Aim: Sarcopenia and malnutrition are highly prevalent in older adults undergoing hemodialysis (HD) and are associated with negative outcomes. This study aimed to evaluate the role of sarcopenia and malnutrition combined on the nutritional markers, quality of life, and survival in a cohort of older adults on chronic HD.Methods: This was an observational, longitudinal, and multicenter study including 170 patients on HD aged >60 years. Nutritional status was assessed by 7-point-subjective global assessment (7p-SGA), body composition , and appendicular skeletal muscle mass (Baumgartner's prediction equation). Quality of life was assessed by KDQoL-SF. The cutoffs for low muscle mass and low muscle strength established by the 2019 European Working group on sarcopenia for Older People (EWGSOP) were used for the diagnosis of sarcopenia. Individuals with a 7p-SGA score ≤5 were considered malnourished, individuals with low strength or low muscle mass were pre-sarcopenic, and those with low muscle mass and low muscle strength combined as sarcopenic. The sample was divided into four groups: sarcopenia and malnutrition; sarcopenia and no-malnutrition; no-sarcopenia with malnutrition; and no-sarcopenia and no-malnutrition. Follow-up for survival lasted 23.5  months.Results: Pre-sarcopenia, sarcopenia, and malnutrition were present in 35.3, 14.1, and 58.8% of the patients, respectively. The frequency of malnutrition in the group of patients with sarcopenia was not significantly higher than in the patients without sarcopenia . When comparing groups according to the occurrence of sarcopenia and malnutrition, the sarcopenia and malnutrition group were older and presented significantly lower BMI, calf circumference, body fat, phase angle, body cell mass, and mid-arm muscle circumference. In the survival analysis, the group with sarcopenia and malnutrition showed a higher hazard ratio 2.99 (95% CI: 1.23: 7.25) for mortality when compared to a group with no-sarcopenia and no-malnutrition.Conclusion: Older adults on HD with sarcopenia and malnutrition combined showed worse nutritional parameters, quality of life, and higher mortality risk. In addition, malnutrition can be present even in patients without sarcopenia. These findings highlight the importance of complete nutritional assessment in patients on dialysis. Chronic kidney disease (CKD) has been recognized as one of the main and most prevalent public health problems worldwide. In fact, in 2017 it was estimated that 1.2 million of people died from CKD with an increase of 41% in the global mortality rate between 1990 and 2017  being one of the therapeutic options. If, on the one hand, HD enables patients with CKD to live, on the other hand, it can contribute to the development of nutritional disturbances malnutrition, sarcopenia, and frailty. Among these patients on HD, malnutrition and sarcopenia stand out due to their high prevalence in dialyzed patients .According to the sarcopenia consensus from the European Working Group on Sarcopenia for Older People (EWGSOP2), sarcopenia is defined as a progressive and generalized skeletal muscle disorder characterized by the occurrence of low muscle strength and low quality or quantity of muscle mass . The coeMoreover, data from the United States shows that 40% of end-stage patients were over 65 years in 2013, and projections for 2030 indicate that this proportion will increase to 55–61% . Given tThis is an observational, longitudinal, and multicenter study including 170 patients under HD treated in six dialysis units in Brazil. A detailed description of the methodology can be found elsewhere . All parPatients were eligible for inclusion if aged over 60 years, undergoing HD for at least 3 months, three times per week, with each session lasting 3.5–4 h. The exclusion criteria comprised patients using a wheelchair, with amputated limbs and with HIV, cancer, and Alzheimer's and Parkinson's diseases. The study was approved by the Ethics and Research Committee of Rio de Janeiro State University, Brazil registered with protocol number 039.3.2011, and a written informed consent was obtained from all patients before their admission in the study.At baseline, all participants had the nutritional status assessed by the 7-point-subjective global assessment (7p-SGA) translated to Portuguese , by anthThe 7p-SGA was applied by experienced renal dietitians. The nutritional status of a patient was classified as well-nourished when the 7p-SGA score was equal to 7 and 6 and, as malnourished when the 7p-SGA score ≤ 5 .The Baumgartner's prediction equation  was usedA previous study, conducted by our research group and which included patients on HD, showed that this equation had good agreement with the ASM assessed by dual-energy X-ray absorptiometry (DXA) with an intraclass coefficient correlation (ICC) of 0.92 (95% CI: 0.86–0.95) , high-sensitive C-reactive protein , and 25 hydroxyvitamin D . Serum urea was assessed before and after dialysis session for calculation of the urea Kt/V according to the formula of Daugirdas  from a mQuality of life was assessed using the Short Form 1.3 questionnaire (KDQoL-SF) , which w2 for male and <5.5 kg/m2 for female : Comprised by patients with positive criteria for sarcopenia/pre-sarcopenia and for malnutrition (7p-SGA score ≤ 5).- Group sarcopenia and malnutrition (n = 28): Comprised by patients with positive criteria for sarcopenia/pre-sarcopenia, but without criteria for malnutrition (7p-SGA score = 6 and 7).- Group sarcopenia and no-malnutrition (n = 44): Comprised by patients without criteria for sarcopenia/pre-sarcopenia, but with positive criteria for malnutrition (7p-SGA score ≤ 5).- Group no-sarcopenia with malnutrition (n = 42): Comprised by patients without criteria for sarcopenia/pre-sarcopenia and for malnutrition (7p-SGA score = 6 and 7).- Group no-sarcopenia and no-malnutrition .The comparisons between the survival and deceased groups were done by chi-square test, independent Considering that the presence of two nutritional disturbances—malnutrition and sarcopenia were investigated, we evaluated whether the frequency of malnutrition differed among the sarcopenia groups. p = 0.019). This finding was confirmed in the Cox regression analysis adjusted for age, gender, and hs-CRP, where the group with sarcopenia and malnutrition had a hazard ratio of 2.99 (95% CI: 1.23: 7.25) as compared to the reference group no-sarcopenia and no-malnutrition  the one with lower survival rate  was present in 58.8%, which was similar to that found by Cianciaruso et al.  where 51Markers of muscle abnormality, such as low muscle strength or low muscle mass, named as pre-sarcopenia in the current study, were present in 35.3% of the patients, a percentage similar to that found by Isoyama et al. in incident dialyzed patients (39% of the patients with either low muscle strength or low muscle mass) . MoreoveFurthermore, we identified that among the groups stratified by sarcopenia status, 66.7% of the patients from the group sarcopenia had also malnutrition . In anotSurprisingly, when comparing the frequency of malnutrition among the sarcopenia groups , 51.2% oIt was interesting to note that within the sarcopenia and malnutrition group, the mean values of body fat markers, such as BMI, percentage of body fat, and standard triceps SKFs were within the normal range for non-CKD individuals , 30, 31.Regarding quality of life, the domains most affected were social interaction, role physical, social function, and SF12 mental composite, which had worse scores in the group sarcopenia and malnutrition. We are not aware of studies in patients with CKD evaluating the role of sarcopenia and malnutrition combined on quality-of-life domains, but in a previous study from our group, we showed that patients on HD with low muscle strength had worse quality-of-life domains than that of the group with low muscle mass . MoreoveFinally, when evaluating survival, we found that the mortality risk of the groups with sarcopenia and malnutrition was close to three times higher than the group without any of these abnormalities. As far as we are concerned, there are no previous studies assessing the role of malnutrition and sarcopenia combined in older adults on HD, but studies in older adults hospitalized without CKD, showed that older adults with combined sarcopenia and malnutrition had a risk for mortality of close to five times higher when compared to the group with none of these nutritional disturbances . In patiSome limitations and strengths of this study can be listed. As a limitation, the observational study design can