardized and effective interventions to people who are hard to reach. Ebert et al. (d = 0.33) of an unspecific self-guides stress management training program on sleep quality.Elevated stress and impaired sleep are strongly associated  and cognFurther secondary outcomes were examined in several studies evaluating cognitive-behavioral stress-management interventions in healthy individuals delivered face-to-face or internet-based, including emotional exhaustion e.g., , 38, 39], 3938, 3In the present study, we investigated effects of a standardized self-guided cognitive-behavioral 6-week ISBM program distributed solely over the internet, without any personal contact with a mental health professional on healthy employees. Therefore, we compared a training-group to a waiting-list control group. We hypothesized that the training group would improve their stress management skills and perceive reduced stress, which in turn would lead to better sleeping quality, and thus reduce the subsequent health burden.A randomized controlled trial was conducted with two conditions: a standardized self-guided IBSM program and a waiting condition. Participants randomized to the waiting group were allowed to access the training program after the post-treatment measure without further professional support. Assessments took place at baseline (T1) and post-treatment . The study protocol was approved by the institutional review board of the University of Freiburg (Germany). The trial is registered in the German Clinical Trials Register (DRKS00014837).via newspapers advertisements. In all, 432 persons responded to our invitation and were sent a link to an online screening test to determine eligibility in line with our inclusion and exclusion criteria. We included individuals who claimed to be currently working full-time or at least half-time, were above the age of 18 years, experiencing elevated stress levels and interested in improving their stress management skills, and who had adequate internet access and sufficient skills in reading and writing German. We excluded individuals who were currently under or who had within the previous 6 months undergone medical or psychotherapeutic treatment for a psychiatric disorder or a mental-health problem, and any who reported traumatic experiences or suicidal ideation within the previous 6 months. All information concerning our participants' inclusion or exclusion criteria were collected via online questionnaires.We employed two ways to recruit participants. Potential healthy participants who enrolled for a larger project announced as longitudinal study on stress and burnout in the region of Dresden (Germany) , were coIn total, 393 passed our screening procedure and were sent written informed consents; 230 returned the consent form and were randomized by an individual random assignment (“coin toss”) to one of our two treatment conditions: the IBSM program or the waiting list control group. Pre-treatment questionnaires (t1) were completed by 105 participants in the IBSM group, and 93 in the control group. After 8 weeks, 46 participants in the IBSM group and 88 in the control group completed the post-treatment questionnaires (t2) and were available for statistical analyses. For the flow of participants, see The Internet-Based Stress Management (IBSM) program is a self-guided cognitive-behavioral training program, structured in six modules. The program addresses both cognitive processes to improve adequate reappraisals of demanding situations, and behavioral strategies for managing resources more beneficially.Hence, the evaluated ISBM program relies on a transactional stress-model by Lazarus , 43, usiAfter receiving an anonymous access code to start training, participants could register in the web-based training program and work on the lessons on a weekly basis. During a 6-week training period, each participant is requested to complete one module per week. As the training is available with no time limit, the participants are free to decide, when during the week they will execute the content. The subsequent module is unlocked each week, provided the previous module has been completed successfully. To finish a module, participants had to work through the module as well as elaborate on the content by transferring it to an individual, work-related, daily stress-situation. Therefore, after executing the content, each module ends with the request “Now it´s your turn” and the participants have to work on their own stressful situation, adapting the skills presented to alleviate their stress. If the participants fail to reach their weekly goal, they receive a standardized e-mail reminder sent automatically.via the internet and could be accessed with a standard PC, tablet or mobile phone. The content was visualized through various web-based multimedia applications, e.g., text, video clips, audio files, animations, and interactive elements. Total working time for a single module was approx. 45 min. For a detailed description of the modules included in the IBSM program, see Domes et al. (The six weekly modules contained the following: (1) understanding stress and the effects of stress on health and performance, (2) strategies to deal with acute stress and a first-aid kid, (3) creating personal space and building up resources against stress, (4) reappraising stress-facilitating cognitions, (5) active coping strategies and systematic problem-solving, and (6) keeping in balance and transfer to everyday life  originally developed by Carver and colleagues , namely via the Satisfaction with Life Scale (SWLS). The German version of the SWLS was evaluated in a large German sample  and revealed very good reliability  and exhibited good convergent validity, e.g., by correlations with depression (r = −.44) and social support (r = .39)  and calculated the PSQI total score as a global measure of overall sleep quality for the previous 2 weeks for the purpose of this study. The PSQI demonstrated