The Janus kinase–signal transducer and activator of transcription (JAK/STAT) pathway are known to be involved in inflammatory immune-mediated skin diseases, including psoriasis. The development of drugs targeting the JAK/STAT signaling pathway presents new treatment opportunities for psoriasis. However, the application of JAK inhibitors for the treatment of dermatological disorders is still in its early stages of development. This review summarizes available evidence in an attempt to identify knowledge gaps for conducting further research studies and improving clinical decision-making.The objective of this study is to conduct a scoping review of the use of drugs targeting the JAK/STAT pathway in the treatment of psoriasis.A priori protocol for scoping review was published in 2019. The Joanna Briggs Institute Reviewer's Manual and the PRISMA Extension for Scoping Review were used for the review. MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases and ClinicalTrials registry were referred to in April 2019 and March 2021, respectively. References in English involving evidence on the use of drugs targeting the JAK/STAT pathway in patients with psoriasis were included. Data charting was performed by two authors using tables and figures.The evidence found on the efficacy and safety of drugs targeting the JAK/STAT pathway in patients with psoriasis comes from 118 articles reporting the results of 34 randomized clinical trials (RCTs). Nine different drugs administered through various routes were identified . Knowledge articles are mainly created and published by pharmaceutical companies and authors through their own funding or by those related to them. Only tofacitinib and deucravacitinib have undergone phase III clinical trials, being the only ones tested with active comparators etanercept and apremilast, respectively. Proportions of Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) were the efficacy variables most frequently studied in systemic treatments. Only two RCTs declared the safety data collected by systematic assessment; the only systemic drug with phase III data was tofacitinib. Tofacitinib 5 mg two times daily (BID)/10 mg BID efficacy was compared with etanercept 50 mg/week and a placebo. At 12–16 weeks, PASI 75/PGA 01 ranges were as follows: 38.07–80%/37.16–67.4% for tofacitinib 5 mg BID; 54.79–100%/50–75.6% for tofacitinib 10 mg BID; 58.8/66.8% for etanercept, date from one only study; and 0–33.3%/9.04–33.3% for the placebo group. Other drugs in earlier stages of development showed values within these ranges. The most frequent adverse events (AEs) were nasopharyngitis and upper respiratory tract infections in all treatment groups.There is increasing evidence on the use of drugs targeting the JAK/STAT pathway as a treatment for psoriasis, although they are in the early phases of development. The trials conducted to date have been financed directly or indirectly by the pharmaceutical industry, which must be taken into account when interpreting the results of the trials. Psoriasis treatment is currently symptomatic and could potentially present a significant risk of toxicity. Therefore, the design of principal efficacy outcome measures considering the impact of the outcome on quality of life and a drug assessment methodology aimed at improving safety would probably strengthen the evidence and decision-making process. Only tofacitinib and deucravacitinib have undergone phase III studies. None of the drugs have been approved yet.- Most of the evidence produced so far is financed directly or indirectly by the pharmaceutical industry, which must be taken into account when interpreting the results.- The most frequently used primary efficacy variables did not evaluate the quality of life. Few studies focus on safety, and most employ an unsystematic methodology. Standardized psoriasis-specific outcome measures would help reach better decisions.Psoriasis is a chronic, immune-mediated dermatological disease with an estimated prevalence of 0.91–8.5% worldwide . Associa*06:02 risk allele, which codes an aminopeptidase that helps to process antigens for HLA class I presentation, and, specifically, the interaction with a risk variant in the ERAP1 gene, markedly increases the risk and therefore it implies to have a genetic background keen to psoriasis development for an individual  or several of them . These drugs have several advantages compared to biologics: they can be administered orally or topically and do not produce immunogenicity . TofacitA review of the scope is a mean for scientific synthesis that addresses an exploratory research question, with the objective of mapping key concepts and gaps in research related to a defined area or field .In this work, we review the state of science on the study methodology used as well as the dissemination of the current knowledge on the drugs that block the JAK/STAT pathway in the treatment of psoriasis, what would allow to order it and detect gaps. This could be the base to formulate further specific research questions, which could be addressed by conducting a systematic review, later on .The aim of this study is to present current evidence on the use of JAK inhibitors in the treatment of psoriasis, using a scoping review methodology.This article is based on previous studies and therefore does not include any study by any of the authors involving human participants or animals.A scoping review protocol has been published by us a priori . Our stuTo be included in the review, papers had to show evidence of the use of JAK/STAT drugs in patients with psoriasis. Studies were included if they were written in English, involved human participants, and described the conditions formulated in the research question, regardless of the publication date or format. Articles were excluded if they did not fit the conceptual framework of the study. Non-scientific reviews were excluded from the analysis.Eligibility criteria and strategies for literature search are described in Two researchers jointly developed a data charting form to determine the variables to be extracted. A pilot test was conducted on five studies, and the chosen variables were included in a .csv file. The two researchers independently charted the data, discussed the results, and continuously updated the data charting form in an iterative process. Variables related to the study design and metadata from the primary sources are finally reported. Where possible, the data were collected from the clinical trial webpage; otherwise, data from congress abstracts and full-text articles were used.The results of the comprehensive research are presented using a PRISMA flow diagram . We firsBMJ , EMBASE and MEDLINE , MEDLINE (n = 41), Web of Science , SCOPUS , and CINAHL (n = 159)] regarding the use of JAK/STAT-targeting drugs in the treatment of dermatological diseases, 130 references met the criteria for full-text review , nine , one (n = 335 patients), and seven (n = 731 patients) studies, respectively (n = 331)−80% (n = 5)/37.16% (n = 331)−67.4% (n = 43) for tofacitinib 5 mg BID; 54.79% −100% (n = 7)/50% (n = 8)−75.6% (n = 90) for tofacitinib 10 mg BID; 58.8% (n = 335)/66.8% (n = 335) for etanercept; and 0% (n = 6)−33.3% (n = 3)/9.04% (n = 177)−33.3% (n = 3) in the placebo group. Regarding security, most of the data were collected by non-systematic assessment (9/11), and the time frame was not specified (8/11). AEs were described for the different treatment arms at very short (14 days/one study), short (12–16 weeks/four studies), medium (24 weeks/one study), and long term , as shown in The efficacy variables PASI 75 and/or PGA 01 at 12–16 weeks of tofacitinib 5 mg BID, tofacitinib 10 mg BID, etanercept 50 mg/week, and the placebo were evaluated in eight  and 4% (n = 15) vs, placebo (n = 15) and calcipotriol 50 μg/g (n = 15) was evaluated at 12 days (improvement from baseline in psoriatic skin thickness/echo-poor band (EBP). Topical tofacitinib efficacy at four weeks resulted in an improvement in the Percent Change Target Plaque Severity Score (TPSS) at doses of 0.02% (n = 23), 0.2% (n = 23), and 2% (n = 71) vs. vehicle (n = 35). Finally, at 12 weeks, PGA improvement was observed in a study at a dose of 1% (n = 144) and 2% (n = 141) vs. the placebo (n = 145). At 12 days and 4 weeks, as cutoff primary points, no serious AEs, namely frequent burning or stinging, were observed. At 12 weeks, zero, seven, and four severe AEs were described in the tofacitinib 2%, 1%, and placebo groups, respectively.The efficacy of topical tofacitinib  at dosesFour references on topical ruxolitinib treatment—one full-text and three congress abstracts—were published between 2009 and 2012 . OverallThree of the references mentioned above are experimental studies on topical treatment with ruxolitinib conducted between May 2007 and May 2009, two of which were randomized studies . All thrThe efficacy and safety of topical ruxolitinib are shown in A full-text article and a congress abstract on systemic treatment using peficitinib were published in dermatology journals in 2012 and 2015, respectively . StudiesA phase IIa randomized study on systemic treatment with peficitinib was conducted between March 2010 and July 2011 . It inclThe efficacy and safety at 6 weeks are summarized in Four references on systemic treatment using baricitinib were found, three of which were published in dermatology journals and one in a general medicine journal between 2014 and 2019 . Three oA randomized phase IIb study of systemic treatment with baricitinib was conducted between December 2010 and August 2014 . A totalThe study was funded by Eli Lilly.The efficacy and safety results at 12 weeks are presented in A full-text reference on systemic treatment using solcitinib was published in a dermatological journal in 2016 . The pubA randomized phase-IIb study on systemic treatment with solcitinib was conducted from March 2013 to March 2014 . A totalThe efficacy and safety results at 12 weeks are summarized in A full-text reference on systemic treatment with itacitinib was published in a dermatological journal in 2016 . The pubA phase II study on systemic treatment with itacitinib was conducted between June 2012 and February 2013 . A totalThe results for efficacy and safety after 28 days of treatment are presented in A full-text reference on (BMS-986165) systemic treatment with deucravacitinib was published in a general medicine journal in 2018 . The stuEight studies, one in phase I, one in phase-II, and six in phase III with 140, 268, and 3,690 patients, respectively, of both sexes and all ages on systemic deucravacitinib treatment, were conducted from November 2016 to April 2024 . Six of The efficacy and safety at 12 weeks are summarized in A full-text reference on the systemic treatment with abrocitinib was published in a dermatology journal in 2018 . The pubA phase-II study on systemic treatment with abrocitinib was conducted between November 2014 and September 2015 . A totalThe efficacy and safety results are presented in A full-text reference on systemic treatment with brepocitinib was published in a pharmacology journal in 2017 . The pubThree studies, one in phase-I and two in phase-II, on systemic treatment with brepocitinib, with 96 and 452 patients, respectively, of both sexes ranging from 18 to 75 years in age, were conducted from November 2014 to April 2021 . Seven oNo efficacy data were found. Safety data are presented in To our knowledge, this is the first scoping review on the use of drugs targeting the JAK/STAT pathway for treating psoriasis. Nine molecules that inhibit the JAK/STAT pathway were identified. Some of these drugs act on a single-specific component of this pathway, such as abrocitinib and solcitinib (JAK1) and deucravacitinib (TYK2), whereas others do so by inhibiting several components, such as baricitinib, ruxolitinib, itacitinib (JAK1 and JAK2), brepocitinib (JAK1 and TYK2), tofacitinib (JAK2 and JAK3), and peficitinib . All of them, except ruxolitinib applied topically, have been used orally. Tofacitinib was the only drug tested in both forms of administration. These drugs are in different stages of development. Most drugs are being tested in phase-II studies; only tofacitinib and deucravacitinib are being tested in phase-III studies. None of these drugs have been approved for use in the treatment of psoriasis.The evidence available so far comes mainly from clinical trials that are promoted almost entirely by the pharmaceutical industry which also funds the notification of the