impair the identification of a causality–effect association. Second, the relatively small sample size can underpower the comparison among the sarcopenia and malnutrition groups, though statistical differences were already listed with this sample size. Third, the lack of robust methods to estimate muscle mass can hinder muscle abnormalities related to muscle mass. As positive aspects, we consider the originality of evaluating the concomitance of malnutrition and sarcopenia in elderly patients on HD, and the relationship of these conditions with quality of life and survival. In addition, although the methods used to evaluate muscle mass could be influenced by the variation in the hydration status, all measurements were performed after the dialysis session to minimize the influence of fluid retention. In addition, since these are the methods used in the routine care of dialysis clinics and also recommended by the updated guidelines in nutrition and CKD from NKF/KDOQI , our finIn conclusion, patients on HD aged 60 years and older who have sarcopenia and malnutrition showed worse nutritional parameters, quality-of-life domains, and higher mortality risk. In addition, we reported that malnutrition can occur in patients without sarcopenia, and that the body fat markers within the normality range can occur concomitantly with malnutrition and sarcopenia. Altogether, these findings highlight the importance of complete nutritional assessment in older patients on dialysis. Further studies to better understand the role of these abnormalities in the health of older adults undergoing maintenance HD are needed.The raw data supporting the conclusions of this article will not be made available by the authors.The studies involving human participants were reviewed and approved by Ethics and Research Committee of Rio de Janeiro State University, Brazil. The patients/participants provided their written informed consent to participate in this study.CM and TA analyzed and interpreted the data, drafted the article, and gave final approval of the submitted version. JR and FS acquired the data, critically revised the important intellectual content, and gave final approval of the submitted version. CA conceived and designed the study, acquired, analyzed, interpreted the data, drafted the article, critically revised the important intellectual content, and gave final approval of the submitted version. All authors contributed to the article and approved the submitted version.This research received two grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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EphAs are a class of ephrin receptors that belong to the membrane-bound receptor tyrosine kinases group. Accumulating experimental evidence has shown that the EphA family is involved in tumor progression, namely in cell proliferation, invasiveness, and metastasis. EphAs are a promising target for anticancer therapy. However, their role in breast cancer (BC) is still not well understood.We used a series of bioinformatic approaches to analyze the expression of the EphA family members and investigate their prognostic value in BC.Lower expression levels of EphA2, EphA3, EphA4, EphA5, and EphA7 and higher expression levels of EphA10 were found in BC tissues compared to those in normal tissues. The expression levels of the EphA family genes were correlated with molecular subtyping but not with tumor stage. High expression levels of most EphAs indicated a better prognosis in BC.This study suggested that EphA2, EphA3, EphA4, and EphA5 can act as tumor-inhibiting factors as well as biomarkers for the prognosis of BC. Each year, worldwide, there are an estimated 1.5 million new cases of breast cancer (BC), which is one of the most frequently diagnosed malignancies in women (Eph receptors (Ephs) form the largest subfamily of receptor tyrosine kinases (RTKs), with 16 members cloned , 3. BaseThe EphA family has been identified as a new target for cancer treatment , 14. HowBioinformatics provides an effective and feasible method for the analysis of tumors and has become an essential component of biomedical studies. The advantage of using bioinformatics is its ability to explore and collect various data from numerous studies in an unbiased way, which can help us obtain useful information about cancer progression. In this study, we investigated the expression profiles, mutation status, and prognostic values of the EphA family members using bioinformatics and identified prognostic factors for BC.https://www.oncomine.org/resource/login.html) was used in this study to analyze the expression levels of the EphA family genes in different types of cancers. The p-value was defined as 0.01, and the fold change was defined as 2.The Oncomine database (http://gepia.cancer-pku.cn/index.html). The GEPIA database was used in this study to analyze the transcription levels of the EphA family members in BC. Student’s t test was used to produce the p value. The p value cutoff was 0.05.GEPIA is an online database consisting of 9,736 tumor and 8,587 normal control samples . In this study, the UALCAN database was used to analyze the correlation between EphA family member expression and molecular subtyping in patients with BC. Student’s t test was used to produce the p value. The p value cutoff was 0.05.UALCAN is a database that can analyze cancer OMICS data  consists of a variety of genes in different types of cancers, such as breast , ovarian , lung , and gastric  cancer cohorts. In this study, the Kaplan-Meier plotter was used to analyze the prognostic significance of EphA family gene expression in patients with BC.The Kaplan-Meier plotter  is attached to the Memorial Sloan Kettering Cancer Center for Cancer Genomics, and it can provide a comprehensive analysis of complex tumor genomics and clinical profiles in The Cancer Genome Atlas (TCGA). Using the cBioPortal database, we investigated the frequency and form of EphA gene mutations.The cBioPortal (http://cancer.sanger.ac.uk) is a high-resolution resource for studying the effects of somatic mutations in all types of human tumors. In this study, the COSMIC database was used to analyze mutations in the EphA family in BC. Pie graphs were used to depict the substitutions of the EphA genes.The COSMIC database (https://string-db.org/) is a database that collected all publicly available sources of protein–protein interaction. In this study, we conducted a protein–protein interaction network analysis of EphAs to explore the interactions among them with STRING.STRING (http://www.genemania.org) is a website that provides information on protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity of the submitted genes.GeneMANIA  is a functional enrichment analysis web tool. In this study, we explored the potential function of EphAs with WebGestalt. FDR Method is BH.WebGestalt .The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: The aims of this systematic review and meta-analysis were to summarize the current existing evidence on the outcome of critically ill patients with COVID-19 as well as to evaluate the effectiveness of clinical interventions.Data Sources: We searched MEDLINE, the Cochrane library, Web of Science, the China Biology Medicine disc, China National Knowledge Infrastructure, and Wanfang Data from their inception to May 15, 2021. The search strings consisted of various search terms related to the concepts of mortality of critically ill patients and clinical interventions.Study Selection: After eliminating duplicates, two reviewers independently screened all titles and abstracts first, and then the full texts of potentially relevant articles were reviewed to identify cohort studies and case series that focus on the mortality of critically ill patients and clinical interventions.Main Outcomes and Measures: The primary outcome was the mortality of critically ill patients with COVID-19. The secondary outcomes included all sorts of supportive care.Results: There were 27 cohort studies and six case series involving 42,219 participants that met our inclusion criteria. All-cause mortality in the intensive care unit (ICU) was 35% and mortality in hospital was 32% in critically ill patients with COVID-19 for the year 2020, with very high between-study heterogeneity . In a subgroup analysis, the mortality during ICU hospitalization in China was 39%, in Asia—except for China—it was 48%, in Europe it was 34%, in America it was 15%, and in the Middle East it was 39%. Non-surviving patients who had an older age , a higher APACHE II score , a higher SOFA score , and a lower PaO2/FiO2 ratio  