Beta-thalassemia, a heritable condition of abnormal hemoglobin production, is not a core condition on the United States Recommended Uniform Screening Panel (RUSP) for state and territorial newborn screening (NBS) programs. However, screening for sickle cell disease (which is on the core RUSP) also detects reduced or absent levels of hemoglobin (Hb) A and certain other Hb variants associated with beta-thalassemia and, thus, allows for a timely referral to appropriate healthcare to minimize sequalae of the disease. The Association of Public Health Laboratories’ Hemoglobinopathy Workgroup administered a comprehensive survey of all U.S. NBS programs to assess beta-thalassemia testing methodologies, the cutoffs for defining beta-thalassemia major, and the reporting and follow-up practices. Forty-six (87%) of the programs responded. Thirty-nine of the 46 responding programs (85%) report some form of suspected beta-thalassemia; however, the screening methods, the percentage of Hb A used as a cutoff for an indication of beta-thalassemia major, and the screening follow-up vary widely. The standardization of technical and reporting procedures may improve access to specialty care prior to severe complications, increase genetic counseling, and provide data needed to better understand the public health impact and clinical outcomes of beta-thalassemia in the United States. Thalassemias are hereditary hemolytic anemias that stem from mutations altering the normal 1:1 ratio of alpha- to beta-globin chains, necessary for normal hemoglobin (Hb) A assembly, resulting in microcytosis and anemia. Almost 300 beta-thalassemia mutations of varying severity that can occur on one or both alleles have been described. This results in a continuum of phenotypes from clinically insignificant to the total absence of gene expression and severe disease. The anemia and resulting ineffective erythropoiesis of beta-thalassemia can vary from mild laboratory abnormalities with no impact on morbidity to transfusion dependence as well as severe and life-threatening complications, including growth delays, boney abnormalities and deformities, splenomegaly, iron overload and the resultant liver, heart and endocrine tissue damage, and an increased thromboembolic risk, among other complications.0-thalassemia, can lead to a transfusion-dependent thalassemia-major phenotype.Individuals with beta-thalassemia major, a severe transfusion-dependent hemolytic anemia, may experience irreversible bone and organ damage and the sequalae of iron overload if untreated . IndividApproximately 0.6% of the global population are carriers of at least one beta-thalassemia mutation . The prehttps://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html, (accessed on 30 November 2021)) for the 53 state and territorial newborn screening (NBS) programs, the methodologies used for the detection of sickle cell disease, which is a core RUSP condition that is performed by all programs, are also capable of detecting a significantly diminished ratio of Hb A to fetal Hb (Hb F). This diminished ratio is suggestive of beta-thalassemia, as well as certain other hemoglobin variants that can lead to a beta-thalassemic phenotype, which allows for the detection of babies with clinically severe beta-thalassemia. Epidemiologic studies are complicated as distinguishing beta-thalassemia major from beta-thalassemia intermedia is done on a phenotypic basis. Thus, NBS laboratory results do not always allow for the determination of the form of beta-thalassemia. Early detection and reporting may allow for early access to specialty care and the initiation of transfusions before the development of clinical sequalae, thereby avoiding the physical stigmata and morbidity stemming from chronic anemia [While testing for beta-thalassemia is not part of the United States (U.S.) core Recommended Uniform Screening Panel (RUSP)   n = 5. Of the 37 programs using two screening methods, 25 (68%) use IEF followed by HPLC; eight (22%) use HPLC followed by IEF; and four (11%) use IEF followed by DNA mutation analysis for hemoglobin variants. Thirty-nine (85%) of the responding programs report at least some form of potential beta-thalassemia, with 29 (74%) of these referring newborns with possible beta-thalassemia major for a definitive diagnosis. Most of these programs  reported using specific thresholds for detecting possible beta-thalassemia major. Sixteen programs define beta-thalassemia major as “Hb F-only” or <1% Hb A. Six programs define beta-thalassemia major using other Hb A thresholds, ranging from ≤1% to <3% Hb A. The responses from the three remaining programs could not be interpreted. All but one of the NBS programs that report beta-thalassemia results also provide recommendations for retesting/follow-up.A total of 46 (87%) of 53 programs responded to the survey . All rep0-thalassemia results. Twenty-two of the programs (56%) report Hb S/beta0-thalassemia, and 30 programs (77%) report Hb E/beta+-thalassemia. Two (10%) programs share these results with their state’s NBS follow-up team only; seven (33%) programs share these results with a physician only; 12 (57%) programs share these results with both their NBS follow-up team and a physician. One of the programs that provides Hb E/beta0-thalassemia screening results with an NBS follow-up and a physician also sends results to the infant’s parents.Twenty-one (54%) of the programs that report at least some form of potential beta-thalassemia do so for potential Hb E/betaThis nationwide survey of NBS programs’ screening and reporting practices for beta-thalassemia shows that reporting 85% of responding state and territorial programs, report at least one form of beta-thalassemia despite the not being on the core RUSP. The survey also shows that there is variation in the screening methods and reporting of the results, which may contribute to state-to-state differences in definitive diagnostics and access to appropriate specialty care. This highlights an opportunity for increased harmonization, which may result in public health benefits and increased health equity.An infant with beta-thalassemia major will eventually die of heart failure secondary to profound anemia if not transfused. Additional severe complications in children under five include growth and neuro-cognitive deficits and failure to thrive (FTT). Infants with thalassemia intermedia have a more variable clinical phenotype but are at risk for these same complications. If not diagnosed at birth, a definitive diagnosis and intervention can be delayed due to the slowly progressive onset, nonspecific presentation of complications, and not including thalassemia in the differential diagnosis for an infant with growth delay or FTT. This outcome may be accentuated in regions of the United States where thalassemia occurrence and provider awareness are rare. As such, infants may suffer severe clinical complications prior to diagnosis by conventional means. Early diagnosis allows for education, additional health screenings and access to care, such as the appropriate use and timing of transfusions, addressing growth and neurocognitive delays, and the prevention or detection of the onset of complications. In addition, without early detection through NBS, it may take months to obtain an accurate diagnosis, and this may result in a subsequent pregnancy before there is an opportunity for genetic counseling and education.0-thalassemia, which, with rare exceptions, results in a thalassemia-major phenotype. Thus, this recommendation benefits screen-positive individuals with an early evaluation and diagnosed individuals with likely life-long transfusions and aggressive monitoring.The guidelines from the Clinical and Laboratory Standards Institute (CLSI) on Newborn Screening for Hemoglobinopathies  were devWhile infants with no Hb A at birth have beta-thalassemia major, complex genetic influences make it difficult to correlate a specific low level of Hb A at birth to a clinical phenotype. Thus, some infants who display diminished levels of Hb A on the newborn screen may develop beta-thalassemia major but not be reported. Consistent with this, large-scale validation studies have defined cutoffs to define beta-thalassemia major in their systems . In the The importance and impact of screening and detecting beta-thalassemia alleles extends beyond homozygous forms. Although not included in this report, there are beta-thalassemia alleles that, when combined with other mutations of the beta-globin locus, can lead to a variety of clinically significant compound heterozygotic syndromes. The most notable are Hb S/beta-thalassemia, which are not discussed here as they are detected in routine NBS for sickle cell disorders and Hb E disorders. When Hb E but no Hb A is detected on NBS, it could represent Hb E/E, a relatively mild chronic hemolytic anemia, or Hb E/beta-thalassemia. The latter can result in a wide range of phenotypes, including thalassemia major or intermedia. Thus, distinguishing between these diagnoses has large clinical consequences. Despite both potentially leading to similar, severe phenotypes, only 21/39 (54%) of NBS programs reporting beta-thalassemia report Hb E/beta-thalassemia, thus resulting in a potential public health inequity.A limitation of this work is that seven (13%) NBS programs did not respond to the survey. Although it was determined that two of the nonrespondents contract for specimen testing with NBS programs that did respond to the survey, the numbers presented here may not be generalizable to all NBS programs in the United States.An increased uniformity in the screening and referral for the definitive diagnostics and treatment of beta-thalassemia may play a large role in improving timely and appropriate healthcare. An increase in the number of NBS programs reporting beta-thalassemia results for multiple suspected forms of the condition may improve access to specialty care prior to severe complications, increase genetic counseling, and provide data needed to better understand the public health impact and clinical outcomes of beta-thalassemia in the United States. In addition, an increased harmonization of screening and reporting practices will increase equity in at-risk infants and opportunities for families to access medical and genetic counseling services regardless of where a baby is born.