results and conclusions from those studies. The dissemination of knowledge is mainly carried out through journals and congresses related to dermatology by authors belonging to the pharmaceutical industry with declared conflict of interests. Results from some of the registered studies have not been published after the completion of the trials. All systemic treatments have been compared mainly to the placebo, tofacitinib, and brepocitinib being the only drugs that have been tested against other active molecules, specifically, against etanercept and apremilast, and against famotidine, and interferon 2 alpha recombinant, respectively. Drugs administered topically include the placebo, calcipotriol, and betamethasone. The primary objectives of these clinical trials focus mainly on aspects of efficacy rather than safety and present primary endpoints in the short (12–16 weeks) or very short term (days−4 weeks). The effectiveness, measured as the reduction in PASI, PASI 75, and PGA, varies depending on the tested dose. Most of the data regarding security were collected by non-systematic assessments. The short-term data were similar between the different treatment arms, with nasopharyngitis being the most frequent AE. Tofacitinib was the only drug with long-term data available.Regarding the methodology of this study, the study was conducted based on an a priori protocol previously published in a scientific journal and using the latest standards in scoping review methodology; at least two researchers were involved in each phase. This manuscript was prepared according to the recommendations of the PRISMA Extension for Scoping Reviews. We also identified a high number of anti-JAK drugs whose current development phase made them eligible for inclusion in the latest Cochrane living review update .Limitations related to funding and time prevented us from including articles written in languages other than English. Additionally, we were unable to contact the authors of some articles that would have helped reduce the amount of missing data, particularly for studies published as congress abstracts, as we did not exclude these types of publications. This work is a substudy, and although we believe that the global search strategy was a complete one, and that the three-phase search minimized overlooking of relevant articles, it is still possible that we did not include some articles describing studies related to the research topic. In March 2021, an update of the previously identified anti-JAK drugs was carried out, but only on the clinical trial webpage. Finally, most of the studies have been carried out, founded, and disseminated by pharmaceutical industry, and the validity of the conclusions may be comprised.The creation and notification of knowledge about drugs that act on the JAK/STAT pathway are funded almost exclusively by the pharmaceutical industry. Further, knowledge diffusion is carried out by authors with conflict of interest, most of whom belong to the pharmaceutical industry. In addition, a high percentage of references are congress abstracts that are not subjected to any peer review process, and it is a known fact that the products of sponsors are favored . Also, iThe objective of the studies is found to most frequently focus on the efficacy outcomes, whose readout is the extension of the lesions, PASI, and PGA. Although these outcomes are the most widely used in the trials of drugs for psoriasis, standard measurement criteria are essential for the results to be accepted by the clinical community. However, it is also true that a key determining factor of the scientific value of clinical trials is the choice of measures of outcomes . In thisThe number of drugs targeting the JAK/STAT pathway for treating psoriasis is increasing, tofacitinib being the most widely known. The evidence available must be interpreted considering that the funding for conducting studies on these drugs and notification of their results comes mainly from the pharmaceutical industry. The sources of knowledge are RCTs, whose primary objectives are focused on the issues of efficacy rather than safety, and their cutoff points are located in the very short or short term; we put evidence enough together to point out that principal efficacy primary outcome scales did not take into account fundamental aspects that impact the quality of life, such as symptoms and the location of the lesions, which are very variable depending on the doses administered. Also, only tofacitinib and deucravacitinib are being tested in phase III clinical trials. The methodology used in investigating and reporting on the safety of the drugs used suggests that the current high level of confidence in the findings of these studies is overrated.The original contributions presented in the study are included in the article/JR and FG-G: conceptualization. FG-G and EP-P: data curation and writing—original draft. JR: funding acquisition. FG-G, PG-A, AM-L, JH-P, JS-C, and EP-P: investigation. JR and EP-P: supervision. FG-G, EP-P, and PG-A: validation. JR, FG-G, and EP-P: visualization. EP-P: writing—review and editing. All authors contributed to the article and approved the submitted version.This work was supported, in part, by project ICI1400136 to JR, integrated into the National Plan of R+D+I 2008-2011, and cofinanced by the ISCIII-Subdirección General de Evaluación and European Regional Development Fund (ERDF), project PIN-0316-2017 of the Consejería de Salud, Junta de Andalucía (Spain) to JR, and by Grant PP13/009 of Plan Propio de movilidad para investigadores del Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.FG-G has received honoraria for research from Pfizer and for lecturing from AbbVie, Janssen-Cilag, and Novartis. JR has received honoraria for lecturing and grants for research from Pfizer, honoraria for lecturing from Janssen-Cilag and Novartis, and other financial benefits from AbbVie and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The prevalence of diabetes mellitus is growing worldwide, as well as in the aging population, and its comorbidity and mortality rates are higher in aging people than they are in young people. It has been observed that the number of drugs used increases in aging patients, especially in diabetic patients. This study aimed to investigate the relationship between polypharmacy and modified Charlson Comorbidity Index (CCI) and Katz Index of Independence in Activities of Daily Living (Katz ADL) scores in aging diabetic and non-diabetic patients.This prospective study included 184 diabetic and 62 non-diabetic subjects who were ≥65 years old. Comorbidity was determined with CCI, and dependency on daily basic activities was assessed with Katz ADL.P = .001). In all subjects and in the diabetic group, there was a negative correlation between CCI and Katz ADL ; there was a positive correlation between CCI and number of drugs .CCI and the number of drugs were significantly higher in diabetic groups (We found an increase in the number of drugs taken by the aging patients, positively correlated with the CCI score. The increase in the number of drugs used is closely related to the insufficiency in daily life activity and comorbidity, and this predicts 10-year survival. Patients should be directed to special centers or physicians who will be scheduled for multidisciplinary treatment for the prevention of polypharmacy, especially in the aging. It is estimated that by 2050, the aging population will rise from 900 million to 2 billion people, which means that the proportion of the world’s population over 60 years old will nearly double between 2015 and 2050, from 12% to 22%.4Aging patients are more susceptible to issues caused by an increased number of drugs, which is called polypharmacy, than young people. Yet, there has been a considerable increase in polypharmacy in the geriatric population.8In the hope of improving quality of life on newly developed drugs, more and more drugs are given to patients, especially elderly patients. We think that multidrug use may decrease quality of life and negatively affect the survival of aging patients. When we look at the geriatric patient population that we followed in our outpatient clinic, we found that DM was a very comorbid disease because the frequency of diabetes increases with age and we thought that the number of drugs used in these patients may be greater and that diabetic patients may be more exposed to the risk of polypharmacy. In this prospective study, we aimed to investigate the relationship between polypharmacy, the modified Charlson Comorbidity Index (CCI), and the Katz Index of Independence in Activities of Daily Living (Katz ADL) to determine whether polypharmacy affects CCI and/or Katz ADL scores in aging diabetic and non-diabetic patients.This prospective study was conducted from January 2017 to January 2018 after receiving institutional ethical approval from Ethics Committee of Bakirkoy Dr. Sadi Konuk Training and Research Hospital (2018/336). The study included 184 diabetic (group 1) and 62 non-diabetic (group 2) subjects who were 65 years or older and visited our Diabetes or Internal Medicine outpatient clinics. The non-diabetic patient group consisted of patients who had not previously been diagnosed with DM type 2, had a glycolyzed hemoglobin (HbA1c) level below 6.5%, and had a fasting glucose level below 140 mg/dL. Written consent was obtained from all participants. Before obtaining blood samples, data  of the patients enrolled in the study were recorded on standardized forms.CCI, a prognostic assessment tool, is based on comorbid conditions with varying assigned weights, resulting in a composite score; it predicts 10-year survival in patients with multiple comorbidities.t test was used for comparing two independent groups in variables with normal distribution. A P-value < .05 was considered significant.Statistical analyses were conducted with SPSS version 23 . Mean, standard deviation, median, minimum, and maximum values of variables were given for descriptive calculations between groups. Mann-Whitney U test was used in comparison of two independent groups for variables that did not display normal distribution, and Spearman’s rank correlation coefficient was used to determine the relationships between variables. Student’s P = .472). There was a significant difference between the two groups regarding HbA1c, random urine albumin/creatinine ratio, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), dual-energy X-ray absorptiometry, and serum iron, magnesium, hemoglobin, and albumin levels  and group 2 consisted of 62 (46 women) subjects with mean ages of 71.15 ± 5.28 years and 71.58 ± 5.35 years, respectively (P = .001 for both). Katz ADL did not differ between the groups (P = .059)  .r = 0.525, P = .001) and weak positive correlations with HbA1c  and random urine albumin/creatinine ratio . In addition, CCI had weak negative correlations with glomerular filtration rate (GFR) and serum magnesium, iron, and hemoglobin levels. Katz ADL had weak positive correlations with GFR and serum magnesium and iron levels; in addition, it had a weak negative correlation with HDL-C levels. Number of drugs had a weak positive correlation with HbA1c and a weak negative correlation with GFR, LDL-C, and serum magnesium, iron, and hemoglobin levels .In all subjects, CCI had a moderate positive correlation with age ; in addition, there was a positive correlation between CCI and number of drugs ; moreover, there was a positive correlation between CCI and number of drugs . In addition, age of DM diagnosis had positive correlations with CCI and number of drugs . Similar studies conducted in the future may focus on these issues.The increase in the number of drugs taken by aging patients with and without diabetes is positively correlated with CCI score. As we know, this scoring system is being used as a predictor of 10-year survival in patients with multiple comorbidities. Thus, polypharmacy could be a quick determinant of prognosis in such a group of patients. Further detailed studies are needed to verify this.Polypharmacy decreases quality of life and affects the survival of aging patients.The number of drugs taken by the patients had a statistically significant positive association with modified Charlson Comorbidity Index in aging people with and without diabetes mellitus.Patients should be directed to special centers or physicians who will be scheduled for multidisciplinary treatment for the prevention of polypharmacy, especially in the aging.