than those who survived. Among clinical interventions, invasive mechanical ventilation , kidney replacement therapy , and vasopressor  were used more in surviving patients.Conclusions: Mortality was high in critically ill patients with COVID-19 based on low-quality evidence and regional difference that existed. The early identification of critical characteristics and the use of support care help to indicate the outcome of critically ill patients. With the rapid spread of coronavirus disease 2019 (COVID-19) globally, as of June 2, 2021, a total of 171,222,477 confirmed cases had been reported in 215 countries, areas, or territories, and COVID-19 has been responsiblefor at least 3,686,142 deaths  the type of study was cohort, case–control, or case–series designs, (2) the study topic was related to the mortality, clinical characteristics, and interventions or supportive care of critically ill patients with COVID-19, which is defined as a positive result of a real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs , and (3)In this review, the primary outcome was the mortality of critically ill patients with COVID-19. The secondary outcomes included all sorts of supportive care, including non-invasive respiratory support, IMV, KRT, and vasopressor. Critically or severely ill patients were defined as those patients who were admitted to the ICU or required respiratory support. Surviving patients were defined as those discharged from the ICU or hospital or who remained hospitalized. Non-surviving patients were defined as those who died in the ICU or hospital. Immunoregulation therapy includes corticosteroids, interferon, and intravenous immunoglobulin G.via PubMed), the Cochrane library, Web of Science, China Biology Medicine disc, China National Knowledge Infrastructure, and Wanfang Data. The main terms were “mortality,” “critically ill patient,” “severely ill patient,” “novel coronavirus,” “2019-novel coronavirus,” “Novel CoV,” “SARS-CoV-2,” “COVID-19,” “2019-CoV,” “invasive mechanical ventilation,” “high flow nasal cannula,” “non-invasive ventilation,” “extracorporeal membrane oxygenation,” “renal replacement therapy,” “kidney replacement therapy,” “vasopressor,” and so on (the details of the search strategy can be found in https://www.ssrn.com/index.cfm/en/), medRxiv (https://www.medrxiv.org/), and bioRxiv (https://www.biorxiv.org/)] for further potential studies.Two reviewers (ZQ and SL) carried out the search independently in the following six electronic databases from their inception to May 15, 2021: MEDLINE  extracted data independently with a standard data collection form. Any disagreements were resolved by consensus, and a third reviewer (XL) checked the consistency and accuracy of all data. The following data and information were extracted for each included study: basic information , information on the participants , details of the intervention and control conditions, outcome information .Two reviewers (ZQ and SL) assessed the potential risk of bias of each included study independently. Discrepancies were resolved by discussion and consensus with a third researcher (XL). We assessed the risk of bias in cohort studies using Newcastle–Ottawa Scale , which cP-values. For continuous outcomes, we calculated the standardized mean difference and its corresponding 95% CI if means and SD were reported. Furthermore, 95% prediction interval (PI) was used to evaluate the range that, we assert with 95% certainty, will fall into during a future validation test. We reported the effect size with 95% CI by using random-effects models. Two-sided P < 0.05 were considered statistically significant. Heterogeneity was defined as P < 0.10 and I2 >50%.When effect sizes could not be pooled due to only one study for a comparison, we reported the study findings narratively. We used sensitivity analyses to evaluate the stability of mortality outcomes of the included studies. For a result that included more than 10 studies, publication bias was tested by visual funnel plots.All statistical analyses were performed using RStudio, version 1.3.1056. Comparable data from studies with one outcome were pooled using forest plots according to the Cochrane Handbook by using random-effects model separately . MortaliThe quality of evidence for each outcome was assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The judgments of quality for specific outcomes were based on five main factors: study design and execution limitations, inconsistency, indirectness, imprecision of results (random-effects model), and publication bias across all studies , 16. TheThe literature search retrieved 9,362 records through database searching and 51 additional records through other sources, which included 36 from the Google Scholar and 15 from preprint platforms. After removing duplicates, we screened the titles and abstracts of 5,138 records and reviewed the full text of 101 articles. Finally, we included 33 studies (cohort studies and case–series) –51 that 2/FiO2 ratio, and SOFA source were suggestive of publication bias ], a higher APACHE II score , a higher SOFA score , and a lower PaO2/FiO2 ratio  than those who survived.We evaluated the quality of evidence for 11 outcomes. Among them, two outcomes (18%) were graded as of moderate quality, four outcomes (36%) were graded as of low quality, and five (45%) outcomes were graded as of very low quality. We produced “GRADE evidence profiles,” and the details of GRADE can be found in We conducted a sensitivity analysis on each result by omitting one study at a time. No study had a significant impact on the results of the meta-analysis . A sensiThe epidemic of COVID-19 is not stopping yet, especially in western countries. In previous reports, the incidence of mortality associated with critically ill patients remains poorly characterized. The novel findings in this study include the mortality of critically ill patients with laboratory-confirmed COVID-19 worldwide and the clinical interventions between surviving and non-surviving patients. The results show that all-cause mortality in ICU was 35% and mortality in hospital was 32% around the world for the year 2020. Differences were distinct between regions. The incidence of mortality that occurred in Southeast Asia was as high as 48%, followed by 39% in China and the Middle East. The lowest incidence occurred in America, which is 15%. The plausible explanations for the high mortality in China and other Asia countries are that the arrival and peak of the COVID-19 pandemic in Asia were earlier than in any region, and there was a shortage of ICU resources and experience. Moreover, data may be subject to patient selection for ICU admission, and some nations adopted a stringent strategy , but mos2/FiO2 ratio is an important index to reflect the severity of respiratory failure. Our results also showed that the PaO2/FiO2 ratio is helpful to predict the outcome.Early identification and prompt organ function support care would provide relief in critical cases . Among tWith regard to the outcome of the clinical interventions of this meta-analysis, respiratory support is the most important part of life sustaining treatments. According to this study, HFNO during ICU hospitalization was more often used in non-surviving patients, and IMV was more often used in surviving patients. In previous studies, Auld and Capone , 54 repoIn a previous research, as high as 31% of patients in a cohort developed severe acute kidney injury requiring renal replacement therapy during hospitalization . High crThere were some limitations in the current study that must be acknowledged. First is the high level of heterogeneity in the study. Plausible explanations for the heterogeneous risks of mortality include differences in age, nation and race, disease severity, and insufficient length of follow-up. It was difficult for us to control for the effects of these confounding factors. The heterogeneity in the component studies was addressed with random-effects models. Second, as for the secondary outcomes, is that this part of the clinical interventions was derived from an observational cohort, not a randomized controlled trial, so these results should be treated cautiously. The key purpose of this study is to describe the effect of the actual use of various clinical interventions in the surviving group and non-surviving group rather than the impact of individual measures on the prognosis. Third is that most studies were retrospective and recall bias might have occurred.Mortality was high in critically ill patients with COVID-19 based on low-quality evidence, and intercontinental differences existed. The early identification of critical characteristics and the use of support care help to indicate the outcome of critically ill patients.