The inclusion of self-reported differential treatment by race/ethnicity in population-based public health surveillance and monitoring systems may provide an opportunity to address long-standing health inequalities. While there is a growing trend towards decreasing response rates and selective non-response in health surveys, research examining the magnitude of non-response related to self-reported discrimination warrants greater attention. This study examined the distribution of sociodemographic variables among respondents and non-respondents to the South Carolina Behavioral Risk Factor Surveillance System (SC-BRFSS) Reactions to Race module .Using data from SC-BRFSS , we examined patterns of non-response to the Reactions to Race module and individual items in the module. Logistic regression models were employed to examine sociodemographic factors associated with non-response and weighted to account for complex sampling design.Among 21,847 respondents, 15.3% were non-responders. Significant differences in RTRM non-response were observed by key sociodemographic variables . Individuals who were younger, Hispanic, homemakers/students, unreported income, and uninsured were over-represented among non-respondents. In adjusted analyses, Hispanics and individuals with unreported income were more likely to be non-responders in RTRM and across item, while retirees were less likely to be non-responders. Heterogeneity in levels of non-responses were observed across RTRM questions, with the highest level of non-response for questions assessing differential treatment in work (54.8%) and healthcare settings (26.9%).Non-responders differed from responders according to some key sociodemographic variables, which could contribute to the underestimation of self-reported discrimination and race-related differential treatment and health outcomes. While we advocate for the use of population-based measures of self-reported racial discrimination to monitor and track state-level progress towards health equity, future efforts to estimate, assess, and address non-response variations by sociodemographic factors are warranted to improve understanding of lived experiences impacted by race-based differential treatment. The online version contains supplementary material available at 10.1186/s12889-021-11748-y. There is an extensive scientific literature documenting the persistence of racial/ethnic health inequities , 2. ResePopulation-based health surveys provide important information about the health and well-being of the U.S. population and serves as the foundation for national objectives. The Behavioral Risk Factor Surveillance System (BRFSS) was designed to collect state-level data on adults to assess health-related risk behaviors, chronic health conditions, and use of preventive services for public health programming, planning, monitoring, and evaluation . Data arSince the initiation of the BRFSS, researchers have been concerned about the impact of non-response bias on the interpretation and inferences drawn from survey data , 18. StuSince 2002, a total of 23 states and the District of Columbia have administered the RTRM for at least 1 year. Even fewer states administered the RTRM in consecutive years. Most recently, the South Carolina BRFSS, employed the RTRM in consecutive years (2016 and 2017). We leverage this opportunity to compare the distribution of sociodemographic variables among respondents and non-respondents to the SC-BRFSS RTRM and RTRM items. We expect to find differences in the distribution of sociodemographic variables by response type. Findings related to item-specific non-response bias could potentially identify populations under-represented in capturing experiences of and reactions to discrimination reported by the SC-BRFSS.n = 10,886 respondents; 2017: n = 10,961 respondents).This study utilized data from the 2016 and 2017 South Carolina Behavioral Risk Factor Surveillance System (SC-BRFSS). The SC-BRFSS is managed by the South Carolina Department of Health and Environmental Control (SCDHEC). The survey was administered by the University of South Carolina’s Institute of Public Service and Policy Research (administration has subsequently been transferred to Winthrop University). To adjust for both sampling techniques and non-response, population weights assigned by the CDC were used . In 2016, the survey reached 11,236 respondents and in 2017, the survey reached 11,311 respondents. SC-BRFSS response rates in 2016 and 2017 were 45.8 and 47.3%, respectively, which is slightly higher than average national BRFSS response rates , 22. TheThe Children’s Trust of South Carolina, a nonprofit organization focused on preventing child abuse and neglect, researchers at the University of South Carolina School of Public Health, and SCDHEC partnered to finance the inclusion of the Reactions to Race Module (RTRM) in two consecutive years. RTRM, developed by the CDC Measures of Racism Work Group in 2001, is comprised of six-questions  in comparison to Black (16.2%) and White (14.5%) respondents. Those respondents with missing income data (21%) had higher levels of non-response compared to those with reported income. Retired respondents had the lowest level of non-response (9.3%) while homemaker and student respondents have the highest level of non-response (18.4%). Individuals who were uninsured (19.4%) had a higher percentage of non-response in comparison to those who reported health insurance (14.7%).RTRM item-non-response is presented by race/ethnicity Table . RTRM itThe distribution of sociodemographic characteristics by RTRM item non-response is presented in Table Table In sensitivity analyses, we explored the distribution of sociodemographic factors by RTRM item non-response for each racial/ethnic group  and healthcare settings (26.9%) had the highest levels of non-response. There were significant differences in non-response by age, race/ethnicity, socioeconomic status and employment status.In this SC-BRFSS sample, response patterns to the RTRM varied across population subgroups. Individuals who identified as Hispanic, indicated unreported income, and were uninsured had higher percentages of non-response to the RTRM, while individuals who were older and retired had lower percentages of non-response. These categories are similar to the groups that are typically non-responders to the BRFSS core. BRFSS makes efforts to weight the sample data by age, gender and race/ethnicity, with more recent administrations of the BRFSS employing a raking weighting methodology that additionally considers marital status and socioeconomic status  to reduce bias and improve representativeness not only in the BRFSS core but potentially in optional modules.RTRM item-specific non-response ranged from 16.3 to 54.8%, with the highest levels of non-response observed among the questions inquiring about differential treatment in work and healthcare settings. Reasons for the high level of non-response for differential treatment in work settings may be attributed to labor market participation. In our sample, only 55.4% of the population reported being currently employed. The other portion of respondents comprised of those who reported being unemployed, retired, homemaker/student, or unable to work, and may have decided to not answer the question because of their work status. The question querying respondents about differential treatment in healthcare settings also had relatively increased levels of non-response . We do not suspect this is a function of health insurance status since many respondents reported having some type of health insurance. However, research assessing specific psychometric properties of these questions may be needed to further refine this important question about one’s lived experience.Racial/ethnic differences were observed in item-specific non-response. In general, Black and White respondents had relatively similar levels of non-response across RTRM items. Hispanic respondents had the lowest levels of non-response for the questions about differential treatment in work settings. Labor market participation and age of Hispanic respondents may partially explain these differences. Moreover, Hispanic respondents had the highest levels of non-response to the questions about socially-assigned race, race-consciousness, and emotional and physical reactions to race-based treatment. Willingness and motivation to respond to the aforementioned questions may be dictated by several factors. Hispanics respondents may experience a unique constellation of structural disadvantages  that intersect with the traditional axis of inequality that emphasizes race which may influence actual and perceived encounters with negative and differential treatment . A higheTo our knowledge, BRFSS does not report response rates of optional modules in the annual data quality report. We are aware of one prior study that assessed non-response to a BRFSS optional module . Crouch It is imperative that studies using these data consider employing analytic techniques that can accommodate patterns of missingness during the analysis stage. Typical approaches to compensate for variations in probability of selection and overall nonresponse, including weighting the sample data, may not fully address item-specific nonresponse. Prior research has shown that developing weights for a subset of respondents answering specific modules, for example, is not practical . For datAs with any study using the BRFSS, we acknowledge that the data is limited by its retrospective, self-reported nature. Similar to questions about sensitive and stigmatizing life circumstances  or health conditions , responding to experiences of race-based differential treatment may be subjected to recall and social desirability bias. While these results may be comparable to other states in the American South, they are not generalizable nationally given the limited sample size of Asians, Native Americans, and Hawaiian/Pacific Islanders. The RTRM was developed specifically for public health surveillance of racialized lived experiences in a US context. Despite these limitations, our paper has some important implications. Valid and reliable measures of experiences of racial discrimination in population-based surveys may be critical for guiding anti-racist action in public health practice and programs and informing anti-racist, data-driven policy implementation. This public health surveillance data is valuable for illuminating sources of inequities between specific populations. Additional research is needed to consider whether the observed factors influencing non-response in RTRM are consistent across other states with different proportions of Hispanics, Asians, and Native Americans, and multiracial populations groups. However, to provide this type of insight, it is incumbent among more states to administer this optional module as part of the BRFSS to provide additional insight regarding the contribution of racial discrimination to health and well-being.We observed that responders and non-responders to the RTRM and items varied across key sociodemographic variables. Examining patterns of differential non-response could provide insight towards our understanding of estimates and trends of self-reported discrimination and race-related differential treatment and associations with health outcomes collected in public health population-based monitoring and surveillance systems. Public health surveys such as the BRFSS are essential tools for identifying and monitoring population health inequalities. However, tools for collecting, monitoring, and tracking racialized lived experiences at the state and local levels are limited. Enhancing the utility and generalizability of the RTRM across diverse groups has the potential to serve as a state-wide population-based tool to understand the relationship between population health and self-reported racial discrimination in different settings, inform data-driven population-based practices and policies for improving health promotion, disease prevention and management, and evaluate progress towards achieving health equity through avoidable inequalities, historical, and contemporary injustices .Additional file 1: Supplementary Table 1. Distribution of sociodemographic characteristics by RTRM item non-response among Blacks respondents, South Carolina Behavioral Risk Factor Surveillance System, 2016–2017. Supplementary Table 2. Distribution of sociodemographic characteristics by RTRM item non-response among White respondents, South Carolina Behavioral Risk Factor Surveillance System, 2016–2017. Supplementary Table 3. Distribution of sociodemographic characteristics by RTRM item non-response among Hispanics respondents, South Carolina Behavioral Risk Factor Surveillance System, 2016–2017.