acceptable reliability of Cronbach´s alpha = .75 in a widespread study in the general population   and has via the nine-item Patient Health Questionnaire; PHQ-9 . Level of significance was set to Randomized groups did not differ in age, sex distribution, occupational background, and pre-stress level. However, the IBSM training group reported a higher level of workload in terms of working hours per week (see The participants represented a wide range of occupations including office and administration Jobs (35.8%), engineers and technical staff (24.6%), health professionals (20.9%), social occupations (9%), teachers (6.7%), and others (3%).F = 12.6; p = .001; η2 = .09) and a significant time x group interaction , indicating an overall reduction in the reported stress level that was more pronounced in the IBSM group. In the IBSM group, we noted a medium pre-post effect size of Cohen's d = 0.49 , whereas no such effect was evident in the control group, Cohen's d = 0.12  .). For the total score, the IBSM group attained a medium pre-post effect size of Cohen's d = 0.39 , whereas, as the control group reported lower coping-skills levels after the waiting period, Cohen's d = −0.22 . For the subscales, we found increased abilities in appropriate anger expression  and relaxation  , a significant group-by-time interaction indicated an overall increase in reported stress-coping skills in the IBSM group compared to the control group : Life satisfaction significantly increased in the IBSM group , whereas there was no such effect in the control group  , the control group showed no such effect , although in the ANOVA the group-by-time interaction was not significant     program. We, therefore, conducted a randomized controlled trial comparing an IBSM group with a waiting control group, and analyzed the effects on perceived stress and subjective coping skills as primary outcome measures. In addition, we assessed sleep quality, depressive symptoms, burnout, and life satisfaction as secondary outcome measures.Our results show that a 6-week self-guided IBSM program reduced self-reported perceived stress levels in the training group compared to the waiting list control group, thus replicating the previously found stress-reducing effects in a larger sample of participants . Moreoved = 0.49). Although stress reduction might be regarded the most relevant outcome of a stress management program, the effects of such a training should not be limited to the perceived stress level, but rather focus much closer on improving coping abilities to enable demanding daily stressors to be better managed. Accordingly, we identified a small to medium effect (d = 0.39) in the training group, while the waiting group's self-reported coping abilities declined (d = −0.22).Hence, our results suggest that a self-guided online training program involving no contact with a health professional can support employees in handling everyday stress. Regarding perceived stress, our findings resemble the effect-sizes reported by Heber et al.  in theird = 0.34) are similar to other self-help stress management training programs not developed specifically to treat impaired sleep.Regarding our further outcomes, sleep quality is an important indicator for stress-related health complaints , 59. In This study supports the finding that self-help internet-based stress management training programs are suitable to help healthy employees strengthen their ability to handle daily stressors better and ease stress-related complaints. Taking into account that the placebo effect might have affected our results, it is difficult to judge whether improvement occurred because of the treatment. Research indicates that some individuals who do not undergo treatment often improve, but those undergoing some type of psychotherapy are more likely to improve faster, and with a lower chance of relapsing . In thisThe training program we investigated consists of a variety of potent cognitive-behavioral stress management techniques. While the perceived stress level is a frequent outcome of studies evaluating the effects of stress management interventions, this study focuses beyond that on analyzing the improvement in coping skills in a structured way, using a validated psychometric instrument.In this study, we focused on a low entry threshold to include a wide range of healthy people interested in improving their stress management skills. We investigated an employment of a standardized and scalable training program but with restricted personal contact limited only to technical problems. In our study, we noted a dropout rate of 28% of the participants who started the treatment, a percentage that is comparable to other internet-based stress management interventions for healthy employees  and welIn sum, the present study demonstrates that a brief 6-week cognitive-behavioral Internet-Based Stress Management program promotes coping skills, improves sleep quality and well-being, and reduces the perceived stress of healthy participants reporting moderate levels of work-related stress. Our results might encourage large-scale studies on the long-term stability and clinical significance of such beneficial effects of internet-based stress-management interventions. Altogether, the main strengths of such stress management training programs are their low entry threshold character, their cost-effectiveness, and potential reach to preventively improve stress-coping skills in working populations.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Institutional Review Board of the University of Freiburg. The participants provided their written informed consent to participate in this study.TS, GD, and MH designed the study. GD, MW, and MP conducted data collection. GD and TS analyzed the data. All authors contributed to interpreting these results and to writing the manuscript. All authors have approved the final version of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.