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/LL, YC, and ZQ: concept and design. LL: administrative, technical, or material support. ZQ and SL: statistical analysis and drafting of the manuscript. LL and YC: supervision. All authors critical revision of the manuscript for important intellectual content, acquisition, analysis, or interpretation of data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Adjusted hazard ratios (HRs) and adjusted odds ratios (ORs) were estimated. The prevalence of preexisting RA was greater among patients with HS relative to controls . The odds of being diagnosed with HS were 1.6-fold higher in patients with a history of RA . The incidence rate of new-onset RA was estimated at 4.3  and 2.4  cases per 10,000 person-years among patients with HS and controls, respectively. The risk of RA was comparable between patients with HS and controls . Compared to other patients with HS, those with HS and comorbid RA were older, had a higher prevalence of diabetes mellitus, hypertension, and hyperlipidemia, and had a comparable risk of all-cause mortality. In conclusions, a preexisting diagnosis of RA predisposes individuals to develop HS. Clinicians managing patients with HS and RA should be aware of this association. Further research is required to delineate the underlying pathomechanism of this observation.Despite some common pathogenic themes, the association of hidradenitis suppurativa (HS) and rheumatoid arthritis (RA) has been poorly investigated. We aimed to evaluate the bidirectional association between HS and RA. A population-based study was conducted to compare HS patients (The online version contains supplementary material available at 10.1007/s12026-021-09221-4. Hidradenitis suppurativa (HS), previously termed ‘acne inversa’, is a chronic recurrent inflammatory cutaneous disease involving the pilosebaceous unit . HS is cRheumatoid arthritis (RA) is a chronic debilitating disease that manifests as persistent synovitis, which might lead to the destruction of joints and deformation of bones. It affects 0.5–1.0% of western populations, with the prototypical patient being a middle-aged woman. RA has a severe impact on patients’ quality of life owing to its debilitating nature and chronic course .Numerous anecdotal case reports suggested the coexistence of HS and RA in individual patients , 8. HoweAiming at elucidating the bidirectional association between HS and RA, the current study followed two study designs. A case–control study that evaluates the prevalence of preexisting RA among patients with HS was conducted to identify the odds of RA in individuals with a history of HS. In addition, a retrospective cohort design that longitudinally follows patients with HS for the incidence of new-onset RA was performed to assess the risk of RA after HS. The study was approved by the institutional review board (IRB) of Ben-Gurion University in accordance with the declaration of Helsinki .The current study relied on data retrieved from the computerized database of Clalit Health Services (CHS). CHS is the largest healthcare maintenance organization in Israel, providing a wide assortment of private and public healthcare services for 4,540,768 enrollees as of October 2018, representing 52% of the general Israeli population. The computerized dataset of CHS continuously retrieves data from several sources covering both ambulatory and hospitalized care settings. CHS is additionally typified by free access to healthcare service, comprehensive documentation, and negligible loss to follow-up, which renders its database highly compatible for valid and reliable epidemiological data (8).To enroll the current study population, the computerized database of CHS was systematically screened for enrollees with a new-onset diagnosis of HS between January 2000 and December 2018. Patients were subject to inclusion if an (i) HS-specific code was registered by a CHS board-certified dermatologist or (ii) a diagnosis of HS was registered in discharge letters of patients admitted to dermatological inpatient wards , 10.A control group encompassing up to 5 individuals per case of HS was additionally formed. Controls were matched to cases upon sex, age, and ethnicity. Control individuals were enrolled at the same date on which the diagnosis of HS was documented in the corresponding cases. The diagnosis of RA was based on its documentation in the chronic registry of CHS. Cases of RA were defined on the grounds of documentation by board-certified rheumatologists, the purchase of RA-related drugs, and suggestive laboratory and imaging data , 12.Outcome measures were controlled for underlying comorbidities utilizing the Charlson comorbidity index (CCI), an epidemiological scale evaluating the severity of comorbidities among study participants. The latter was proved reliable in predicting mortality (9) and is under widespread usage in epidemiological studies. To avoid overadjustment bias, a modified version of CCI excluding collagen tissue diseases was adopted in the current analysis. Outcome measures were additionally adjusted for body mass index (BMI) and demographic variables. The date of death of study participants was ascertained by linking the study cohort with the National Registry of Deaths Database. In the mortality analysis, all eligible patients were followed up from the onset of HS until December 31st, 2018, or death, whichever occurs earlier.t-test for categorical and continuous variables, respectively.Baseline characteristics were described by means and standard deviations (SD)s for continuous variables and percentages for categorical variables. The comparison between subgroups was performed using the chi-square test and Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to compare cases and control with respect to the presence of preexisting RA. The association was calculated based on individuals who developed HS following the diagnosis of RA in accordance with the presence of a temporal relationship between exposure and outcome in case–control studies.p-values less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software, version 25 .Incidence rates of RA were calculated for both HS patients and controls and expressed as the number of events per 10,000 person-years. The incidence of these outcomes was calculated merely for individuals without a history of RA prior to the study initiation. Hazard ratios (HRs) and 95% CIs for the risk of new-onset RA were obtained by the use of Cox regression models. The cumulative survival of HS patients with and without RA was calculated using Kaplan–Meier method and compared between the subgroups via stratified log-rank test. Two-tailed The current study was comprised of 6779 patients with HS and 33,260 age-, sex-, and ethnicity-matched control subjects. The mean (SD) age at the diagnosis of HS was 33.1 (15.1) years, and 4071 (60.1%) were females. The mean BMI and the prevalence of smoking, diabetes mellitus, hyperlipidemia, and hypertension were significantly greater in cases than in controls. The demographic and clinical features of the study participants are outlined in Table p = 0.019). Therefore, the odds of being diagnosed with HS were 1.6-fold higher in patients with a history of RA . In an age-, sex-, and, ethnicity-stratified analysis, the association of RA with subsequent HS was greater among individuals older than 40 years , males , and Arabs  as well as to a model adjusting for age, sex, ethnicity, BMI, and comorbidities .We then carried out a multivariate analysis adjusting for putative confounders. The association was robust to a model adjusting for age and sex  and 2.4  cases per 10,000 person-years in patients with HS and controls, respectively . The risk of RA in HS fell short of significance after adjusting for age and sex  as well as for age, sex, ethnicity, BMI, and comorbidities .We then evaluated all-cause mortality of patients with HS and comorbid RA as compared to the remaining patients with HS. The risk of all-cause mortality was comparable between the two subgroups  of patients was the main of these drawbacks.In conclusion, the current population-based study attested that a history of RA is associated with an elevated risk of subsequent HS. In addition, HS patients older than 30 years are at an increased risk of developing RA. Compared to other patients with HS, those with HS and comorbid RA were significantly older, had a greater burden of comorbidities, and higher lifetime prevalence of metabolic syndrome. Overall survival was comparable between the two subgroups. Our findings emphasize the significance of a multidisciplinary approach as clinicians managing patients with both diseases should be aware of symptoms suggestive of HS and RA and refer patients to specialists at an early stage. In patients with a dual diagnosis of HS and RA, treatment modalities that have been proved effective for both conditions might be preferred. Further research is necessary to delineate the pathomechanism underlying this observation.Supplementary file1 (JPG 152 kb)Below is the link to the electronic supplementary material.