Background: As a caspase-independent type of cell death, necroptosis plays a significant role in the initiation, and progression of gastric cancer (GC). Numerous studies have confirmed that long non-coding RNAs (lncRNAs) are closely related to the prognosis of patients with GC. However, the relationship between necroptosis and lncRNAs in GC remains unclear.Methods: The molecular profiling data (RNA-sequencing and somatic mutation data) and clinical information of patients with stomach adenocarcinoma (STAD) were retrieved from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted to identify the necroptosis-related lncRNAs (NRLs). Subsequently, univariate Cox regression and LASSO-Cox regression were conducted to establish a 12-NRLs signature in the training set and validate it in the testing set. Finally, the prognostic power of the 12-NRLs signature was appraised via survival analysis, nomogram, Cox regression, clinicopathological characteristics correlation analysis, and the receiver operating characteristic (ROC) curve. Furthermore, correlations between the signature risk score (RS) and immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and anticancer drug sensitivity were analyzed.Results: In the present study, a 12-NRLs signature comprising REPIN1-AS1, UBL7-AS1, LINC00460, LINC02773, CHROMR, LINC01094, FLNB-AS1, ITFG1-AS1, LASTR, PINK1-AS, LINC01638, and PVT1 was developed to improve the prognosis prediction of STAD patients. Unsupervised methods, including principal component analysis and t-distributed stochastic neighbor embedding, confirmed the capability of the present signature to separate samples with RS. Kaplan-Meier and ROC curves revealed that the signature had an acceptable predictive potency in the TCGA training and testing sets. Cox regression and stratified survival analysis indicated that the 12-NRLs signature were risk factors independent of various clinical parameters. Additionally, immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and half-inhibitory concentration differed significantly among different risk subtypes, which implied that the signature could assess the clinical efficacy of chemotherapy and immunotherapy.Conclusion: This 12-NRLs risk signature may help assess the prognosis and molecular features of patients with STAD and improve treatment modalities, thus can be further applied clinically. Global Cancer Report 2020, GC accounts for over 1 million new cases and nearly 760,000 deaths worldwide each year (Gastric cancer (GC) is a highly aggressive and extremely heterogeneous malignancy that causes high morbidity and mortality globally. According to ach year . The mosach year . Due to In vivo, different RIPK1 inhibitors can prevent tumor growth and limit metastasis (Necroptosis is a new type of cell death mediated by Receptor Interacting Protein Kinase1/3 (RIPK1/RIPK3) and executed by Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) . The exatastasis . In a motastasis .Long non-coding RNA (lncRNA) is a class of non-protein-coding RNAs (ncRNAs) with a length of over 200 nucleotides but several special functions, such as mRNA splicing, transcription regulation, and mRNA post-transcriptional regulation . LncRNAsIn this study, NRLs were mined from TCGA-STAD transcript data via Pearson correlation analysis. Then, a 12-NRLs signature for predicting the survival of STAD patients was proposed through univariate analysis and LASSO regression analysis. Moreover, molecular characteristics exploration based on the 12-NRLs signature was crucial to supplying a robust theoretical basis for applying immunotherapy and chemotherapy to STAD patients.https://portal.gdc.cancer.gov/repository, up to 13 September 2021). The RNA-seq data from the TCGA database had been normalized to Fragments Per Kilobase Million (FPKM) format for subsequent data analysis. To improve research accuracy, only samples with integral clinicopathological information were included for analysis after pre-processing based on the Perl programming language . Subsequently, all patient information was randomly allocated into the training and the testing sets via the “caret” package in R . A total of 39 necroptosis-related genes was acquired by searching published studies  profile of STAD patients were retrieved from the TCGA platform  website, 4,497 lncRNAs were identified from the TCGA-STAD RNA-seq data. Subsequently, the co-expression relationships between necroptosis-related genes and all lncRNAs in STAD samples were examined by Pearson correlation analysis, and those lncRNAs were considered significantly associated with necroptotic mRNAs. |Coefficient| > 0.3 and p-value < 0.01 were considered as the cutoff.Using the GTF annotation files of human lncRNAs retrieved from the GENCODE (https://www.string-db.org/) website to build the protein-protein interaction (PPI) network.To demonstrate the mutually regulated connection between NLRs and corresponding target mRNAs, we visualized the lncRNA-mRNA network using the “igraph” package in R. Additionally, the necroptosis-related genes regulated by candidate lncRNAs were uploaded to the STRING  in TCGA-STAD. Then, the LASSO Cox regression algorithm was adopted to ascertain the optimal panel of prognostic lncRNAs and establish an optimal signature. Next, each STAD patient’s survival risk score (RS) was calculated based on the standardized expression levels of NRLs and the corresponding regression coefficients derived from the LASSO regression analysis. The calculation is as follows: RS = Coef (i) and x(i) represent the coefficient and the standardized expression levels of each NRLs, respectively. The median RS of the training set was utilized as the demarcation point to categorize all included STAD samples into the low-risk or high-risk subsets. Kaplan-Meier (K-M) curves were adopted to contrast the overall survival (OS) of the high-risk and low-risk subsets in the training and testing sets using the “survival” package. The time-dependent ROC curves were used to evaluate survival prediction, and areas under the ROC curve (AUC) were calculated to assess the predictive accuracy and specificity of the NRLs signature.Univariate Cox proportional regression analysis was applied to determine the prognosis-related lncRNAs  curve was plotted to appraise the clinical effect of the nomogram by calculating the net benefits of a series of risk threshold probabilities using the “rmda” package.The components of the immune and stromal cells in the tumor microenvironment (TME) of each STAD sample were computed to verify the differences of microenvironment features between unequal risk groups using the ESTIMATE algorithm. The “CIBERSORT” package was adopted to extract the relative proportions of 22 types of human infiltrated immune cells, which could reveal the correlation between the risk signature and immune-cell characteristics. Additionally, the enrichment levels of 29 immune-related functions between the two sets were evaluated by Single sample Gene Set Enrichment Analysis (ssGSEA) scores.In order to clarify the differences of enriched pathways between the low-risk and high-risk subsets, the Gene Set Enrichment Analysis (GSEA) software (version 4.10) was utilized to carry out the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.http://tide.dfci.harvard.edu). To estimate the clinical response to immune checkpoint inhibitor (ICI) therapy for STAD patients, TIDE analysis was conducted to predict the potential effect of immunotherapy in different risk subsets.In order to predict the response of STAD patients in the two different risk subsets to chemotherapy drugs, the “pRRophetic” package was used to assess the half-maximal inhibitory concentration (IC50) of 20 ordinary chemotherapy drugs highly recommended by the 8th American Joint Committee on Cancer (AJCC) guidelines, such as Paclitaxel, Cisplatin, and Imatinib. The differences in IC50 values between the high-risk and low-risk subsets were analyzed by Wilcoxon signed-rank test. The discrepancies of 5 immune checkpoint blockade-related molecules between low-risk and high-risk subsets were examined to appraise the predictive effect of the signature for STAD immunotherapy. The file of Tumor Immune Dysfunction and Exclusion (TIDE) score, T cell dysfunction score, and T cell exclusion score was retrieved from the TIDE website  or the testing set (n = 184) at a ratio of 1:1. According to the equation above, the clinical RS of each STAD patient was calculated. The median RS of the training set was utilized as the cut-off value to assort both the training and testing sets into the low-risk and high-risk subsets. As exhibited in the scatterplot and risk curve, death cases increase significantly with higher RS   . The San= 0.011) . The ROC= 0.011) . The resp < 0.001), stage (p < 0.001), and age (p = 0.002) were significantly correlated with the OS of STAD patients  = 1.665), stage , and age  were independent risk factors affecting the prognosis of patients with STAD , stage M (p < 0.05), stage T (p < 0.05), and the histological grade (p < 0.001) were significantly different in the high-risk and low-risk subsets  and Tregs  was positively correlated with RS, indicating that the poor prognosis of patients in the high-risk subset may be partly due to the immunosuppressive microenvironment   . In addid Tregs) . INC0109The IC50 values of 20 conventional chemotherapy agents in low-risk and high-risk subsets were calculated using the “pRRophetic” algorithm to assess the responses of STAD patients to chemotherapy. The two risk subsets had no statistically significant difference in their responses to the 16 chemotherapy agents but significantly different responses to the 4 anticancer drugs . Moreovep = 0.075)  between the low-risk and high-risk subsets were compared to