Background: The paper aims to analyze the impact of key labor market indicators on the self-assessed health of the population of older workers (aged 55–64).Methods: Authors build the econometric models where the dependent variable is the self-perceived health status (for women and men separately). Explanatory variables are selected key indicators of the labor market, covering unemployment, including long-term, inactivity, or under-employment. The average household income is used to control the effect of wealth. Additionally, the models incorporate the variable describing the proximity of retirement. The research sample consists of nine countries of Central and Eastern Europe: Poland, Czech Republic, Slovakia, Hungary, Lithuania, Latvia, Estonia, Bulgaria, and Romania.Results and Conclusions: The study confirms that in the group of elderly workers, the perceived state of health is influenced by long-term unemployment, inactivity, and, in the case of women, time-related underemployment. Rich literature describes how the social gradient affects the population's health. Social determinants of health (SDH) consist of non-medical factors deriving from the social and economic environment—these dimensions significantly affect the health state . The mosAmong the determinants listed above, employment status and working conditions are perceived as crucial. As a result, several studies of SDH include more or fewer variables related to the labor market. These are, for example, the employment status  or occupImportantly for further analysis, the link between health and labor market status is bidirectional. Better health promotes employment and increases income . Being uThe study aims to analyze the impact of selected labor market indicators on self-assessed health. It gives a fresh look at the decomposed problem of unemployment, including long-term unemployment or labor market inactivity, based on critical indicators of the labor market (KILM) developed by the International Labor Organization. The research focuses on the age group 55–64; this group at higher risk of unemployment or permanent inactivity. Along with age, the health status deteriorates—it is reflected both in mortality rates and subjective health state self-assessment. Additionally, the decisions of elderly workers related to their professional activity can be affected by social, cultural, and economic factors and perceived health. The choice of this age group also responds to the current demographic problems—the process of aging societies, manifested by the declining share of young workers, encourages employers to retain their employees representing older age groups. It can be one of the possible answers to the demographic problems, but only if they are ready to extend their working lives.The research sample covers nine countries of Central and Eastern Europe (CEE). Although their demographic situation is currently relatively favorable compared to western European countries, this could change drastically in the coming decades. The fall of communism and the economic transition has dramatically declined fertility rates, which will soon affect the labor market . DemograAs previously mentioned, the labor market's impact on health status is still a vital research area. It is mainly due to previous inconsistent results. The reasons for this “inconsistency” are multiple. Most of all, the labor market is a comprehensive concept and can be analyzed from different perspectives. Finally, the researchers usually focus on two main areas: working conditions  or a broader picture of unemployment, including losing a job, long-term unemployment, or inactivity. Different measures of health state  are the next potential source of conflicting results.Generally, the previous findings, in the area of the relationship between unemployment and health, can be split into two categories—studies that support the hypothesis of the detrimental effect of unemployment on health, mainly via a mechanism of lowered income and impaired social status, and results that suggest quite the opposite mechanism.Many works confirm that a loss of a job, or broadly being unemployed, impacts health negatively. Brenner was the first who described this inverse relationship. Therefore, in the literature, it is often called the “Brenner hypothesis” , 12. ThiInspired by Preston's law, researchers usually accept the assumption that higher-income individuals are healthier than those with lower incomes. Several previous studies confirm this thesis , often dOne of the recent studies by Economou et al. , based oThis relationship between job status and health has potentially many explanations. As a result of job loss, lowered income usually translates into lower availability of health services, especially in private insurance systems. Having or not having health insurance is, in several countries, strongly linked to the labor market. As confirmed by Van Doorslaer et al. , people The inverse relationship was pioneered by the works of Ruhm –32, GerdTo summarize, earlier studies usually suggest that unemployment affects a population's health negatively. It seems that, although the evidence supporting this hypothesis is relatively new, the latest studies suggest quite remote conclusions. Tapia Granados and Ionides partially described this problem, and they found that in the second half of the twentieth century, economic growth started to affect health negatively, in contrast to earlier decades .Some differences in previous results may also be rooted in analyzed countries' characteristics, as Hessel and colleagues report . ContextData covering the years 2005–2018 for nine countries of Central and Eastern Europe (CEE): Poland (PL), Czech Republic (CR), Slovakia (SL), Hungary (HUN), Lithuania (LT), Latvia (LV), Estonia (EST), Bulgaria (BUL), and Romania (ROM) are investigated. This research group is consistent in terms of economic development, demography, culture, or historical baggage despite their different population potential. The data come from the following sources: EUROSTAT and LABORSTA, provided by the International Labor Organization (ILO).The very formulation of the hypothesis on the health effects of unemployment appears to be risky in the context of previous studies; hence the research bases mainly on exploratory data analysis, focusing on the effects of individual labor market characteristics on the health of older workers. Several aspects of the labor market are considered, like unemployment, including long-term and time-related underemployment, labor inactivity, and informal economy employment.The following research questions are formulated:Which characteristics of the labor market influence health status more significantly?Is the strength and direction of this relationship the same for men and women subpopulations?To answer those questions, two GMM models, separately for men and women, are calculated , 46. GMMIn the model based on the first differences, there are no personal effects. The assumption that there is no correlation between explanatory variables and particular outcome results is no longer required. The use of instrumental variables eliminates the problem of endogeneity of variables and estimator mismatch .The Chow test examines the stability of the model parameters.The dependent variable describes the populations' health state (variable SP18). Generally, there are two types of health state measures—objective and subjective. The most popular objective measures are mortalities or life expectancies. They are reliable as they base on actual events and public statistics. The subjective indicators require survey research where respondents are asked to assess their health state , usually using the five-degree Likert scale .The subjective indicators, especially self-assessed health (SAH), although biased by their subjective component, are very inclusive and capture all aspects of health  not covered by other health variables –57. HencApart from this strong advantage, SAH is also biased by socio-economic factors like gender, age, income, occupation, race, cultural background –61. DiffThis research bases on SAH for the population aged 55–64. The data concerning SAH comes from the European health interview survey (EHIS). Respondents assess the general perceived health by answering the question: “How is your health in general? Is it …” Very good/Good/Fair/Bad/Very bad? It is a standardized question recommended by the World Health Organization .The dependent variable (SP18) covers the percentage of respondents aged 55–64 (men and women separately) who assess their health as “good” or “very good.”Explanatory variables are selected key indicators of the labor market (KILM) , coverinThere are also additional variables that go beyond the characteristics of the labor market. Since the test sample involves persons of pre-retirement age, the variable RA-55 describes the timespan to the retirement for persons aged 55 years , taking into account different retirement schemes in the individual countries. We assume that the proximity of retirement benefits may affect individuals' decisions to stay active or transit into a state of inactivity. A lower value of RA-55 should contribute to higher ratios of inactivity.The variable INCOME helps to control the impact of the financial situation on health. The level of generated income may also impact the decision to leave the labor market .A decreasing KILM1 disparity over time, measured by the mean share in the maximum value, can also be observed. A smaller disparity applies to the male population than to women . The concentration of KILM1 (Gini coefficient) is also minimal, which means an even distribution, especially for men. For women, we also see more significant variability between countries −23% compared to 9% for men .The more significant disparity of KILM6, measured by the average at the maximum value, affects men rather than women. The share of the average maximum in 2018 is 61.89% for men. The Gini coefficient for men and women adopts similar values does not exceed 0.21. Right-hand asymmetry (1.24) for women means that part-time work as a percentage of women's total employment is below average in most countries. For men, we observe a moderate left side asymmetry (0.47) .About half of unemployed people were unemployed for more than 12 months. The long-term unemployment rate in 2008 for women was the lowest in Hungary (43.4%) and the highest (79.1%) in Slovakia. In 2018 KILM11 was the lowest for Poland, compared with the other surveyed countries −33.9%. The KILM11 disparity, measured by the mean's share in the maximum, is similar for men and women. The concentration measured with the Gini coefficient is low both for the men and women population. Distributions are characterized by right-sided strong asymmetry in women's cases .KILM 12 describes the problem of underemployment as a percentage of workers who would like to extend the number of working hours. In 2008 the lowest value of KILM 12 for women was reported in Estonia (1%) and the highest in Poland (14.2%). On average, 4.31% of women and 5.07% of men would like to work longer in 2018. The KILM12 disparity, measured by the