P < 0.0001). Erythrodermic psoriatic patients also had a higher prevalence of MetS components, including abdominal obesity, dyslipidemia and hypertension, whereas hyperglycemia was similar. Adjusted for confounding factors, MetS, abdominal obesity, hypertension, smoking and alcohol use were positive independent predictors of EP . The area under the receiver operating characteristic curve calculated from determined risk factors for predicting the EP’s incidence was 0.934 (95% CI 0.902-0.966). There was no correlation between the severity of EP and the prevalence of MetS. Compared with patients with mild EP, patients with moderate-to-severe EP had higher body mass index, waist circumstance and blood pressure (P < 0.05). We concluded that the prevalence of MetS and its components was higher in patients with EP. MetS an independent predictor of EP, which can favor CVD and should be encouraged to correct these cardiovascular risk factors aggressively for managing EP.Erythroderma psoriasis (EP) is a rare and severe form of psoriasis, which is a chronic inflammatory skin disease that usually occurs simultaneously with cardiovascular disease (CVD). Metabolic syndrome (MetS) is a significant precursor of CVD. This study was to investigate the association between EP and MetS in the Chinese population. We conducted a retrospective study on 86 consecutive patients with EP and 100 healthy controls from Huashan Hospital between 2013 and 2018. Demographic, biochemical parameters for MetS, and other relevant data including the severity of EP, family history of EP, age of onset, and treatment history involved in those individuals were recorded. The prevalence of MetS in erythrodermic psoriatic patients was 88.37%, which was significantly higher than that of controls ( Psoriasis is a chronic inflammatory skin disease and a significant public health challenge affecting about 2-3% of the population . ErythroMetabolic syndrome (MetS) is a cluster of conditions involving central obesity, dyslipidemia, hypertension and impaired glucose tolerance and is a strong precursor of cardiovascular diseases, diabetes and incident stroke –7. RecenGiven the serious comorbidities of the MetS, it should be well-recognized and taken into account in the treatment of individuals with psoriasis. However, there is no data on investigating the association of MetS in patients with EP, probably because it’s rare and severe. The limited clinical evidence available for EP indicates that it necessitates more researches to provide optimal therapeutic options for managing this challenging disease. This study aimed to assess the association between EP and MetS based on the Chinese population, which to our knowledge, is the first case-control study regarding of EP.The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Huashan Hospital, Fudan University (KY2020-1202) and written informed consent was waived for this retrospective analysis.This case-control study consisted of 86 erythrodermic psoriatic patients (cases) and 100 healthy controls from Huashan Hospital affiliated to Fudan University. In this retrospective study, patients admitted at the hospital’s dermatology outpatient clinic, ward and intensive care unit diagnosed with EP between January 1, 2013 and December 31, 2018 were consecutively enrolled. Patients with EP who had received systemic antipsoriatic treatment including acitretin, methotrexate, oral or intravenous corticosteroids and Tripterygium wilfordii Hook F within three months before admission were excluded in this study. Healthy subjects who attended the hospital’s physical examination center with the exclusion of a history of a diagnosis with generalized scaly, erythematous skin disorders such as EP, psoriasis, pityriasis rosea and eczema were randomly selected simultaneously. EP was defined as a generalized, inflammatory erythematous dermatosis involving at least 90% of the body surface area, with or without associated exfoliation, and having the characteristic clinical and/or histological features of psoriasis with the exclusion of the other main differential diagnoses for erythroderma (2).We recorded demographic, biochemical and metabolic parameters and other relevant data from all subjects. We collected demographic factors from the cases and the controls, including age, gender, weight, height, and blood pressure on the first day at admission. Body mass index (BMI) was calculated by weight in kilograms divided by the square of height in meters (kg/mAfter fasting overnight (more than 8 hours), venous blood samples were collected in all subjects for analyzing fasting plasma glucose (FPG), serum high-density lipoprotein (HDL)-cholesterol and triglyceride (TG) levels. The serum samples were analyzed at the clinical biochemistry laboratory in Huashan hospital of Fudan University using Roche Cobas 6000 series C501/E601 . FPG was estimated by the hexokinase method, TG and HDL-cholesterol were determined by enzymatic colorimetric assay. We also calculated the prevalence of abdominal obesity, hypertension, impaired glucose tolerance, hypertriglyceridemia and low HDL-cholesterol.Other relevant data including smoking and drinking status, age of onset for EP, course of psoriasis, family history of psoriasis and the quality of life assessed by using the Dermatology Life Quality Index (DLQI), were also recorded.The severity of EP was assessed according to a previous study , where a(1) body temperature higher than 37.3°C on admission;(2) swelling and exudation of more than half of the skin lesion or lower extremity edema;(3) superficial lymphadenopathy.MetS was defined in the presence of three or more modified diagnostic criteria provided by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) groups for Asians :(1) abdominal obesity (waist circumference ≥90 cm in men and ≥80 cm in women);(2) reduced HDL cholesterol (HDL cholesterol <1.03 mmol/l in men and <1.30 mmol/l in women);(3) hypertriglyceridemia (serum triglyceride ≥1.7 mmol/l);(4) hypertension (systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥85 mm Hg or current use of antihypertensive drugs);(5) elevated fasting glucose (FPG ≥5.6 mmol/l or having diagnosed diabetes).P < 0.05) in univariate analysis. Hosmer-Lemeshow test was applied for the goodness of fit for logistic regression models. We used the receiver operating characteristic curve (ROC curve) to determine the best cut-off value of the model by applying Youden’s index. A P <0.05 was considered statistically significant.All the statistical analyses were performed using SPSS . Descriptive statistics were shown as frequency, percentage, and mean ± standard deviation (SD). We adopted univariate analyses to compare the difference between cases and controls by using Student’s t-test for continuous variables, Mann-Whitney U test for non-parametric data, and Fisher’s exact test or Chi-square test for categorical variables. We divided clinical parameters which were continuous variables into two parts according to their medians, and they were allowed to become categorical variables. The relationships between EP and clinical parameters were performed using Spearman correlation analysis. To analyze the independent factors of EP, we performed unconditional logistic regression with backward  for all indexes with statistical significance . The proportions of MetS in patients with EP was 88.37%, which was significantly higher than that of the control group (P <0.0001).In the present case-control study, a total of 186 participants were enrolled, including 86 cases and 100 controls. The demographic and metabolic characteristics of the study population were recorded and shown in vs. 23.62 ± 2.65, respectively; P <0.0001) and were more frequently smokers  and drinkers . Moreover, the levels of MetS components were significantly different between the two groups. The levels of waist circumference (P <0.0001), TG (P <0.0001) and blood pressure (P <0.0001) in the case group were markedly higher than that in the control group, and the level of HDL cholesterol (P <0.0001) showed the opposite trend, whereas the level of FPG was similar (P <0.0001), hypertriglyceridemia (P <0.0001) and hypertension (P <0.0001) were also higher in the case group, and the prevalence of hyperglycemia was similar between two groups . Besides, male, body weight, BMI, smoking and drinking were also significantly positively correlated with EP levels . Height and HDL cholesterol level were negatively related to the levels of EP . However, age and FPG levels seemed not associated with the levels of EP.In order to explore the potential factors that may be associated with the incidence of EP, we converted the continuous variables of clinical parameters into categorical variables according to their medians, and performed the Spearman correlation analysis between EP and clinical characteristics. As indicated in P < 0.05) in univariate analysis were incorporated into the regression analysis model. As shown in P = 0.006]. Abdominal obesity , hypertension , smoking  and alcohol use  were also independent predictors of EP, as 1 + 3.429X2 + 1.825X3 + 1.611X4 + 1.506X5, wherein X1 denoted abdominal obesity, X2 denoted hypertension, X3 denoted smoking, X4 denoted alcohol use, X5 denoted MetS. To estimate the goodness of fit for logistic regression models, we performed the Hosmer–Lemeshow (HL) test. The HL test results showed that the model is a good fit, with HL statistic=2.873 (P = 0.720). Accordingly, the EP risk scores were calculated for the entire study group using this model and the ROC curve was plotted. Then, in order to further address the independent factors associated with EP, we conducted the unconditional logistic regression analysis. All indexes with statistical significance , a higher rate of men , an older age of onset  and a longer course of psoriasis . However, there was no difference in the prevalence of MetS in patients with mild or moderate to severe EP . The waist circumference (P = 0.009), systolic blood pressure (P = 0.020), body weight (P = 0.028) and BMI (P = 0.016) were significantly higher in moderate-to-severe EP patients than in mild EP patients. In contrast, we found no significant correlation between psoriasis severity with fasting plasma glucose, triglyceride and HDL cholesterol.We classified the patients as mild or moderate-to-severe EP according to their condition to further investigate whether the prevalence of MetS was correlated to the severity of EP. Comparing EP patients of mild or moderate to severe Table 4,EP is a rare and severe subtype of psoriasis, and the underlying pathogenic mechanisms are not fully elucidated to date. Recently, increasing epidemiologic studies have shown that psoriasis was closely associated with cardiovascular risk factors such as MetS, obesity, hypertension and dyslipidemia , 21–23. The prevalence of MetS in our control population was 30.00%, comparable to that recently estimated among 97,098 Chinese adults with 33.9% of the overall population . The meaOur study demonstrated that the prevalence of MetS was significantly higher in erythrodermic psoriatic patients compared with controls. Patients with moderate-to-severe EP had higher BMI, waist circumference and systolic blood pressure than those with mild EP. We also found that the components of MetS  were more significantly common in EP subjects than controls. This was endorsed by some other studies that psoriasis was closely associated with MetS and its components , 22, 23.To further investigate the association between EP and MetS, we established a logistic regression analysis finding that MetS and its components  were independent risk factors of EP. In addition, we found the other cardiovascular risk factors including smoking and alcohol use, were also independent predictors of EP. These determined risk factors have a good diagnostic performance when predicting the incidence of EP, and we proposed that MetS can be used as a novel risk factor for EP. To date, there are no specific biomarkers to predict or monitor the development of EP, and the use of these observations to find a clinical biomarker for EP may be attempted. It is important to emphasize that the association alone was proven and not causality, although logistic regression analysis provided strong evidence for causality. The underlying mechanism between metabolic comorbidities and EP remains uncertain. There is an urgent need for further prospective research with well-designed longitudinal studies to establish a cause-effect  relationship between EP and MetS.via the continuous release of proinflammatory cytokines, including tumor necrosis factor-α, interleukin 6, which favor MetS and cardiovascular diseases  and previous classification. Former studies have generally evaluated the condition of patients using the psoriasis area and severity index and body surface area scoring. However, as EP patients were defined as erythematous dermatosis involving at least 90% of the body surface area, psoriasis area and severity index and body surface area scoring may not be appropriate for EP severity evaluation. We adopted the selected characteristics to classify severity because they are common manifestations in EP patients and indicate systemic inflammatory reaction as well as skin barrier destruction . This stdiseases . We foundiseases . Importadiseases , 31.The main contribution and novelty of our study were to determine the association between MetS and EP based on 86 Chinese EP patients. To our knowledge, this was the first observational study on the possible association between EP and MetS in China, which fills up the research gap in the field of metabolic syndrome in EP patients. Although EP is considered a subtype of psoriasis, the pathogenic mechanisms involved in EP are not identical to plaque psoriasis and have not been fully elucidated. Studies found that the increased Th2 and Th17 immune response may play a role in EP pathogenesis, endorsed by the higher serum level of interleukin (IL)-13, IL-4, IL-6 and IL-10 in EP patients than patients with plaque psoriasis –34. HoweHowever, our study also presented some limitations. Firstly, our study was conducted in a tertiary teaching hospital, where patients enrolled in this study are biased toward having more severe EP. Secondly, it was a cross-sectional study that does not allow the directionality of the association. Thirdly, our results were based on a single-center study conducted among the southeast Chinese population, and the population analyzed may not represent the general population. Fourthly, although our study has included multiple explanatory variables, some variables such as inflammation markers inherent in EP pathogenesis may also result in changes in the response variable (EP). We look forward to enrolling more patients with more explanatory variables to further elucidate the association of MetS and EP in the subsequent prospective study.In conclusion, we have found the prevalence of MetS and some other cardiovascular risk factors  were higher in patients with EP, which may play a relevant role in accelerating the morbidity and mortality of the cardiovascular disease. The causality of MetS and EP and the hypothesis that obesity can favor EP needs to be urgently addressed in prospective studies. We suggest that all patients with EP are encouraged to deal with the skin lesions and to correct aggressively their modifiable cardiovascular risk factors, particularly MetS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of Huashan Hospital, Fudan University (KY2020-1202). The ethics committee waived the requirement of written informed consent for participation.JD, XL, and A-rM contributed to the conception and design of the study. JD and XL contributed to collect the clinical data. RW, YW, FL, LL and A-rM analyzed the data. A-rM, JD and QLcontributed to writing manuscript. A-rM, RW and LL gave critical comments to this manuscript and revised the primary manuscript. All authors contributed to the article and approved the submitted version.This research was funded by National Natural Science Foundation of China  and Science and Technology Commission of Shanghai Municipality (No. 19ZR1407600).