evaluate the responses of STAD patients to immunotherapy. In comparison with STAD patients in the low-risk subset, five common immune checkpoint molecules had a higher expression in the high-risk subset, but the overexpression of CTLA4 was non-significant (= 0.075) . This inIt was reported that TIDE algorithm can be applied to assess patient’ clinical response to ICI therapy. The higher the TIDE score, the greater the likelihood of immune escape, which might mean more limited response to ICI therapy and the shorter survival time. To predict the clinical response to ICI therapy for STAD patients, TIDE analysis was carried out to evaluate the potential efficacy of immunotherapy in different risk subsets. Patients in the high-risk subset had higher TIDE, T cell exclusion, and T cell dysfunction score, indicating that STAD patients in the high-risk subset might less likely to benefit from ICI therapy than in the low-risk subset .p < 0.001) (p < 0.001) (Given the significance of the tumor mutation burden (TMB) affecting the clinical responses of immune checkpoint inhibitors, information on somatic gene mutations of STAD patients was employed to investigate the correlations between TMB and RS. The detailed gene mutation information and regularity of STAD patients are presented in < 0.001) . Spearma< 0.001) . The mut< 0.001) . Signifi< 0.001) . The OS in vivo by increasing the activity of necroptosis , which eventually induces cell death . Recent roptosis . Combiniroptosis . Howeverroptosis . The invroptosis .Considerable literature has focused on the effect of necroptosis on GC, while studies concerning the effects of NRLs are extremely lacking. Thus, investigating the prognostic value and molecular characteristics of NRLs in STAD is essential for the diagnosis and treatment of GC patients. In this study, NRLs were derived from the TCGA-STAD Transcript data using Pearson correlation analysis. Then, univariate analysis and LASSO regression analysis were employed to determine the most valuable NRLs for STAD prognosis. Eventually, 12 lncRNAs were selected to create the prognostic signature of necroptosis-associated lncRNAs .It has been reported that LINC00460 can enhance epithelial-mesenchymal transition (EMT) by promoting peroxidase-1 entrance into the nucleus in HNSCC . MoreoveIn order to demonstrate the practical value of the 12-NRLs signature, all STAD samples included were randomly distributed into the training and testing sets at a 1:1 ratio. The AUC values of ROC curves indicated that the signature had an acceptable predictive accuracy in both the training and testing sets . The signature proved broadly applicable and independent via Cox regression and stratified survival analysis. Calibration and DCA curves were plotted to confirm the predictive capability of the nomogram.The immune cell infiltration in TME typically evolves along with tumorigenesis and development. In this study, samples in the high-risk subset had higher immune scores and lower levels of tumor purity based on TME scores. Further analysis revealed that the expression of T cells regulatory, macrophages M2, eosinophils, dendritic cells resting, and mast cells resting in the high-risk subset were significantly upregulated, indicating that these abnormal infiltrating immune cells may be correlated with STAD initiation and development. In particular, the infiltrated degree of immune‐suppressive macrophages M2 and Tregs was positively correlated with RS, suggesting that the unfavorable prognosis of patients in the high-risk subset may be partly due to the immunosuppressive microenvironment.Chemotherapy and immunotherapy accompanied by surgery have become the primary approaches for GC. The sensitivity of 20 common chemotherapy agents in the low-risk and high-risk subsets were compared to guide clinicians in selecting appropriate anticancer drugs for STAD patients. Given the significance of immune checkpoint inhibitor-based immunotherapy, the discrepancies of five immune checkpoint blockade-related molecules between the low-risk and high-risk subsets were examined to assess the sensitivity of STAD patients to immunotherapy. The expressions of five common immune checkpoint molecules were higher in the high-risk subset, revealing that STAD patients in the high-risk subset may up-regulate the expression of immune checkpoint genes to mediate immune evasion, which might confer patients’ unfavorable prognosis. TIDE score had been extensively applied to predict the therapeutic sensitivity with ICI treatment in many solid tumors. TIDE encompassed two underlying mechanisms of tumor immune escape: T cell dysfunction and T cell exclusion . PatientIn short, the 12-NRLs signature was successfully created to predict the survival of STAD patients in this study. Additionally, investigating the molecular features based on the 12-NRLs risk signature was essential to expand new strategies and ideas for improving the therapy for STAD patients.The 12-NRLs risk signature may help assess the prognosis and molecular features of STAD patients and improve the treatment modalities, which can be further applied clinically.


Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine ( Functional disorders of the gastrointestinal (GI) tract are frequently associated with neurological diseases, including migraine, and are a serious diagnostic problem due to nonspecific syndromes . Migrl-Trp) is an essential exogenous amino acid metabolized in the human body in three main pathways: serotonin , kynurenine (l-kyn), and microbiota-related indole pathway. Although the role of 5-HT in the central nervous system (CNS) is well established, the kynurenine pathway of l-Trp metabolism is the main route of l-Trp transformation as it accounts for about 95% of l-Trp metabolism in normal conditions and is implicated in behavioral and cognitive symptoms of neurological diseases [Tryptophan  [l-Trp intake and metabolism as compared with controls [l-Trp metabolism in functional GI disorders associated with neurological syndromes  , a condih (SIBO) . We alsocontrols . Severaliewed in ). These iewed in ,15). l-Trp may prevent migraine occurrence or attenuate its GI-related symptoms, such as nausea and vomiting, and photophobia . We . We l-Tr  receptor agonists remain a main group of drugs in migraine prevention and treatment [l-Trp metabolism may be important for this mechanism [Migraine therapy is still challenging, but significant progress has occurred lately in this field. Triptans, serotonin 5-HT1B/1D and 5-HT1F receptor agonists, gepants, calcitonin gene-related peptide (CGRP) and its receptor antagonists; ditans, antagonists of metabotropic glutamate receptor 5, and others are used in migraine treatment (reviewed in ). The drreatment . Howeverechanism .The involvement of the gastrointestinal microbiota in the kynurenine metabolic pathway and the activation of this pathway in neurological and psychiatric diseases have recently been reviewed ,25,26.Many papers report an association between migraine and functional GI disorders, and most of them underline the need for further research to identify common areas of physiology, but few works show a specific direction of such studies l-Trp metabolism that may be important in functional GI disorders and migraine. Although migraine often associates with organic GI diseases, our review is limited to functional disorders in the GI tract. Consequently, we focus on the impairments in the GI tract that may share pathophysiology with migraine, and not on conditions in which migraine comorbidity may be a secondary symptom, as in many GI cancers [In this review, we present some general aspects of the role of the gut–brain axis in neurological diseases and these features of the kynurenine pathway of  cancers . The movement and functions of the GI tract are normally regulated by the brain, although it shows a substantial degree of autonomy due to intrinsic neural plexuses within the enteric nervous system (ENS) . The ENSThe composition of the intestinal microbiota plays a major role in the gut–brain axis as the microbiota-derived neurotransmitters, hormones, and inflammatory mediators may influence CNS functions . The intl-kyn and its metabolites is presented further in this review.The blood–brain barrier (BBB) is a physical and functional separator between the brain and gut/microbiota. Therefore, it is rational to ask how the BBB influences the communication within the gut–brain–microbiota axis. The concept of the BBB has evolved from a static physical barrier between the brain and blood to a part of neovascular unit containing brain microvascular endothelial cells, neurons, microglia, astrocytes, pericytes, and extracellular matrix (reviewed in ). Therefl-Trp metabolism may be involved in pain pathogenesis, and the most likely effect associated with this involvement is neuroinflammation . The moiewed in ). The aciewed in ,46). Gasiewed in ). In geniewed in ,49.Nutritional status and diet are reported as critical modifiable factors regulating microbiota both in physiological and pathological conditions (reviewed in ). The mil-tryptophan is an essential exogenous amino acid that in humans must be provided with diet or as a diet supplement. After uptake, it is included into protein synthesis or undergoes metabolic transformations dependent on the tissue-specific expression of enzymes and cofactors involved in l-Trp metabolism. l-Trp metabolism. There are three main pathways of l-Trp metabolism in humans—the kynurenine pathway, the serotonin pathway, and the microbiota-mediated indole pathway (reviewed in [The GI tract is the major site of iewed in ). These iewed in ,54,55).l-Trp is catabolized to N-formyl-l-kynurenine (NFK) by rate-limiting enzymes tryptophan 2,3-dioxygenase (TDO), expressed