share of mean in the maximum value, is high for both women and men. The concentration is high, especially for men—an uneven distribution is observed. Right-side asymmetry is extreme for both sexes, and values are characterized by very high volatility. In Poland, 15.9% of employed women and 16.4% of working men would like to extend their working hours. These values stand out from other countries .The inactivity rate is the proportion of the working-age population excluded from the labor force. The KILM13 rate for women was the lowest in 2008 in Estonia (38.6%) and the highest in Poland −78.6%. In the period 2008–2018, there is a clear positive tendency for female and male populations. In the case of women, the inactivity rate dropped from 60.6 to 43.33% during the years 2008–2018. The lower disparity, measured by the share of mean in the maximum value, applies to men. Men's and women's concentration coefficients are low with weak right-side asymmetry for both subpopulations (2018) .To summarize, the preliminary analysis of variables indicates a vital gender gap. 43.3% of women aged 55–64 are inactive—women do not look for employment for various reasons. It is significantly higher than for men (31.73%). Simultaneously, the number of inactive women decreased substantially between 2008 and 2018 (from 60.6 to 43.33). The reasons may be related to reforms in the area of retirement policy aiming to increase the retirement age, especially for women, and equalize retirement age for both sexes . This chAbout half of unemployed people are unemployed for more than 12 months, both women and men. Only a tiny proportion of those who work (4.31% of women and 5.07% of men) would like to do more, although the situation is sharply different between countries. This need for extra hours of work is evident in Poland and Romania.good” and “very good.” We observe that this percentage for women significantly increases between 2008 and 2018, while for men slightly decreases. The disparity of the variable SP18 is high both for men and women. A moderate left side asymmetry similar for both men and women can be observed.The variable SP18 describes the percentage of persons who assess their health as “Some analyzed variables show very high volatility or inequality between countries. Hence, in the next step, we test the significance of differences between means of selected variables for women  and men Separate models for men and women due to the significant variation in variable values are estimated. Models 1 and 2 explain the self-perceived health for women and men, respectively. Both models are estimated using explanatory variables number 1–5 , 11.The general form of the model 1and 2 are as follow:F = 0.59331, with p-value 0.7051, and for women, F = 2.48539 with p-value 0.0643.The models do not contain any structural changes. The Chow test, in both cases, confirms the stability of the parameters. The null hypothesis assumes the absence of structural changes. For the male model, In model 1, estimated for women aged 55–64, three variables explain the self-perceived health—long-term unemployment (KILM11), time-related underemployment (KILM12), and inactivity rate (KILM13). Other variables did not enter the model. For KILM 11, the partial regression coefficient is −0.0540644 with an error of ±0.0298267, which allows the following interpretation: when the long-term unemployment rate increases by 1 (%), health perception decreases by 0.054 (%), provided that the values of other variables do not change. When the time-related underemployment (KILM12) increases by 1%, the self-perceived health decreases by 0.0742690 (%). Analogically, the partial regression coefficient for KILM13 in (%) is −0.764447, with an error of 0.0358556. Hence, if the inactivity rate increases by 1 (%) on average, the perception of health decreases by 0.764447 (%), provided that the size of other variables does not change .The dependent variable's [SP18(f)] arithmetic mean is 31.45357 and the standard deviation of the dependent variable is 10.89073. GMM criterion: Q = 1.69439e-022 (TQ = 1.89772e-020).The self-perceived health of men aged 55–64 (model 2) is explained by only two variables: long-term unemployment (KILM11) and inactivity rate (KILM13).The partial regression coefficient for KILM 11 is −0.112940 with an error of ±0.0422647, which allows the following interpretation: as the long-term unemployment rate increases by 1 (%), health perception decreases by 0.112 (%), provided that the values of other variables do not change. Analogically, the partial regression coefficient for KILM13 in (%) is −0.608790, with the error of 0.0722067. Hence, if the inactivity rate increases by 1 (%) on average, the perception of health decreases by 0.609 (%), provided that the size of other variables does not change .Models 3 (for women) and 4 (for men) are estimated using all explanatory variables. It allows for analyzing the potential effect of retirement age and income.The general form of the model 3 and 4 are as follow:F = 7.10122, p-value = 3.96467e-005], and for women (model 3), it is indisputable .The models do not contain any structural changes. The Chow test in both cases confirms the stability of the parameters. The null hypothesis is the absence of structural breaks in a time series. In the male model (model 4), this is a low value  arithmetic mean is 31.45357 and the standard deviation of the dependent variable is 10.89073. GMM criterion: Q = 6.8816e-024 (TQ = 7.70739e-022).Model 4 also includes additional variables . In this case, only one variable describing the labor market enters the model (the long-term unemployment ratio). The partial regression coefficient for KILM 11 is −0.0744426 with an error of ±0.0298090, which allows the following interpretation: as the long-term unemployment rate increases by 1 (%), health perception decreases by 0.0744426 (%), provided that the values of other variables do not change .For women, the household income impacts self-perceived health marginally. When the household income increases by 1 (%), the perceived health very slightly increases by 0.00302122 (with the error of 0.000459543). In the case of RA-55, a healthy relationship but in a different direction is observed. When RA-55 increases by 1 (%), the perceived health increases by 2.30497% (with the error of 0.489014). Hence, men who expect to work for a longer time assess their health state as better.The dependent variable's [SP18(f)] arithmetic mean is 31.45357 and the standard deviation of the dependent variable is 10.89073. GMM criterion: Q = 6.8816e-024 (TQ = 7.70739e-022).To summarize, the labor market characteristics which influence the perceived health are, depending on the model, long-term unemployment (KILM 11), time-related underemployment (KILM 12), and inactivity rate (KILM 13). All those factors affect perceived health negatively. When we include income, we observe a positive relationship; however, it is relatively feeble. It seems that the retirement age plays an important role. Estimated models suggest that women who expect a longer timespan of work perceive their health as worse. This relationship is relatively high and statistically significant. For men, and the opposite relationship is detected—men who expect to work up to longer age assess their health as better. It is potentially an exciting finding but, in our opinion, requires further research.The research involves people aged 55–64. It is a period in life when health progressively deteriorates. Lack of success in the labor market, like losing a job, can also contribute to the deterioration of health. Previous studies do not expressly answer the link between employment and health.As summarized in section Literature Context, several studies confirm the detrimental impact of unemployment on health outcomes, regardless of the dependent variables. The negative effect of being unemployed is reflected in higher mortality and morbidity rates or lower health state self-assessment , 66–68. The impact of unemployment on health is evident in various health indicators—the authors usually analyze health in the context of mortality, maturity, and self-health (SAH). If mortality is examined, most studies, especially earlier ones, suggest a negative impact. In one of earlier studies, Brenner, based on British data, concludes that a negative impact of unemployment is expressed by slowing the decline in mortality . Also, WPanel studies in this area are not so consistent. Based on data from 13 European Union countries, Economou et al. confirm a strong, positive relationship between adverse economic conditions, including unemployment and mortality . On the When morbidities describe a health state, results are, by far, more consistent. They usually indicate a higher risk of heart disease , 74–81. From the point of view of this research, the most interesting are the studies in which respondents assess their health independently (SAH). Binder and Coad conclude that unemployment cause a substantial decrease in subjective well-being in the UK population . László By contrast to that, Tøge and Blekesaune, using data from 28 European Countries, including CEE ones, suggest that unemployment and health are partly due to decreased self-rated health as people enter unemployment. This study also emphasizes the detrimental impact on older workers' health . AgainstIn light of the presented findings, only long-term unemployment impacts health detrimentally. The constant lack of professional activity has a similar influence. Additionally, women's self-assessed health suffers from time-related underemployment. Previous studies show that women are at higher risk of underemployment as underemployment is most common in women's professions .This study also confirms that among the group of elderly workers, the perceived state of health is affected not simply by unemployment but primarily by its structure. Short-term unemployment is often perceived as desirable—it allows job seekers to find suitable employment. It can be a time of relief from a daily routine for stressed workers, especially when social support schemes offer satisfying financial security levels. However, in light of those findings, long-term unemployment harms self-assessment health. However, this effect is more substantial for men. This negative impact is possibly rooted not only in lower economic status but social factors that may also contribute to lower perceived health status . Those rIn contrast to many earlier studies, significant gender differences are not observed, which is a little bit puzzling in the context of research suggesting that unemployment has a more substantial impact on men's health , 86–88. Women are also at higher risk of underemployment due to the structure of jobs they usually take . To a moApart from the problem of unemployment, presented findings highlight the importance of labor market inactivity. Three of four estimated models suggest the negative impact of inactivity on health—this impact is more substantial compared to other characteristics of the labor market. At the age of about 60 years, both women and men usually decide when to retire. From the labor market