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bifidobacterium longum subspecies detected in infant stool have been associated with numerous subsequent health outcomes and are potential early markers of deviation from healthy developmental trajectories. This analysis derived indicators of carriage and early colonization with B. infantis and B. longum and quantified their associations with a panel of early-life exposures and outcomes. In a sub-study nested within a multi-site birth cohort, extant stool samples from infants in Bangladesh, Pakistan and Tanzania were tested for presence and quantity of two Bifidobacterium longum subspecies. The results were matched to indicators of nutritional status, enteropathogen infection, histo-blood group antigens, vaccine response and feeding status and regression models were fitted to test for associations while adjusting for covariates. B. infantis was associated with lower quantity of and decreased odds of colonization with B. longum, and vice versa. Length at birth was associated with a 0.36 increase in log10B. infantis and a 0.28 decrease in B. longum quantity at 1 month of age. B. infantis colonization was associated with fewer viral infections and small reductions in the risk of rotavirus and sapovirus infections, but not reduced overall diarrheal disease risk. No associations with vaccine responses, HBGAs or later nutritional status were identified. Suboptimal intrauterine growth and a shorter duration of exclusive breastfeeding may predispose infants to early intestinal colonization with the B. longum subspecies at the expense of B. infantis, thus denying them potential benefits of reduced enteric virus episodes. Bifidobacterium genus of bacteria, gram-positive anaerobes that proliferate in the mammalian gastrointestinal tract, are thought to be particularly beneficial for gut homeostasis, immunomodulation, nutritional status, and protection against diarrhea and pathogens  detected in infant fecal samples has been positively associated with improved weight gain, thymic development, gut health and response to oral vaccines  genes, and enteropathogen exposure all interact to have lasting impacts on an infant's health and nutritional prospects –3. Recenathogens –8. Bifiddulthood , 9. The m longum ] is a pam longum , 12. Thevaccines , 13, 14,vaccines , 15–18.  highest , 20. Howudinally .B. infantis and B. longum subsp. longum (B. longum). Indicators of carriage and early colonization were derived, described, and included in regression models to quantify their associations with a panel of early-life exposures and outcomes. The a-priori hypothesis to be tested was that subjects that were already colonized with B. infantis and had higher levels of carriage at 1 month of age would have improved nutritional, vaccine response and enteropathogen risk profiles in ways that would not be true of B. longum.In this sub-study, nested within a multi-site birth cohort, stool samples from infants in three low-resource communities were tested for This sub-study was nested within the Etiology Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) project at three of that parent study's sites in Bangladesh, Pakistan and Tanzania, which have been described previously –23. For DNA was extracted from extant stool samples collected from MAL-ED subjects at 1, 2, and 3 months of age using the QIAamp DNA Stool Mini Kit  with a modified manufacturer's protocol described previously . DNA speBifidobacterium results by MAL-ED subject and included in the analysis based on documented or hypothesized potential associations with Bifidobacterium colonization:The following variables were matched to the Z-scores  were calculated for each subject at each available anthropometric assessment based on their length/height, weight and age using the WHO Child Growth Standards STATA igrowup package, with implausible values recoded as missing  (EAEC), typical enteropathogenic E. coli (EPEC), heat-labile enterotoxigenic E. coli (LT-ETEC), and heat-stable ETEC (ST-ETEC), Shigella/enteroinvasive E. coli (EIEC) (qPCR uses the same gene target for these two closely related pathogens), Cryptosporidium, and Giardia. Samples from the same subject that were positive for the same pathogen were considered discrete infection episodes if separated either by an intermediate negative sample or a period of 14 days, with the exception of Campylobacter spp. and norovirus, for which a period of 30 days was used, and the two protozoa for which three intermediate negative samples were required . Fostimates  and R 3.stimates .Four hundred and seventy-two of the original 804 subjects met the criteria for inclusion in this sub-study , includiB. infantis colonization ranged from just under two thirds of subjects having attained high (Ct <30) carriage by the first month of life in Pakistan, to over three quarters in Tanzania , and with a 0.69 decrease in B. longum quantity.Coefficient estimates from regression models of the associations between the time-fixed, early-life exposures and the four indicators of nization  indicateBifidobacterium colonization variables in turn as time-fixed exposures and variables ascertained in later childhood as outcomes are shown in 2 polio 1 titer with increases in B. infantis quantity. A 1 log10 increase in B. infantis quantity measured at 1 month was also slightly statistically significantly associated with a 0.26 decrease, and early B. infantis colonization with a 1.24 decrease, in the cumulative number of enteric viral infections experienced from 1 to 24 months, but no equivalent effects on this outcome were observed for B. longum.Coefficient estimates from linear regression models that treated each of the Bifidobacterium colonization indicators and time-varying anthropometric and enteric infection outcomes from ages 1–24 months are shown in 10 increase in B. infantis quantity at 1 month of age was associated with a 4% decrease in the relative risk of rotavirus and a 3% decrease in sapovirus risk between 1 and 24 months of age. The equivalent effects of early B. infantis colonization were, respectively, a 19% and a 16% decrease in relative risk of infection. B. infantis quantity was also statistically significantly associated with a 2% increase in the risk of a diarrheal episode and a 3% increase in Campylobacter jejuni/coli infection, but the equivalent estimates for early B. infantis colonization were not statistically significant. No statistically significant effects were observed of B. longum colonization on any of the time-varying outcomes—with the exception of a 4% decrease in Cryptosporidium infection—or of B. infantis on the anthropometric outcomes or protozoal infections.Equivalent results from longitudinal models of the associations between the Bifidobacterium longum subspecies are a ubiquitous presence in the gut microbiota of human infants, transmitted vertically from the mother at birth via vaginal delivery or shortly after in the first breastmilk meals and thereupon proliferating by metabolizing the HMOs consumed through subsequent breastfeeding .We also did not find evidence in support of the hypothesis that B. infantis subspecies, there is a considerable diversity of strains exhibiting heterogeneity in their repertoire of HMO utilization genes  is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation (BMFG 47075), the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. Additional diagnostics for this sub-study was also supported by BMFG (INV-000372) to JP-M.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


There were also significantly fewer episodes of ESI complicated with catheter-related blood stream infection (CRBSI) requiring the CTC removal . The REDS scale appears to be a simple, cost-effective tool reducing the frequency of the tunneled CTC exit site infection and associated bloodstream infections.Central tunneled catheter (CTC)-related infections are a leading cause of a catheter loss, thus being the source of significant morbidity and mortality. The study aims at evaluating the impact of the implementation of the innovative redness, edema, discharge and tenderness, symptoms (REDS) scale (devised by the authors) for the description of the tunnel condition on the frequency of infection in long-term catheter users. The same cohort of the 40 patients was observed for 4 years altogether: 2 years before and 2 years after REDS application. The results, as well as follow-up evaluation of participants, were compared. The 2-year cumulative incidence of the CTC exit site infection (ESI) dropped significantly (log-rank  Central tunneled catheter (CTC) is used in a large part of hemodialysis patients awaiting arteriovenous fistula maturation or as the only possible vascular access option when other ones have been exhausted and/or prevented by comorbidities. Improper use of CTC carries a risk of life-threatening catheter-related bloodstream infections (CRBSI), often complicated