in the liver, and indoleamine 2,3-dioxygenase 1 and 2 (IDO1/IDO2), expressed in many tissues [l-kynurenine (l-kyn) by kynurenine formamidase (KFO), expressed in the liver, kidney, and brain. l-kyn is further metabolized by kynurenine monooxygenase (KMO) to 3-hydroxykynurenine (3-HK), which is subsequently degraded to 3-hydroxyanthranilic acid (3-HAA) by kynureninase (KYNU). Then, 3-HAA is metabolized to 2-amino-3-carboxymuconic 6-semialdehyde (ACMS) by 3-hydroxyanthranilic acid 3,4-dioxygenase (3-HAO). ACMS is cyclized nonenzymatically to quinolinic acid (QUIN) or alternatively converted to 2-aminomuconic-6-semialdehyde (AMS) by 2-amino-3-carboxymuconate-semialdehyde decarboxylase (ACMSD). AMS is metabolized to acetyl-CoA by 2-aminomuconic semialdehyde dehydrogenase (AMSD) or cyclized to picolinic acid (PICA). QUIN can be a substrate for quinolinate phosphoribosyltransferase (QPRT) to produce NAD+ , a cofactor for many enzymes of bioenergetics and genome maintenance [l-kyn may be converted to kynurenic acid (KYNA) in the brain and liver by kynurenine aminotransferase (KAT), which also converts 3-HK to xanthurenic acid (XANA). KYNA may further produce quinaldic acid in an unknown pathway [In the kynurenine pathway, occurring mainly in epithelial and immune cells,  tissues  , which is a ligand-activated transcription factor with many physiological functions, including regulation of the GI tract and modulation of the gut-brain axis [iewed in ). l-kyn ain axis ,61,62,63l-kyn production and induction of regulatory T cell production mediated by TGFβ (transforming growth factor β) [l-Trp metabolites showed that some AhR agonists caused proinflammatory polarization of dendritic cells [l-Trp metabolism with the involvement of the kynurenine pathway.In its inactive state, AhR is a part of a protein complex containing a dimer of the 90 kDa heat shock protein (HSP90), AhR-interacting protein (AIP), the co-chaperone p23, and the protein kinase SRC  (actor β) ,71,72. Hic cells . These, N-methyl-d-aspartic acid (NMDA) receptor and an agonist for G protein-coupled receptor 35 (GPR35) [KYNA influences brain functions as an antagonist for the 7 nicotinic acetylcholine receptors (7nAchRs) and the  (GPR35) ,75,76. T (GPR35) ,78. Thisl-Trp is a substrate to produce 5-HT, which is about 90% produced in the distal GI tract by enterochromaffin cells and serotonergic neurons of the myenteric plexus that express tryptophan hydroxylase 1 (TPH1) and 2, respectively [N-acetylated by serotonin N-acetyl transferase to N-acetyl-serotonin, which is then methylated by hydroxyindole O-methyl transferase to melatonin.In the serotonin pathway, ectively . TPH1 anectively . The 5-Hectively . The 5-Hl-Trp can be absorbed and metabolized by the GI tract microbiota mainly to indole and its acid derivatives, but also to tryptamine, indican, and skatole [l-Trp metabolites participate in the regulation of the intestinal permeability, inflammation, and host immunity, and some of them are ligands for AhRs. Some dietary molecules directly activate AhR [Free  skatole . Indole vate AhR ; 5-HT isvate AhR ,84.Migraine, a common brain disorder with severe headaches and accompanying neurological symptoms, may occur as episodic or chronic disease, with or without aura, which may precede a headache attack, occur during the attack, or occur without a headache ,86. AuraThe pathogenesis of migraine is largely unknown and many factors, both genetic/epigenetic and environmental/lifestyle, may be implicated (reviewed in ). MigraiFor a long time, migraine was considered as a vascular disease. That view is justified by the considering alterations in mechanical properties of vessels as the reason for the throbbing, pulsating quality of headache (reviewed in ). HoweveGaps in the knowledge of migraine pathogenesis make challenging its prevention and treatment, but some migraine drugs targeting the CGRP signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists, ditans, and gepants approved by the FDA, create a hope for the future ,62,68. IDiet may play an important role in migraine pathogenesis, as many dietary compounds, including chocolate, alcohol, dairy products, fatty and fried foods, tea, coffee, and others, were reported to associate with migraine (reviewed in ). Conseql-Trp metabolism in migraine and other neuropsychiatric diseases is reported in much research  and is iewed in ).l-Trp metabolites may act on the glutamatergic system, which is involved in pain transmission, central sensitization, and CSD . The gliewed in ,105,106.iewed in ,108. Sinmigraine .l-kyn, KYNA, 3-HK, 3-HAA, 5-HIAA, and QUINA in the serum of migraineurs, as compared to controls. The concentrations of l-Trp, anthranilic acid (ANA), and XANA were significantly higher in these patients. The authors concluded that l-kyn was metabolized in migraine into ANA at the cost of KYNA and 3-HK. As KYNA is a competitive antagonist of NMDA receptors, its reduction supports the hypothesis on the hyperactivity of NMDA receptors in migraine [Curto et al. were the first to measure the concentration of the kynurenine pathway products in chronic migraine in humans . They obmigraine . Increasmigraine .l-kyn to rats to determine whether it could provoke KYNA-induced CSD [l-kyn singly and in combination with PROB increased cortical concentration of KYNA in both males and females, and they decreased CSD frequency in females. The latter effect was observed in males only for the l-kyn/PROB combination. The authors concluded that l-kyn intake inhibited CSD, likely by increasing KYNA concentrations in the cortex, and females were more sensitive to that inhibitory effect of l-kyn than males. These results point at a potentially important role of the kynurenine pathway of l-Trp metabolism in migraine and underline the role of sex hormones in migraine prevalence.Olah et al. studied the effects of KYNA on CSD and BBB permeability in rats . They obuced CSD . In addil-Trp and its metabolites, l-Kyn, ANA, KYNA, 3-HAA, 5 hydroxy-indoleacetic acid, PICA, and melatonin, in the interictal period of episodic migraineurs as compared to controls [l-Trp metabolism products and the occurrence of attacks were noted. The authors concluded that migraineurs might have a metabolic imbalance manifested by a depressed peripheral l-Trp catabolism during the interictal period, which might act as a trigger of migraine attack.Tuka et al. showed decreased plasma concentrations of controls . This efl-Trp metabolism were presented. They pointed to general metabolic imbalance in migraine, suggesting the involvement of glutamatergic system and NMDA receptors as mediators between kynurenines and migraine.In conclusion, some associations between migraine occurrence and changes in the kynurenine pathway of l-Trp metabolism and functional GI diseases are related to irritable bowel syndrome (IBS) . This aogenesis . Clarke controls . The levl-Trp level in the IBS patients with predominant diarrhea subgroup as compared with the IBS with predominant constipation and control groups. In addition, they observed that the l-kyn/l-Trp ratios tended to be lower in the total IBS and IBS–diarrhea groups compared to controls. Associations within the control group included melatonin/l-Trp with polysomnography–sleep efficiency and weaker positive correlations with the other ratios for either sleep efficiency or percentage time in rapid eye movement sleep. That study shows that a decrease in melatonin/l-Trp levels may influence sleep quality in IBS patients, especially those with dominant diarrhea.Heitkemper et al. studied sleep quality in female patients with IBS . They obl-Trp metabolism. An important aspect of that study was the fact that the correlation between l-Trp metabolites and mental conditions in IBS was observed in the GI mucosa and not in the blood.Keszthelyi et al. showed that IBS patients had significantly lower duodenal mucosal and higher systemic concentrations of both 5-HT and KYNA compared to healthy controls . A positl-kyn/l-Trp ratio than controls [l-kyn production after TLR activation in IBS patients compared to controls. That alternated profile included changes in TLR1/2, TLR2, TLR3, TLR5, TLR7, and TLR8. The authors suggested that the kynurenine metabolites of l-Trp detected downstream of TLR activation may be an IBS marker. Interestingly, Ramachandrian et al. observed that TLR4 signaling was important in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation through myeloid differentiation primary response gene 88 (MyD88) in the mouse [TLR-4 gene might be a risk factor for migraine [Altered cytokine production following activation of the toll-like receptor (TLR) family might play a role in IBS pathogenesis (reviewed in ). In thecontrols . The authe mouse . Earliermigraine . Therefomigraine . Collinsmigraine .l-Trp in plasma because of alterations in l-Trp metabolism [l-Trp would reverse this change and reduce symptoms of d-IBS. The d-IBS patients showed higher levels of serum l-Trp and lower tryptophan dioxygenase and total l-Trp oxidation, as measured by the l-kyn/l-Trp to free l-Trp and total kynurenines to free l-Trp ratios. A dairy-free diet neither changed the levels of metabolites of the kynurenine pathway, nor decreased IBS symptoms. The authors concluded that l-Trp metabolism along the kynurenine pathway was inhibited in d-IBS, and a dairy-free diet did not alter that. They hypothesized possible enhanced serotonin activity in d-IBS.Christmas et al. hypothesized that diarrhea-predominant IBS (d-IBS) patients would have elevated levels of tabolism . They all-Trp and l-kyn in the cerebrospinal fluid of the subjects. However, the authors’ observations did not confirm earlier studies showing a high l-kyn/l-Trp ratio due to enhanced l-Trp catabolism by the kynurenine