perspective, it means a transition into a state of inactivity or significantly reduced working hours. According to Eurostat, 15.9% of unemployed aged 55–64 who left the labor market chose early retirement, while 15.8% were forced to retire due to illness or disability . It indiThe lack of activity, rather than unemployment, might be a source of health state deprivation. Inactivity has a significant negative impact on both sexes' perceived state of health . Hence, There is a group of researchers that reports a positive impact of retirement on health. Che concludes that the probability of “fair” or “poor” self-reported health among white-collar workers decreases substantially after retirement , 101. SoThe results also suggest that the retirement age influences importantly perceived health, but this relationship's direction is damaging for women and positive for men. It contrasts with studies suggesting that the statutory retirement age is unrelated to an individual's health . AlthougAs previously mentioned, CEE countries form a homogenous group in terms of economy, demography, and social systems, including retirement schemes, making the estimation results more reliable. The research results generally confirm the relationship revealed in previous studies, both on the direction and strength of the dependencies. However, there are a few limitations to consider. Firstly, the previous findings are significantly inconsistent, so it is difficult to identify some universal conclusions.Secondly, most studies in this area cover data from highly developed countries—the US and Western Europe. Research in developing countries is relatively scarce and most often points to a positive link between unemployment and health , 108. HoTherefore, it is justified to conduct further comparative studies to capture possible differences between Western Europe countries and CEE countries. Although the microeconomic structure of unemployment in the nations of eastern Europe appears to be similar to the industrialized west —some stuThe process of demographic change is an undeniable fact. In the coming years, pre-retirement age employees will form a significant group in the labor market. This part of the population is, by nature, at higher risk of health state deterioration, as a part of the aging process. Any difficulties in the labor market may boost these problems and push workers out of the labor market, as we remember the bidirectional relationship between health and its socio-economic determinants. Taking into account the potential shortage of workers, it may pose severe problems for the economy.Unemployment, especially when it has a long-term character, harms the health of employers from the older age groups—unemployed assess their health state as worse than those who have a job. Interestingly, the impact of labor inactivity is, importantly, more wasting than an unemployed status. Although this effect's mechanism requires further studies, we presume that permanent resignation from job-seeking reinforces the social gradient's detrimental impact, leading to a worsen economic situation or deepen social isolation.Apart from long-term unemployment, women also suffer from time-related underemployment. It suggests that public politics promoting employment should concentrate not only on unemployed but also part-time workers.Being inactive is a natural consequence of taking retirement. In this context, the problem of retirement age plays an important role. All CEE countries, except Poland, gradually increase the statutory retirement age, especially for women. It can be a source of, on average, lower perceived health status (compared to men).To conclude, there are several advantages of an active senior policy aimed at galvanizing older workers' activities, promoting employment, and gaining new competencies. This tailor-made policy should address the identified determinants of labor inactivity to prevent early retirement.This study has several advantages comparing to the existing literature: firstly, to our best knowledge, this is the first study on this group of countries, which may open the discussion on potential differences between European countries. Secondly, the analysis covers diverse aspects of unemployment , catching the most critical dependencies. Thirdly, the research includes the variable describing the proximity of retirement to control potential differences of retirement schemes, which plays a crucial role in studies on older workers.https://ilostat.ilo.org/.Publicly available datasets were analyzed in this study. This data can be found here: PU-J and AB: conceptualization and writing—original draft preparation. PU-J: data curation, formal analysis, methodology, resources, and visualization. AB: investigation and writing—review and editing. 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.


Background: Dietary Inflammatory Index (DII) scores have been consistently associated with several chronic diseases. This study explored the correlation between the DII and hyperuricemia in Chinese adult residents. Methods: The study included 7880 participants from the China Health and Nutrition Survey (CHNS), which was taken in in 2009. A 3-day 24 h meal review method was used to collect diet data and to calculate the DII score. Serum uric acid was obtained to determine hyperuricemia levels. Subjects were divided into a hyperuricemia group and a non-hyperuricemia group, according to their serum uric acid level. Multilevel logistic regression models were used to examine the association between DII scores and hyperuricemia. Results: After adjusting for covariates, a higher DII score was determined to be associated with a higher risk of hyperuricemia. Compared to those in the highest DII score group, the lower DII score group had an inverse association with hyperuricemia risk . The intake of energy-adjusted protein, total fat, MUFAs, PUFAs and saturated fatty acid was higher in the hyperuricemia group. Conclusions: A higher DII score is significantly associated with a higher risk of hyperuricemia. Controlling the intake of pro-inflammatory food may be beneficial to reduce the risk of hyperuricemia. Hyperuricemia is defined as an increased concentration of uric acid in the blood and occurs due to urate overproduction or because of impaired urate excretion through the kidney and gastrointestinal tract ,2. It isAlthough risk factors for hyperuricemia have not been fully determined, recent studies have shown that chronic inflammation is correlated with hyperuricemia ,11. HypeDiet is one of the main modulators of subclinical inflammation and is associated with hyperuricemia ,15,16. PThe Dietary Inflammatory Index (DII) was developed in 2009 and updated in 2014 ,24, and At present, research on the relationship between DII scores and hyperuricemia in developing countries is very limited. With the growing interest in the role of inflammatory modulation in preventing and controlling hyperuricemia, we conducted a cross-sectional study based on the China Health and Nutrition Survey (CHNS) to investigate the association of DII scores with the risk of hyperuricemia in the Chinese population.We used data from the China Health and Nutrition Survey (CHNS), an ongoing open cohort of more than 30,000 subjects from 15 provinces and municipal cities, designed to reflect the nutritional and health status of the Chinese population. The first round of the CHNS started in 1989, and a total of 10 surveys have been carried out so far. Biomarker data were collected in the 2009 survey. Details of the CHNS have been described previously . In thisAccording to the conclusion of previous relevant studies ,26, our The CHNS was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill, and the National Institute for Nutrition and Health  at the Chinese Center for Disease Control and Prevention (CCDC), and all participants gave written informed consent. Subjects with uric acid (UA) ≥ 420 μmol/L (7 mg/dL) for men, or 360 μmol/L (6 mg/dL) for women were determined to have hyperuricemia .In brief, the DII was developed after a comprehensive audit of peer-reviewed literature, aimed at measuring dietary inflammatory potential. The China Food Composition Tables Standard Edition (CFCTSD) provided general nutrition data for more than 3000 kinds of foods and ingredients in China. We combined the dietary data obtained from the 3-day 24 h meal review method with the CFCTSD to obtain the data used to calculate the DII.The DII score in this study was calculated by scoring 28 out of 45 food parameters, including 7 pro-inflammatory parameters and 21 anti-inflammatory parameters. The food parameters included energy, protein, carbohydrates, total fat, saturated fatty acid, cholesterol, monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), fiber, β-Carotene, vitamin A, vitamin C, thiamin, riboflavin, niacin, folic acid, Fe, Mg, Se, Zn, garlic, ginger, onion, green/black tea, isoflavones, pepper, thyme/oregano and alcohol.We defined four DII groups according to the quartiles of the DII scores .In addition to diet, the CHNS questionnaire also asked questions on lifestyle and demographic characteristics. In this research, demographic information included gender, age, region , marital status  and education level . Current smoking status was divided into two groups: current smokers and non-smokers. Body mass index (BMI) was calculated from the subjects’ physically measured height and weight at the survey.The descriptive sociodemographic analysis was summarized by the subjects’ gender and hyperuricemia group. Mean values and standard deviations were used for continuous and normally distributed variables. Continuous variables were analyzed by Student’s t-tests and categorical variables were analyzed with the chi-square tests. Multilevel logistic regression models were used to estimate the odds ratios and 95% confidence intervals for the associations between DII groups and hyperuricemia. For the main analysis, two models were established: model 1 was adjusted for age and gender, and model 2 was further adjusted for BMI, region, education level, smoking status and marital status.p values less than 0.05 were considered significant.The data preprocessing and statistical analyses were all completed by R v4.1.0. All tests were two-sided: alpha was set at 0.05 as the level of significance, and There were 7880 subjects included in this study. The average age of subjects was 50.7 years . There wIn this study, we identified 1235 (15.7%) subjects with hyperuricemia. The prevalence of hyperuricemia was 20.5% in males (748/3628) and 11.5% in females (487/4252). The DII score for the sample ranged from −4.0 to 2.3. The distribution of participants’ characteristics by gender and hyperuricemia status is shown in The total energy and energy-adjusted dietary intakes of carbohydrates, proteins, fats, fiber and vitamins are presented in The results of the correlation between the DII score and the risk of hyperuricemia (stratified by gender) were shown in In this cross-sectional analysis, we observed that a higher DII score, which is indicative of a pro-inflammatory diet, was associated with a higher risk of hyperuricemia. These findings