with metastatic abscesses, endocarditis, not infrequently with fatal consequence –5. RecenForty-eight patients were initially included in the study. For all of them, a tunneled CTC was the only possible vascular access option. During the observation period (from 2012 until the end of 2015), five patients died due to cardiovascular events and two more due to cancer disease. One patient was transferred to peritoneal dialysis because the possibility of a further CTC use had been exhausted. After 2015, further eight death cases occurred: five—due to cardiovascular causes, one—due to complicated cholecystitis, one—due to complicated diverticulitis, and one as a consequence of kidney cancer. Finally, the study group consisted of 40 patients hemodialyzed through CTC from January 2012 until December 2015. For those individuals, complete follow-up records of a period of 2 years before and 2 years after the REDS scale application were available. The database included characteristics of the patients, REDS scoring, actions taken, and the patients' follow-up evaluation, as shown in 0—normal exit site .1—exit site redness .2—exit site redness and edema .3—exit site redness and edema, and discharge or discharge only .4—exit site redness and edema, tenderness and discharge, and systemic symptoms .Systemic symptoms were defined as body temperature >38 or <36°C, chills, hypotonia with systolic blood pressure <90 mmHg, tachycardia >90/min, and unusual patient confusion. After exit site scoring with the REDS scale, the following actions were taken accordingly:REDS 0—no action was taken; the score was recorded.REDS 1—incident was recorded in the notes, and the staff was alerted to evaluate the CTC exit site on the following HD sessions.REDS 2—the incident was recorded in the notes, the senior staff/doctor was informed, and the patient was evaluated. Special alertness on the following HD sessions was called for.REDS 3—the incident was recorded in the notes, senior staff/doctors were informed, and the patient was evaluated; blood samples were collected for tests, exit site swabs, and blood cultures, both from CTC and peripherally, were taken. An oral or intravenous antibiotic empirical treatment was initiated for 3 weeks, in accordance with our hospital infectious disease control committee guidelines . The patient was evaluated using the REDS scale on every session, and the blood tests were repeated weekly. When REDS decreased to 2 and 1, the treatment was completed as planned. If the blood cultures were positive, the CTC, when possible, was removed, and a temporary catheter was inserted in a different location. When no alternative venous site was available, the CTC was exchanged for an acute line over-the-wire during antibiotic therapy, and then modified in relevance with the microbiologic tests results.REDS 4—the senior staff and the doctor were informed immediately; the exit site swab and blood samples were taken for cultures from the CTC and peripheral vein, as well as for blood tests. Empirical antibiotic was given . Afterwards, the catheter was removed when possible, and a temporary catheter was inserted in a different location. When no alternative sites could be found, the CTC was exchanged for an acute line over-the-wire. In case of an indication for urgent hemodialysis , the procedure was carried out through the infected CTC, and further actions were taken thereafter.Tunnel infection (TI) was diagnosed when pain, swelling, redness of skin along the CTC, as well as purulent discharge from the exit site were observed. The same actions were taken as in the REDS 4 score. CRBSI was suspected when systemic symptoms were present, confirmed by blood and culture tests, with or without REDS 3 to 4 or tunnel infection signs. However, in the case of the last option CTC, the patient was put on systemic empirical antibiotic, with blood cultures taken from the line and peripherally, at the beginning of the evaluation and 48 h later. In case of no response to treatment, the CTC was exchanged over-the-wire for a temporary line. The next exchange of the catheter was carried out after clinical improvement, with negative blood culture tests, and the regression of the inflammation confirmed by the blood test. The nurses, as well as senior medical staff, were trained in the use of the REDS scale; appropriate materials were prepared, including posters and forms, which were attached to the patients' records. It was crucial, as the nursing staff was responsible for the CTC dressing change, exit site scoring and, when necessary, the sample collection. On the basis of that initial evaluation, the doctor was informed to take proper action. The results were analyzed monthly, and a complete report was prepared yearly from January 2014 until December 2018.In pre-REDS period, the exit site infection was defined, at the nursing staff's discretion, by the presence of redness, swelling, and discharge. In that case, blood samples and skin swabs were taken routinely and an empirical antibiotic was given. When discharge was absent, blood was tested and the beginning of treatment depended on the clinician's decision, i.e., when CRP and WBC were significantly elevated. The presence of discharge without the accompanying exit site skin changes was an indication for a swab, blood test, and empirical treatment based on the obtained results, and modified accordingly to microbiologic report. In the case of the appearance of systemic symptoms like fever, chills, hypotonia, tachycardia, and unusual confusion suggesting CRBSI—after other sources of infection were excluded —blood samples for culture and tests were obtained peripherally and from CTC, followed by empiric antibiotic administration, as mentioned above.All investigated procedures aimed at the treatment of complications threatening the vascular access for life-supporting hemodialysis. The CTC exit site REDS scale scoring was an improvement of the already existing vital signs recording and physical examination performed before every hemodialysis session. Due to this fact, an opinion from the Opole University Bioethics Committee was expressed that this type of observational study dictated by the clinical needs does not require authorization. Informed consent was obtained from all the individual patients before the procedure requiring catheter removal and reimplantation. Those procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki from 1964 and its later amendments.n  and continuous variables as mean (SD). All the CTC-related infectious complication were presented as episode per 1,000 catheter-days , then a cumulative incidence of all episodes was calculated using the Kaplan-Meier survival analysis method, including 95% confidence interval. Log-rank Cox-Mantel test was used to compare cumulative incidence level between pre-REDS and REDS periods (based on 4-year data). Additionally, the Cox hazard ratio regression analysis models were used to identify the factors significantly impacting the incidence of infections. The analyses were carried out with the use of statistical software R .Nominal variables are presented as Patient group characteristics are presented in p < 0.001; p = 0.04, in pre-REDS and REDS time, respectively; p = 0.05; p = 0.5).After the REDS scale introduction, ESI  occurrence decreased to the rate of 0.26 and 0.47 episode/1,000 cd in 2014 and 2015, respectively, compared with 0.89 episode/1,000 cd in both 2012 and 2013, in pre-REDS time . From 20p = 0.05; Infections are the second leading cause of death among dialysis patients, and central venous catheter (CVC) use for hemodialysis (HD) is associated with the increased rates of infection, as compared with other types of vascular access –3. For tThe introduction of the formal evaluation of the tunneled catheter exit site before each dialysis session using the innovative REDS scale reduced significantly the frequency of the exit site infections and the associated catheter-related bloodstream infections in the long-term catheter carriers.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.TP was an author of REDS scale, leading Interventional Nephrologist in the centre performing CTC insertion procedure and was responsible for study concept, data collection, analysis and manuscript preparation. ES was a Senior Renal Nurse leading dialysis unit nursing staff and was responsible for REDS scale introduction, quality monitoring and data collection. MK was the Department Director and was responsible for study concept, data analysis and manuscript preparation. 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.