pathway in IBS [l-Trp and products of its metabolism. We signalized a similar problem describing the work of Keszthelyi et al. [To explore the association between functional GI disorders and neurological symptoms, Farup et al. observed a high prevalence of GI comorbidity in subjects with depression and unexplained neurological symptoms, including headaches . They shy in IBS ,126. Thii et al.  and willl-Trp metabolism may be involved in IBS pathogenesis by various mechanisms, including TLR stimulation, which may be also important in migraine through MyD88 activation  is a chronic functional disorder of the gut–brain interaction characterized by episodic nausea and vomiting, which should be jointly treated by generalists and specialists (reviewed in ). CVS asAamodt et al. studied associations between headache and GI syndromes in a large questionnaire-based cross-sectional study (the Head-HUNT Study) . A higheNausea and vomiting are considered as syndromes associated with migraine attacks . On the Di Stefano et al. observed a relatively high ratio of migraine occurrence among patients with epigastric pain syndrome (54%) and postprandial distress syndrome (76%) . The autLe Gal et al. enrolled children and adolescents diagnosed with either migraine or tension-type headache, as well as age-adjusted children without a history of recurrent headaches . The occIn a similar study, Inaloo et al. observed a higher ratio of headache  prevalence in children with functional constipation (Rome III criteria) than in the control group—19.8% vs. 5.6% . HoweverMeucci et al. investigated migraine prevalence in patients aged 18–55 years undergoing endoscopic examinations due to dyspeptic symptoms . They obHelicobacter pylori infection in several studies (reviewed in [H. pylori infection in migraineurs than controls (33%) [H. pylori association. Some reports suggest that H. pylori eradication may be associated with relief of migraine symptoms [H. pylori infection is an event which is associated with structural changes in the GI epithelial cells and macroscopic changes in the GI epithelium that may progress to GI ulcers and cancers. Therefore, the infection may initiate and progress an organic GI disease, and in this respect, it is rather independent of migraine as any other infection. This statement does not exclude some overlapping areas in pathophysiology of migraine and susceptibility to H. infection, which may contribute to observed associations, but a cause–effect relationship between H. pylori infection and migraine is, at present, not justified. However, several symptoms associated with H. pylori infection, such as immune, inflammatory, and vascular responses, result in the release of immune cells and inflammatory and vasoactive agents into the gastric mucosa which may lower some threshold for migraine and make it an H. pylori side effect [H. pylori infection and migraine or headaches, several variables that can influence this association should be considered. These include various strains of the bacterium and variation in their distribution in various geographical regions, ethnicity of the population under study, and different subtypes of migraine/headache . A mels (33%) . Stratifsymptoms ,142. Howe effect ,140. Finiewed in ).Migraine shares some important features with IBS (reviewed in ). Both dp = 0.03) causal association between IBS and migraine [Several studies confirmed the association between migraine and IBS. In a large-scale cohort study, Cole et al. observed 60% higher odds of having migraine, fibromyalgia, and depression in IBS cohort as compared with non-IBS population ,144. In migraine . In a lemigraine . Chang emigraine . The oddmigraine . They fomigraine ,149,150.migraine . It was migraine .In summary, many studies provide convincing evidence on the association between migraine and IBS. A neuroendocrine mechanism is frequently postulated as a common pathophysiological mechanism of migraine and IBS (reviewed in ). Cady eSome studies on the association between migraine and functional GI disorders are summarized in Several works link migraine and functional GI diseases through the gut microbiota. Georgescu et al. observed a strong positive correlation between severity of migraine and dysbiosis assessed in fecal microbiota of IBS patients . The samUsing a wide spectrum of antibiotics and germ-free mice, Tang et al. observed that antibiotics treatment prolonged nitroglycerin (NTG)-induced acute migraine-like pain in wild-type (WT) mice and its blockade by deletion of tumor necrosis factor-alpha (TNFα) or intraspinal trigeminal nucleus caudalis (Sp5C) injection of a TNFα receptor antagonist . AntibioSeveral other studies report an association between gut microbiota dysbiosis and migraine, but neither a mechanism underlying this association, nor a causal relationship were reported (reviewed in ).l-kyn synthesis was enriched in migraineurs. The higher l-kyn degradation module suggested an increased level of its catabolites, including neuroexcitatory QUIN and neuroinhibitory KYNA, both related to CNS diseases [Chen et al. performed a metagenome-wide association study to determine the relationship between gut microbiota and migraine in elderly women suffering from migraine and controls . They obdiseases .Some results showed that probiotic treatment resulted in a beneficial effect on the frequency and severity of migraine headache attacks (reviewed in ). HoweveIn summary, migraine can associate with many functional GI disorders, first of all IBS. This association can be mediated by the gut microbiota or occur independently of it.l-Trp metabolism is reported to be modulated in functional diseases of the GI, and such diseases associate with migraine. Therefore, alteration of the kynurenine pathway may link migraine with functional GI disease, so it may be targeted to efficiently treat both classes of diseases. We do not claim that this the only link between migraine and functional GI diseases. The serotonin pathway of l-Trp metabolism, with melatonin as its final product, is also an established candidate to link these disorders .l-kyn and its metabolites on migraine are performed in laboratory animals, the difference in the kynurenine pathway of l-Trp metabolism in humans and nonhuman species should be explored.The identification of a common trigger in migraine and functional GI diseases is hampered, as both conditions represent many disorders with different pathophysiologies. As many studies on the effects of Most of the studies cited in this review were performed in blood of migraine and/or GI diseases patients. This provokes the question of the choice of a proper tissue to investigate the effects of interest. Some discrepancies obtained for GI mucosa and cerebrospinal fluid, as compared with peripheral blood, point out the need for verification of some reported blood-related mechanisms.Migraine, per se, creates several diagnostic problems that may be enhanced by comorbidities, including functional GI diseases, especially in children and adolescents. Therefore, the interpretation of obtained results in these groups should be performed with great care and double-checked. A differentiation between migraine and nonmigraine headaches is in many cases problematic and, again, comorbidities and young age of patients may affect the right diagnosis. It should be considered that an association between migraine and GI disorders may result from side effects of antimigraine drugs in the GI .Most of the studies on the association between migraine and GI disorders are characterized by a considerable heterogeneity in the data gathering and analysis techniques, which makes a reliable comparison between them hardly possible (reviewed in ). TherefMost studies on the association between migraine and functional GI diseases and the kynurenine pathway were performed on IBS. Does it mean that this is the main functional GI disease that is associated with migraine? Unfortunately, we could not find too many studies excluding other functional GI diseases from such association. Therefore, there is a need to search for the association between migraine and other functional GI diseases as specified by Rome IV criteria.l-Trp metabolism shows a hopeful therapeutic potential in migraine and functional GI diseases, and further experimental studies on animals, as well as clinical studies on individuals suffering from both migraine and functional GI disorders, are needed to determine stages and enzymes of the pathway to be targeted in the therapy of both diseases. It should be considered that the enzymes of the pathway are expressed by specific cell types, and a potential pathological stimulus for their activation/deactivation also shows cell specificity, depending on the affected tissue/organ . Moreoviewed in ).l-Trp metabolites produced in the indole pathway by the gut microbiota.Mechanistically, the involvement of kynurenines in migraine and functional GI disorders may be underlined by AhR, TLRs, and MyD888 activation. Due to possible interaction between kynurenines and AhR, AhR signaling can be targeted in the modulation of the kynurenine pathway, but due to the involvement of AhR in cancer transformation, such manipulation should be performed with great care on the target tissue or even cell type ,169. TarAlthough very few studies report an association of changes in the kynurenine pathway in migraine coexisting with functional GI diseases, such changes may provide common triggers for these diseases and may be underlined by the activation of TLR, AhR, and MyD88. Therefore, changes in the kynurenine pathway may belong to the common areas of pathophysiology of both classes of disorders, and so may be a therapeutic target in migraine associated with functional GI disorders.