remained true after adjustments were made for a range of confounding factors. We also found positive associations between higher intakes of proteins, fats and alcohol with uric acid.Previous studies have examined the relationship between dietary inflammation and hyperuricemia. A Korean study suggested that women in the highest DII score group had a higher risk of hyperuricemia than those in the lowest group , which iWe found that there was a difference in diet between the hyperuricemia and the non-hyperuricemia groups in the Chinese population. The hyperuricemia group had a lower average energy intake and higher energy-adjusted protein and fats. This finding is contrary to previous studies, which have suggested that weight-loss diets may lower serum urate . These dDietary factors can affect the development of hyperuricemia and the severity of the symptoms, as well as the inflammatory response. Vitamin C and vitamin E reduce serum uric acid levels through their antioxidant activity ,32. FlavIt is noteworthy that some foods might exert both beneficial and detrimental effects on uric acid levels at the same time. Legumes, for instance, are rich in purine and soybean isoflavones . PreviouStrengths of this study include the accuracy of dietary intake data and population-based design. The data were obtained from the CHNS, covering 15 provinces or municipalities, which is more representative of the Chinese residents. The CHNS used a 3-day 24 h meal review to collect diet data, and nutrients in foods were calculated by the CFCTSD and subsequently determined and compiled by the CCDC.There are some limitations of this study. Firstly, this was a cross-sectional study that cannot account for temporality. Besides this, information about self-aware hyperuricemia or gout history was not available through the questionnaire or interview in the CHNS, and subjects diagnosed with gout or hyperuricemia might change their diet pattern. Therefore, the causality of diet and hyperuricemia cannot be established. Secondly, hyperuricemia was defined by a single blood test of the study population in the CHNS, and the diagnosis in the guideline required two determinations of serum uric acid levels at different times. Therefore, the results of serum uric acid may not represent the true situation. Finally, we included only 28 indicators that were used to calculate the DII, because some of the parameters had insufficient information due to objective conditions. This may have narrowed the effective range of the DII score. Although evidence suggested that the predictive ability was not affected when fewer parameters were used to calculate the DII scores , the posWe documented that a higher DII score was associated with a higher risk of hyperuricemia in China. Increasing anti-inflammatory food and reducing pro-inflammatory food or nutrients in daily life might be a potential strategy to reduce uric acid.


The management of cancer surgeries is under unprecedented challenges during the COVID-19 pandemic, and the breast cancer patients may face a time-delay in the treatment. This retrospective study aimed to present the pattern of time-to-surgery (TTS) and analyze the features of breast cancer patients under the different stages of the COVID-19 pandemic.Patients who received surgeries for breast cancers at West China Hospital between February 15, 2020 and April 30, 2020 (the outbreak and post-peak stages), and between March 10, 2021 and May 25, 2021  were included. TTS was calculated as the time interval between the pathological diagnosis and surgical treatment of breast cancer patients. And the pandemic was divided into three stages based on the time when the patients were pathologically diagnosed and the severity of pandemic at that time point. TTS, demographic and clinicopathological features were collected from medical records.p<0.001) and regular screening (p<0.001), as well as age (p=0.013) and menstrual status (p=0.004). As for clinicopathological features, axillary involvement (p=0.019) was a factor that differed among three stages. The overall TTS was 23.56 ± 21.39 days. TTS for patients who were diagnosed during the outbreak of COVID-19 were longer than those diagnosed during pandemic post-peak and normalization stage (p<0.001). Pandemic stage (p<0.001) and excision biopsy before surgery  were markedly correlated with the TTS of patients.A total of 367 patients were included. As for demographic features, it demonstrated statistically significant differences in insurance type (TTS of breast cancer patients significantly varied in different stages of the COVID-19 pandemic. And breast cancer patients’ daily lives and disease treatments were affected by the pandemic in many aspects, such as health insurance access, physical screening and change of therapeutic schedules. As the time-delay may cause negative influences on patients’ disease, we should minimize the occurrence of such time-delay. It is vital to come up with comprehensive measures to deal with unexpected situations in case the pandemic occurs. The COVID-19 pandemic caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health emergency of global concern, and is unprecedentedly threatening the contemporary healthcare systems (Time-to-surgery (TTS) refers to the time interval between diagnosis and therapeutic surgery. Longer TTS is associated with poorer outcomes in patient with breast cancers , 4 and oThe management of breast cancer demands special considerations during the pandemic. Although the existing studies conducted on TTS changes among patients with breast cancer during COVID-19 are mainly cross-sectional, the available evidence confirmed a time-delay in cancer treatment. High mortality risk diseases, such as cancers should not be neglected during the pandemic –13 and pThe study was approved by institutional review board . Informed consent was waived due to the retrospective nature of this study.Between February 15, 2020 and April 30, 2020, and between March 10, 2021 and May 25, 2021 , patients with breast cancer who received surgeries at West China Hospital of Sichuan University were retrospectively identified from hospital database. The inclusion criteria were patients with breast cancers who received surgeries. The exclusion criteria were as follows: a. male patients; b. Paget’s disease; c. patients who received neoadjuvant chemotherapy; d. patients during pregnancy or lactation; e. recurrent or metastatic diseases; f. patients who have been diagnosed with other malignancies; g. patients with known major disabling medical or mental disorders.The following information of each included patient was collected: demographic, clinical, pathological features and treatment strategies.Conventionally, TTS was calculated as the time interval between the pathological diagnosis and surgical treatment of breast cancer patients. According to TTS, patients were categorized into two groups: TTS < 40 days and TTS ≥ 40 days , 14.Based on the time when the patients were pathologically diagnosed and the severity of pandemic at that time point, we categorized the patients into three groups: outbreak (diagnosed before 1.24 in 2020), post-peak (diagnosed after 1.24 in 2020) and normalization (diagnosed in 2021). As the time point of the suspension of operations, January 24, 2020 was regarded as the cut-off point for pandemic in 2020, which divided the pandemic into the outbreak and the post-peak stage. To be specific, the post-peak stage refers to a period when there was initial progress in containing the virus.t-test and one-way analysis of variance (ANOVA) for continuous data; Pearson’s Chi-square test or Fisher’s exact test for categorical data to compare demographic, clinical and pathological features in different periods of the pandemic; binary logistic regression for univariate and multivariate analysis of TTS. A two-sided p-value less than 0.05 was regarded as statistically significant. All statistical analyses were performed using SPSS 21.0 .We used independent p<0.001). With the progression and control of the pandemic, TTS showed a pattern of first increasing, then deceasing, before finally stabilizing. The mean TTS was 58.55 ± 24.87 days during the outbreak stage of the pandemic, 16.55 ± 11.10 days in post-peak stage, and 22.38 ± 20.43 days in the normalization stage. The differences and patterns of TTS are demonstrated in The overall mean TTS was 23.56 ± 21.39 days. The TTS was distinctly different at different pandemic stages (p<0.001) and regular screening (p<0.001). During the normalization stage, more patients paid medical bills via governmental insurance and received periodic screening than patients in other stages. Patients seen in the normalization stage were generally older (p=0.013), and more likely to be menopausal (p=0.004). Detailed demographic characteristics of the patients are presented in In total, 367 consecutive patients met the inclusion criteria and were included for statistical analysis. None of the patient was infected with SARS-CoV-2. The mean age at diagnosis was 50.74 ± 10.63 years. The demographic features, such as setting, educational level, and marital status were not significantly different among the pandemic stages. Interestingly, statistically significant differences were found in the insurance type (p=0.019). Other clinicopathologic features, such as method of detection, type of surgery, AJCC stage and molecular subtype, were similar among 3 stages. Detailed clinical-pathological characteristics of the patients are presented in A significantly higher proportion of patients exhibited axillary involvement in post-peak stage than outbreak stage. On the other hand, following initial control of the virus the number of patients with axillary involvement decreased markedly during the normalization stage (p<0.001), excision biopsy before surgery , and menstrual status  were related to the TTS (p<0.001), and excision biopsy before surgery  were markedly correlated with TTS. The correlation pattern between these two factors and TTS was consistent with that in the univariate analysis.Results from the univariate analysis showed that pandemic stages . Starting from mid-February, surgeries were gradually resumed on the basis of limited admissions. By April 2020, the daily running of the hospital (diagnosis and treatment) had generally returned to normal.The TTS of patients with breast cancer was the longest during the COVID-19 outbreak stage and the shortest at the post-peak stage. In contrast, the TTS during the normalization stage in 2021 was moderate. In the beginning of the pandemic, transportation between cities and provinces were temporarily cut off to stop the virus from spreading, which led to expected diagnostic and treatment delays. Moreover, little was known about the virus at the start of the pandemic, and the fear of COVID-19 led many to voluntarily and completely avoid social contact, which may be the main reason for the increased TTS.Surprisingly, the TTS dropped shortly after the outbreak stage of the pandemic, to a duration shorter than that in the normalization stage. This may be due to patients choosing to attend local hospitals instead of waiting to be