A subgroup comparison (between UA-IL/UA-L and UA-M) was also performed. The clinical parameters of the patients were also analysed from files for clinicopathological correlation with recurrence. Results: sub-epithelial hyalinisation (SEH) significantly correlated with the recurrence of UA-L and UA-M (p = 0.001). When the histologic types (UA-L and UA-IL vs. UA-M) were grouped and the correlation of SOH with recurrence was checked, it was observed that both groups (p = 0.001) showed strong statistical correlation. UA-M lesions with multilocular radiolucency (p = 0.001) also showed significant correlation with recurrence. SOH can be a reliable histological predictor of recurrence and of aggressive biologic behaviour in UA. The present study shows a significant association of hyalinisation with the biologic behaviour of UA. Further studies with immunohistochemical investigations could validate the presence of hyalinisation and identify the origin of the hyalinised product in UAs. The inductive effect of hyalinisation and its influence on the biologic behaviour of ameloblastoma variants represent a scarcely researched domain of oral pathology. The complexity of the induction effects within the odontogenic apparatus, with the involvement of both ectodermal and mesodermal tissues, is responsible for diverse histopathological characteristics, hyalinisation being the major feature. The present study aims to deduce for the first time the correlation between the severity of hyalinisation (SOH) and recurrence in three unicystic ameloblastoma (UA) variants, namely, intra-luminal (UA-IL), luminal (UA-L) and mural (UA-M). Retrospectively diagnosed archival cases of UA-IL ( Hyalinisation is a condition in which normal tissue deteriorates into a homogeneous, translucent material. The phenomenon of hyalinisation can be physiological or pathological . HyaliniOdontogenic tumours (OTs) are a diverse group of lesions varying from innocuous benign lesions, including hamartomas, to aggressive malignant tumours . The varThe current study tests the hypothesis that the presence of SEH favours recurrence in UA. The UA-L and UA-IL variants are assumed to be less aggressive with non-recurrent potential.  However,The present study aims to assess the possible correlation between SEH and recurrence in three histologic variants of UA with clinicopathological correlation. The clinicopathological correlations obtained in this study could help predict the biologic behaviour of UA variants. This will ensure better treatment outcomes for patients by enabling the surgeon to rationally choose the best management option available.n = 08), UA-L (n = 22) and UA-M (n = 30) from the Department of Oral Pathology and Microbiology, Faculty of Dental Sciences. Clinical data comprising the biological parameters and patient details were retrieved and documented from the outpatient department. The retrieved tissues were heated to 55 °C for 10 min to facilitate deparaffinisation, followed by a xylene dip. The sections were stained with H&E stain for analysis. Ethical clearance was procured from the University Ethics Committee for Human and Animal Trials at MS Ramaiah University of Applied Sciences (MSRUAS), bearing number EC-2021/F/052. The study was performed on FFPE-diagnosed archival cases of UA, UA-IL  to evaluate the SOH; in ambiguous cases, a third pathologist (S.L.) assessed the histopathological features of hyalinisation and its severity. The histologic type of UA was also noted and tabulated. The correlation between SOH and recurrence in UA was statistically analysed. A subgroup comparison  was also performed.The clinical parameters of size , jaw involved (maxilla/mandible), site, radiographic features (multilocular/unilocular), cortical expansion and root resorption were analysed for statistical correlation with recurrence. The SOH was noted in the cases of UA and scored . Photomicrographs of the slides were captured at ×100 magnification using a research microscope. The histopathological and clinicopathological parameter scores were analysed for statistical significance by employing the chi-square test .n = 60) are shown in The descriptive features of UAs (p = 0.001)  .p = 0.001), It was observed that both variants (UA-IL/UA-L vs. UA-M) showed strong statistical correlation between SOH and recurrence (This indicates that the SOH influences the biologic behaviour of UA irrespective of the histologic subtype. p = 0.001) showed strong statistical correlation with recurrence  has emerged as a new, independent prognostic determinant in several cancers, such as colorectal and pancreatic cancers. Desmoplastic reaction is considered mature or immature based on whether the stroma is myxoid, and whether it contains or does not contain keloid such as collagen . HyaliniCottom et al., in 2012, demonstrated a strong correlation between SEH and recurrent odontogenic keratocysts. The authors concluded that the presence of subepithelial hyalinisation may be used as an additional histopathological feature to predict a greater tendency for the recurrence of OKCs. This was the first report on the presence of hyalinisation and recurrence of the OKC . Similarp = 0.001), The current study considered three histologic subtypes of UA and attempted to draw an association between hyalinisation and recurrence aided by clinicopathological correlation. The SOH was compared between the subtypes of UA  between SOH and recurrence in UA-L type, we suggest that this be overlooked, since only 4 recurrent UA-L cases were available compared to 18 nonrecurrent UA-L cases in the present study. The smaller sample of recurrent UA-L is a limitation of the present study. Even though only four UA-L were recurrent, it is of considerable interest to note that the SOH was intense in all four recurrent cases of UA-L. Although the current study shows a statistical correlation , followed by curettage with cryotherapy (40%), with the remainder (15%) being treated with curettage alone. UA-IL and UA-L were treated conservatively by enucleation with curettage or cryotherapy ,23. SMA When the clinicopathological features of size, jaw involved, site, radiographic features, cortical expansion and root resorption were correlated with UA-IL, UA-L and UA-M, no correlation was observed in the UA-IL and UA-L category. However, UA-M showed significant statistical correlation between the presence of multilocular radiolucency and recurrence. Lesions that are multilocular represent different growth sites of an infiltrative lesion. Despite the fact that UA compares favourably with SMA in terms of clinical behaviour and response to therapy, the subsets of multilocular lesions, UA-mural type and UA-L with intense SOH, could have a high risk of recurrence. The role of integrins and the mechanism of cross-talk induced to favour hyalinisation is a future area to investigate in odontogenic tumours. The presence of intense hyalinisation in subtypes of UA should be considered as an indicator of aggressive behaviour in UAs when determining the prognosis. This rational consideration by surgeons can help in deciding on the best therapeutic option to advocate to the patient.


We aimed to examine the feasibility and impact of a short-term occupation-based telerehabilitation intervention (Managing Participation with Breast Cancer (MaP-BC)) on daily participation, health-related quality-of-life, and breast-cancer-related symptoms and understand women’s perspectives regarding strategies to manage daily participation and symptoms during COVID-19 pandemic. A mixed-methods study  included 14 women after their primary medical treatment for breast cancer. Women received six weeks of occupation-based intervention using a video-communication. Sessions focused on identifying functional goals and training strategies to manage daily participation. The primary outcome was perceived performance and satisfaction with meaningful activities by the Canadian Occupational Performance Measure (COPM). Secondary outcomes were participation in the Activity Card Sort (ACS), upper-extremity functioning of Disability Arm Shoulder Hand, self-reported symptom severity, executive-functioning, health-related quality of life, and a question regarding strategies used to manage daily participation. Women significantly improved their daily participation in meaningful activities in the COPM, most ACS activity domains, self-reported executive functioning, and health-related-quality-of-life. Qualitative findings revealed three main themes: (1) daily life under the threats of breast cancer and COVID-19, (2) women’s own strategies to overcome challenges, and (3) contribution of the MaP-BC. Providing telerehabilitation during the COVID-19 pandemic is feasible and successful in improving women’s daily participation after breast cancer. Women with breast cancer cope with decreased daily participation and quality of life (QOL) due to residual symptoms related to the cancer and its medical treatments . These sWorldwide, the COVID-19 pandemic caused restrictions in daily participation and “non-urgent” care, including rehabilitation and follow-up services, which might lead to decreased physical and cognitive functioning and psychological stress . In partTelerehabilitation refers to the use of technology to provide remote personalized health care . It alloDuring the first COVID-19 outbreak, Lopez et al.  reportedTo help fill these gaps, this mixed-methods pilot study aimed to (1) investigate the feasibility and impact of a short-term occupation-based individual and group telerehabilitation intervention named: Managing Participation with Breast Cancer (MaP-BC)  on partiWe carried out a mixed-methods quantitative (single-arm pre–post) and qualitative study design.Fifteen women who had been diagnosed with breast cancer and completed their primary medical treatment were recruited through social media and nongovernment organizations . The inclusion criteria were women with invasive carcinoma Stages I through III, who (a) were at least 3 months post-breast cancer surgery  with or without axillary dissection, (b) had completed chemotherapy and radiotherapy, and (c) had previously been healthy. The exclusion criterion was any severe disability that would affect daily functioning  according to self-reports.The University of Haifa Ethics Committee approved this study . All participants signed informed consent forms. The study is registered in the Australian New Zealand Clinical Trials Registry; number [CTRN12621001295831].This current intervention was adapted from the MaP-BC , which iA trained occupational therapist used Zoom Pro to deliver online synchronic sessions (30–45 min each) of one individual and one small-group meeting weekly for 6 weeks for a total of 12 sessions for each woman. An hour before the prescheduled weekly meetings, each participant received a Zoom link via email from the occupational therapist. The individual sessions focused on identifying occupational-focused goals and barriers to participation, generating, training, and providing metacognitive and self-management strategies to manage and improve women’s daily participation, specifically during the pandemic.According to each woman’s needs, the individual meetings included motor exercises for the upper extremities with the supervision of the occupational therapist. In addition, both the therapist and the woman shared and discussed ideas for adapting the woman’s home and work environments according to her current abilities, functional needs, and limitations. The group sessions included women with similar symptoms, difficulties, and functional needs. During these sessions, women shared examples and experiences of strategies they used to cope with symptoms and difficulties in their daily functioning. Further, they shared ideas and information on how to use environmental resources, such as health and social welfare  services, adjunct therapies, and support groups.The primary outcomes, perceived performance, and satisfaction with performance in meaningful daily activities were measured by the Canadian Occupational Performance Measure (COPM) . The COPThe secondary outcome of retained level of participation was measured using the Activity Card Sort (ACS) , which qHealth-related quality of life (HRQOL) and functional ability were assessed using the Functional Assessment of Cancer Therapy—Breast  Hebrew version . The tooSymptom severity was assessed by using the self-reported symptom severity questionnaire. The questionnaire was developed based on the authors’ clinical experience and qualitative research in people with cancer and has been used in two previous studies ,44. PartUpper-extremity functioning was assessed with the Disability of Arm Shoulder Hand—Quick version (Quick-DASH) , in whicCognitive functioning was tested by the Behavior Rating Inventory of Executive Function—Adult version (BRIEF-A) , whose rQualitative data were collected to deeply understand women’s experiences regarding their breast cancer-related symptoms and daily participation during COVID-19 and strategies they used to manage their daily lives before and after the intervention. An additional aim was to query regarding the contribution of the MAP-BC intervention to daily participation. The semi-structured interviews focused on three main open-ended questions followed by probes, examples, and clarifications: (1) What are your experiences concerning your daily participation, breast cancer symptoms, and medical treatments in general and specifically during COVID-19? (2) How did you manage your daily life facing multiple risks? Post-intervention interviews added another question: (3) How has the telerehabilitation, Managing Participation with Breast Cancer (MaP-BC) , contribAn occupational therapist, who did not provide the intervention, administered all assessments via online meetings pre- and post-a MAP-BC intervention, which was carried out after completing chemotherapy and radiotherapy. Data collection was carried out during the COVID-19 pandemic between lockdowns.t-tests were used to compare the women’s performance with their performance satisfaction . Further, analyses of variance (ANOVA) repeated measures were used to compare between total RAL (ACS) at the three time-points, and multivariate ANOVA (MANOVA) repeated measures to compare between three ACS domains  at the three time points. We followed these with Bonferroni post hoc analyses.We verified normal distributions through Shapiro–Wilk tests. For normally distributed variables, paired For non-normally-distributed variables, we used Wilcoxon Signed-Rank tests to compare symptom severity and the FACT-B pre- and postintervention. We then used Friedman tests to compare participation in the fourth ACS domain  and Spearman’s rho for correlations between symptom severity and participation.The qualitative data were transcribed verbatim while assuring participants’ anonymity by using pseudonyms . The three authors analyzed the data together using a phenomenological approach , echoingThe women had set a large variety of functional goals . Return Overall models of MANOVA repeated measures, as well as the Friedman test, revealed significant differences between the three time points of the five ACS scores .Differences between pre- and postintervention (Time 2 vs. Time 3):The pairwise comparisons represented in the right column showed that significant improvements were found in total RAL and three out of four activity domains: IADL and high- and low-physical demand.Differences between pre-COVID-19 and preintervention, i.e., during COVID-19 (Time 1 vs. Time 2): significant decreases in RALs total score and social–cultural domain score were found, as well as a significant increase in the low-demand leisure domain score.Differences between pre-COVID and postintervention (Time 1 vs. Time 3): significant improvements in RALs of IADL and high-demand leisure were found; however, the postintervention RAL in social–cultural was still reduced compared to pre-COVID.p = 0.05) pre-intervention  compared with postintervention .Further, significant improvements were found in the women’s HRQOL and functional ability, as measured by the FACT-B , the participants described their challenges in pursuing participation and social interactions while experiencing isolation and being homebound with overprotective families and friends. They struggled with symptoms that were revealed in the quantitative data and validated by the qualitative data: pain, fatigue, sleeping problems, hypersensitive and decreased function of the upper extremity, cognitive deficiencies, emotional stress, and depression. All participants described the daily physical and, more importantly, the emotional struggle to pull themselves up from their bed and start their routine. Most of them mentioned challenges coping with high-cognitive demanding activities necessary to manage their family and career life. The COVID-19 pandemic imposed multiple risks and a sense of losing control over their life, especially due to restrictions preventing them from receiving therapy and maintaining participation in activities and social interactions.Theme 2.Using Their Own Strategies to Overcome Challenges.The women reframed their situations and daily experiences, looking for ways to “lift themselves up.” They used a strategy of utilizing personal resources, such as emotional and cognitive abilities, to cope with functional difficulties and to feel alive, essential, and helpful to their families. These included reframing the situation, positive thinking, and looking for comforting activities. Additional strategies were finding meaningful activities they could do at home as well as adjusting out-of-home activities to minimize fatigue and effort. A few  benefitted from strategies of using external resources, such as support of their families and support groups with other survivors, which were mostly online due to COVID-19 restrictions and its health threats. However, they expressed difficulties finding strategies to change their priorities and routines. As Dana (pseudonym) conveyed, “I’m trying to find hobbies, to do good stuff for myself. However, it is tough. I must admit I haven’t found any strategies that help me 100%, not yet.”Theme 3.The MaP-BC Telerehabilitation Intervention Contribution.In the second evaluation, all 14 women focused mostly on the support and strategies they gained during the MaP-BC telerehabilitation intervention. Their responses echoed their ability “to manage” the situation and gain some sense of control over the symptoms, residual medical treatment, and their social and personal roles. They valued the helpful information and strategies to cope with the symptoms and to set, prioritize, and pursue realistic functional goals. They emphasized the legitimacy gained from the therapist and the group to acknowledge their cognitive deficits in front of their families, friends, and employers and to adopt more effective management strategies. The sessions helped the women to accept the current situation and to strive for their goals, despite the COVID-19 lockdown.This study examined the impact of a short-term occupation-based individual and group telerehabilitation intervention, the MaP-BC, on participation and breast-cancer-related symptoms, as well as the participants’ perceived ability to manage their daily lives under the multiple threats resulting from breast cancer, as well as COVID-19. The tele occupation-based intervention was found to be feasible in terms of participants’ compliance and technological aspects and in terms of achieving its main objectives. Significant improvements in the women’s daily participation were reflected in the quantitative outcome measures and confirmed by the qualitative findings. These were accompanied by significant increases in HRQOL, self-reported executive functioning, and the ability to generate metacognitive and self-management strategies to cope with the challenges of breast cancer and COVID-19. However, they were not accompanied by significant improvements in self-reported physical or emotional symptom severity.The women’s enhanced participation in the management of their daily activities following breast cancer after the intervention aligns with previous studies ,11,12,13This study’s findings also confirmed that decreased participation occurs due to breast cancer ,19, but Addressing the qualitative data, women talked about striving to cope with the functional difficulties that arose during the COVID-19 pandemic, especially while they had no social and family support due to the enforced social distancing. In previous studies, women with breast cancer declared external support as the main strategy for coping with the consequences of breast cancer on daily life . Therefohttps://www.reabilityonline.com/tele-motion; accessed on 26 January 2021) [Our results revealed no significant improvements in the women’s self-reported upper extremity functioning or physical symptoms. Moreover, the disability level reported in the Quick-DASH was higher in comparison to what had been reported in other studies in women with BC , and thery 2021) , TeraPlury 2021) , or usinry 2021) ,11,23.Moreover, our results revealed no significant improvements in the self-reported emotional symptoms. This could be explained by the uncertainty imposed by the pandemic in terms of its impact on health status and the provision of health services, as well as social distancing, all limiting the availability of support and increasing stress. In addition, the emotional symptoms were assessed by one question; in the future, it is recommended to use a more comprehensive assessment of the emotional status, as well as integrating psychological interventions.This study used a small sample without a control group, and only women who had access to technology and the Internet were able to take part; therefore, results should be generalized cautiously. Due to COVID-19 restrictions, only self-reported outcome measures were used. Future studies should include additional outcome measures that are performance-based and include a therapist’s observation. In addition, the use of multiple tools may cause results’ bias. Finally, due to the study’s design, we cannot conclude which part of the intervention worked .Providing an occupation-based telerehabilitation program during the COVID-19 pandemic is feasible in terms of compliance and technological aspects. It might improve women’s daily participation after breast cancer while reducing their risk of a COVID-19 infection. Focusing on women’s prioritized activities and tailoring the intervention to their functional needs as well as facilitating the use of strategies may extend improvement in additional daily activities, executive functioning, and HRQOL, despite the lack of improvement in self-reported physical and emotional symptoms. Moreover, we showed that a small group telerehabilitation intervention is possible, broadening women’s repertoire of strategies and practical information. The qualitative data echo lessons the women learned, providing valuable information to be implemented in future interventions. This study may serve as initial evidence and a basis for future studies examining effective telerehabilitation interventions for persons with cancer in times of a pandemic or other crises. The pandemic’s unfortunate restrictions opened an opportunity and showed that telerehabilitation is feasible and may be incorporated with the standard care in other circumstances for people with chronic health conditions. This warrants a change in health policies and the formulation of guidelines and regulations. The evidence from the current study calls for further scientific examination of telerehabilitation services.