admitted in large hospitals. Further, due to the limited access to surgeries at the time, selected patients with operable breast cancers received neoadjuvant chemotherapy instead of surgeries. Consequently, the number of patients waiting for treatment in the hospital reduced, and the patients might be seen and treated more quickly during post-peak stage. The TTS of the normalization stage in 2021 is likely to be maintained for a long time into the future. Many previous studies have reported on the delay associated with cancer surgeries during the COVID-19 pandemic. The time-delay ranged from 1−2 weeks to several months. The risk of patient exposure, turnover times, the patient’s fear, and economic instability could all influence the TTS , 9, 15. Age was a key patient characteristic that was significantly different among the different stages of the pandemic. Patients in the normalization stage were on average, older. Concerning the aging process, older patients with breast cancer tend to have more comorbidities and worse physical conditions than the younger patients . It is pMost of the potential influencing factors of TTS turned out to be irrelevant variables. Meanwhile, different stages of the pandemic accounted for most of the differences in the TTS. During the different stages of the pandemic, not only did the hospital and surgeries run differently, but the patients also experienced different events and possessed different mindsets. In the initial stage of the pandemic, the suspension of hospital operations, diminished healthcare resources, and patient’s resistance to social contact all contributed to the longer TTS. Garcia, et al. also found that delays in oncologic surgery negatively affected many tumor types . While tSome experts have suggested that it is appropriate to delay surgery during COVID-19. The European Society for Medical Oncology (ESMO) recommended that the initial operation of low-risk early breast cancer could be postponed for up to 12 weeks . Tseng, During the COVID-19 pandemic outbreak, a lack of adequate advanced preparation had led to time-delays in cancer treatment. Breast cancer centers should ensure thorough protective measures, adequate social distancing, and quali-quantitative standard of breast cancer care to be well-prepared for potential and anticipated challenges. Our study provided a perspective of how the COVID-19 pandemic affected patients with breast cancer by prolonging the TTS, which in turn inspired us to develop comprehensive methods for challenges such as a pandemic.There are several limitations to this study. Firstly, the TTS can be largely affected by the severity of local epidemics and local government policies. Thus, our findings must be interpreted with the local conditions in mind. Secondly, the retrospective design of this study may inevitably bias patient selection. Thirdly, this is a single-center study, and the sample size was relatively small.In conclusion, the current study presented the pattern of TTS for patients with breast cancers during the COVID-19 pandemic and shared the experience of a single center. Future studies with larger sample populations are warranted to validate our results.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JC, RC, and JY contributed to conception and design of the study. RC and JY performed the statistical analysis. RC and JY wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted versionThis study is supported by the funding from the National Natural Science Foundation of China (32071284) and the Fundamental Research Funds for the Central Universities (2021SCU12021).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.


To investigate whether hybrid repair has supremacy over conventional open repair in aortic arch diseases.A comprehensive search was undertaken in two major databases (PubMed and MEDLINE) to identify all studies comparing the two surgical techniques in five years, up to December 2018, that met the established criteria in this study. The search returned 310 papers, and 305 were selected after removing duplicates. The abstracts of the remaining articles were assessed, resulting in 15 studies that went to full-text analysis. After application of the inclusion and exclusion criteria, 8 papers remained for the final revision.Eight studies met the criteria, with the inclusion of 1,837 patients. From a short-term perspective, hybrid repair and conventional open repair had similar outcomes in terms of postoperative mortality and acute neurological events. Hybrid repair was associated with less respiratory complications and risk of new intervention, as well as reduced hospital length of stay. Conventional open repair showed better mid- and long-term outcomes.Hybrid repair should be used in selected patients, with a high risk or very high-risk profile for conventional surgery. Finally, since most of the current data were obtained from limited to large samples, with narrow follow-up and had great heterogeneity, the best approach to the aortic arch is still variable. Therefore, the decision of the approach should be individualized and evaluated by the whole Heart Team, considering the expertise of the surgical team. However, the procedure is related to high morbidity and mortality and numerous complications, mainly due to prolonged cardiopulmonary bypass (CPB) time and/or hypothermic circulatory arrest (HCA), a condition required to reduce brain tissue damage and multiorgan ischemia and that can have a direct impact on postoperative neurological outcomes. In the last two decades, with the improvement of much less invasive techniques, endovascular repair of the thoracic aorta appeared as an alternative with more desirable outcomes[, a combination of the open technique in association with the endovascular approach, emerged as a modern treatment modality for properly selected patients. Mitchell et al. described a classification of the aortic arch based in zones, as seen in Therefore, anatomical knowledge of the arch is fundamental, which will allow the best approach and the analysis of possible complications. The anatomical variation of the vessels, as well as their angulation, are factors that, in combination with the intense blood flow through the aorta, can make it difficult to release the stent and its duration in a long-term perspective, in a single-time procedure, with no need of HCA, avoiding, therefore, the risks of postoperative neurological impairment. However, the main obstacle of type I hybrid repair is neurological complications with relatively high risks of stroke and endoleaks.There are currently three known types of hybrid repair, in terms of thoracic debranching: types I, II and III, as seen in . For a properly tube graft anastomosis, the use of CPB and HCA plus antegrade selective cerebral perfusion is mandatory. Following the procedure, the next step is the supra-aortic vessels debranching, which, however, can be done without aortic clamping. Finally, the endovascular graft is released in an antegrade fashion through the ascending aorta.In the type II approach, the ascending aorta replacement with a prosthetic graft may be preferred in cases where obtaining an adequate proximal landing zone is not possible due to a diseased aorta, which can be a useful tool to deliver the endovascular stent. This single-stage procedure differs from the original conventional open arch repair, described in the 1980s by Dr. Borst in which a double-stage procedure was carried out, but with a high risk of operative mortality, especially in older patients that could not safely stand a second major procedure.The type III repair, known as frozen elephant trunk, is the procedure of choice for patients in whom the aortic disease extends to the ascending aorta, aortic arch, descending and thoracoabdominal portions of aorta, as seen in . The aortic arch is anatomically challenging and the use of thoracic endovascular aortic repair (TEVAR) might be difficult in some cases, mainly due to inadequate landing zones for endoprostheses. This situation can be overcome using branched or fenestrated grafts, allowing the debranching to be done remotely. One of the most performed cervical debranching technique involves the transposition of the left subclavian and carotid arteries, as well as more complex cases dealing with the vertebral artery and the right-sided supra-aortic vessels, most commonly the carotid-subclavian artery bypass, as seen in Figure 4.Furthermore, there are the modalities of cervical debranching that evolved exponentially in the last decade as another option for the treatment of complex aortic arch diseases, especially using fenestrated or branched grafts.In general, aortic debranching with cervical or supraclavicular incisions is safe and has excellent durability. The main postoperative complications in these cases are neurological. The use of preoperative images, such as angiogram or brain magnetic resonance, to evaluate the vertebral and carotid arterial system, especially in patients with a patent circle of Willis, can guarantee that a unilateral occlusion of one side of the carotid circulation does not cause any cerebral ischemia during the procedure.Branched grafts are built with two interleafed prosthesis, with the “chimney” aspect, and are used to maintain the blood flow of the desired supra-aortic vessels, mainly the brachiocephalic trunk and the left carotid artery. In patients with aneurysms that involve the major portion of the arch or when the stent cannot be properly delivered in the aortic wall, a branched graft is more indicated.Finally, it is possible to conclude that high-risk profile CTAD patients may benefit from hybrid repair, particularly in those with contraindications to the total open repair, with acceptable outcomes in the short and medium term. However, acute neurological events and mortality rates still raise concerns and are considered the “Achilles’ heel” of complex aortic proceduresversus total open repair for the treatment of aortic arch diseases.In view of the above, the authors wanted to recognize what the current literature shows about both interventions, hybrid and open, which is more than necessary, given the rapid development of new technologies. Hence, we aimed to demonstrate, through a comprehensive literature review, the efficacy of HR The study design is a review of articles published in the last 5 years that addressed a comparative analysis between hybrid repair and total open repair for aortic arch disease.hybrid repair versus open repair for aortic arch (with 15 studies found), hybrid endovascular aortic arch repair (with 226 studies found) and total open aortic arch replacement .The selected articles were collected from PubMed and MEDLINE databases. The MeSH descriptors chosen were We included all articles that compared one technique with the other, in adult patients, with samples on any size and followed up in short-, medium- or long-term outcomes, also with the adhesion of retrospective cohorts, in English and in Portuguese. All articles that did not compare the techniques, which included aortic diseases other than the aortic arch, review articles, editorials, randomized clinical trials in progress and meta-analysis were excluded. All abstracts were revised for the application of the inclusion and exclusion criteria. The remaining 15 articles were assessed in the full text, but still did not meet the required criteria. Then, we proceeded to a complete analysis of the eight remaining articles.Then, we proceed to the PRISMA  diagram, as shown in After proper application of inclusion and exclusion criteria, 8 articles were selected, all in English, as seen in , in a sample of 364 individuals, 58 high-risk patients were treated with HR and 124 with COR. Patients treated with HR were older, with more history of malignancy and higher EuroSCORE. Surgical complications were similar in both groups (2.6 vs. 0%), with no statistically significant difference. The CPB and HCA times decreased in HR, but without any impact on patient recovery. The final follow-up extended to 52 months and the survival rate free from aortic adverse events were 79% and 99% for HR and COR, respectively.In the study of Tokuda et al. performed a multivariate analysis of 16 predictors of adverse outcomes. Of 319 patients, 274 underwent COR and 45 underwent HR with exclusion of the 0-landing zone of the arch. The results showed that operative mortality between the two groups did not differ statistically. Nineteen patients (5.9%) had a permanent stroke, with 15 patients from the conventional repair group (5.5%) and four patients from the HR group (8.9%), with a P of 0.32, and two patients, both from the COR group, had permanent paraplegia (P=1.00). The HR group had more total neurological complications (P=0.051), but not more permanent (P=0.32). Previous non-aortic heart disease and congestive heart failure were independent predictors of permanent adverse outcomes, like operative mortality, permanent neurological event or kidney injury. Concomitant coronary artery bypass grafting was predictive of permanent stroke (P=0.032), as well as previous cerebrovascular disease. During an average follow-up of 4.5 years, survival rates for the COR group were 78.7%, with no difference between groups (P=0.14), even after propensity score matching.Preventza et al. analyzed a cohort of 125 patients diagnosed with descending thoracic aortic aneurysm with distal aortic arch involvement, in which 79 underwent COR and 46 underwent HR in landing zones 1 and 2. Both groups were submitted to propensity score matching, which showed no statistically significant in-hospital mortality (P=0.49). The main adverse outcomes were stroke , paraplegia  and pulmonary complications (19% vs. 6.5%), for COR and HR groups, respectively. After adjusting the propensity match, the in-hospital mortality for COR was higher and there was a substantial risk of pulmonary complications. However, both techniques were similar in terms of 30-day mortality, paraplegia and medium-term survival. The 10-year reintervention-free rates were significantly better for COR (85.2%±7.1%) than HR .Joo et al. evaluated a sample of 238 patients, of which 174 underwent COR and 64 underwent HR. A retrospective analysis of the clinical outcomes was performed, in addition to the use of a multivariate analysis after propensity score matching. In-hospital mortality rates were 4,6% (8/174) and 6,3% (4/64) in COR and HR groups, respectively, with P=0.739. The COR group had a lower incidence of permanent stroke. Overall survival rates in 5 and 10 years were significantly different . After propensity adjustment, in-hospital mortality and patient comorbidities did not differ significantly. For those in the HR group, a tendency towards permanent stroke was observed . In the COR group, the 10-year survival  and reintervention-free rates were significantly better .In another trial, Joo et al. conducted a study with a small sample of 25 patients, 13 assigned to HR without CPB and 12 patients assigned to COR. Mortality rates were 23% for the HR group and 17% to COR. Postoperative complication rates were similar in both groups.Souza et al. included 143 and 50 patients admitted for COR and hybrid TEVAR, respectively, for non-dissected aortic arch aneurysms, from 2008 to 2013. The mean values of EuroSCORE II were 4.35±3.65% and 7.78±5.49% for open repair and hybrid TEVAR, respectively. There was no significant early mortality between both groups . Early morbidity was also equivalent in both groups, but the ICU length of stay was statistically shorter in the hybrid group 4.7 vs. 1,6 days, P=0.018). During the follow-up, survival rates did not differ statistically , but arch reintervention was required in a patient from the COR group who developed a pseudoaneurysm and in 5 patients from the HR group . The 3-year reintervention-free rates were 99% in the COR group and 80% in the HR group (P<0.001). The propensity score matching showed shorter ICU and hospital length of stay, as well as a greater need for reintervention in the HR group.Iba et al. had a cohort sample of 2,153 patients who underwent aortic arch repair and, of these, 137 patients, with a median age of 60 years, who were treated with isolated aortic arch resection for non-traumatic aneurysms. COR was assigned to 93 patients, HR to 11 patients and TEVAR for 33 patients, with the last two approaches reserved for high-risk profile candidates who were unable to undergo COR. The propensity score matching and the multivariate analysis were the strategies used to balance the difference in the group of patients, mainly to avoid treatment selection bias. Early mortality rate was observed in 9 patients, defined as in-hospital death or 30-day mortality, and was not statistically different between groups . Morbidity included stroke, paraplegia, need for dialysis or tracheostomy. The 15-year survival rate was 59%, with late mortality rate predicted due to increasing age, presence of peripheral vascular disease and perioperative stroke . The absence of rupture or reintervention in the aorta was 75% and greater after COR.Sood et al. reported a cohort composed of 436 consecutive patients submitted to aortic arch repair, 276 of which were assigned to COR and 118 to hybrid TEVAR. The remaining 42 patients underwent an approach called staged thoracic endovascular aortic repair (STEVAR). The surgical outcomes showed shorter ICU and in-hospital length of stay in the TEVAR group. At 30 days, there was no statistically difference in the groups in terms of neurological outcomes and mortality. In 5 years, survival rates also did not differ statistically.Finally, Yoshitake et al.This review allowed us to select articles of enormous heterogeneity, with large and small samples, and with very diversified outcomes.per se and the preoperative patient conditioning directly contributes to the postoperative outcomes. Despite the number of studies comparing both techniques, there is still no consensus on the superiority of one approach over the other.Surgical indication for aortic arch diseases might be challenging, since the complexity of the procedure In general, the articles showed better short-term outcomes for hybrid repair, equivalent to conventional open repair, and with a lower incidence of complications, especially due to prolonged CPB use and HCA, as well as pulmonary involvement. Despite this, long-term outcomes suggest better efficacy and durability in patients treated with COR. provided clinical data that showed unfavorable outcomes for patients who underwent total arch replacement and had previous diagnose of congestive heart failure, history of smoking and/or previous heart disease. In more recent publications, both techniques had similar results and outcomes in the short term, but in the long term-considered a post-procedure time greater than 5 years-total open aortic repair still remains the gold standard treatment for arch diseases, as noted by Joo et al.. In the HR group, a slightly increase in the incidence of permanent neurological deficits was noted, suggesting that cerebrovascular embolic events are a concern even in less invasive approaches.Preventza et al. showed that respiratory complications were less important in the HR group, which is justified by less manipulation of the lung parenchyma through thoracotomy, in addition to a lower risk of bleeding and edema. Moreover, the prolonged period of mechanical ventilation and tracheostomy had greater impacts on patients in the COR group. Furthermore, the same study did not show benefits in terms of postoperative death and risk of stroke when both procedures were compared.Another clinical outcome evaluated by one of the studies was related to postoperative pulmonary function complications, which can occur in up to 30% of the patients undergoing thoracotomy to aortic arch repair. Joo et al.. Moreover, the aortic arch morphology remains a decision-making factor for either technique, regardless of age or type of comorbidities. Despite being a review with a large sample of patients, our work has few limitations. First, it is complex to generate complete individual patient data from the population, since most articles were retrospective studies. In addition, it is difficult to homogenize the samples, not to mention that retrospection might compromise the statistical quality of the article. On top of that, not all authors used the propensity score matching to diminish the difference between groups. A selection bias might occur, since patients with high operative risk tend to undergo the HR approach than COR, resulting in worse or no higher mortality outcomes. Moreover, most articles had sample sizes in which patients were referred to COR than HR, which may affect the biased outcomes of the hybrid technique.When compared to TEVAR, COR showed inferiority in terms of post-procedure recovery time, but was superior in terms of long-term resultsFinally, another aspect that deserves a spotlight is that the hybrid procedure, due to its relatively new use and indications, is performed with expertise by only few surgeons, which can be another factor that justify the non-superiority of this approach in most of the articles described in this review.Surgical hybrid repair remains a treatment option for aortic arch disease, with outcomes similar to COR in the short and medium terms of mortality and stroke. It is particularly useful when correctly indicated in a right and individual fashion for each patient, especially for those who presents with high or prohibitive risk for COR. Hybrid procedures with cervical or supraclavicular debranching are also a strategy in patients who cannot undergo thoracic incisions, with safely results reported.In a long-term perspective, conventional open repair showed more satisfactory results with regard to reintervention, survival rates and morbidity and mortality. That said, COR remains the gold standard treatment for aortic arch disease in patients who can tolerate the open procedure. Finally, the decision-making about one procedure in relation to another must be very well discussed with the Heart Team and the patient. In addition, the center’s experience on performing those techniques should also be considered to provide the best care and minimize poor surgical outcomes and physical and psychological damage.