The objective of the study was to evaluate the profile of serum autoantibodies and their diagnostic and pathogenetic significance in ovarian endometrioma (OEM) and deep infiltrative endometriosis (DIE). The study enrolled 74 patients with endometriosis (Group 1), including 53 patients with OEM (Subgroup 1a); 21 patients with DIE without ovarian lesions (Subgroup 1b); and 27 patients without endometriosis (Group 2). The diagnosis was confirmed by laparoscopic surgery and histologic examination of resected tissues. Antibodies  to tropomyosin 3 (TPM), tropomodulin 3 (TMOD), α-enolase (ENO), estradiol (E2), progesterone (PG), and human chorionic gonadotropin (hCG) were identified in blood serum using modified ELISA. In endometriosis, antibodies to endometrial antigens, hormones, and ENO were detected more often than antiphospholipid and antinuclear antibodies. Higher levels of IgM to TPM, hCG, E2, and PG and IgG to TMOD, ENO, E2, and hCG were found in Subgroup 1a compared to Group 2. IgM to TPM, hCG, E2, PG, and IgG to E2 and ENO had a high diagnostic value for OEM (AUC > 0.7), with antibodies to TPM having the highest sensitivity and specificity (73.6% and 81.5%). In Subgroup 1b, only the levels of IgM to TPM and hCG were higher than in Group 2. These antibodies had a high diagnostic value for DIE. Thus, endometriosis is associated with autoantibodies to endometrial antigens, α-enolase, steroid, and gonadotropic hormones. A wider spectrum of antibodies is detected in OEM than in DIE. These antibodies have a high diagnostic value for OEM and DIE and potential pathogenetic significance for endometriosis and associated infertility. Endometriosis is a benign estrogen-dependent chronic systemic inflammatory gynecological condition with multifactorial etiopathogenesis. The disease is characterized by the presence of actively functioning foci of endometrium (glandular cells and stroma) or endometrial tissue outside the uterine cavity, i.e., in the muscular layer of the uterine wall or in the other organs of reproductive system, or/and in the adjacent or distant structures ,2,3. BeiEndometriosis often leads to chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and impaired quality of life, significantly burdening health in general ,3, as coThe subtypes and localization of endometriotic lesions are diverse, including superficial peritoneal endometriosis, ovarian endometrioma, deep infiltrative endometriosis (DIE), bowel, bladder, extra-abdominal, iatrogenic endometriosis, and peritoneal adhesions ,7. The tThe gold standard for the diagnosis of endometriosis is laparoscopic identification of endometriotic lesions with subsequent confirmation by histologic examination, but this invasive procedure has several limitations . Among nA number of biomarkers has been proposed for non-invasive diagnosis of endometriosis, i.e., cancer antigen-125 (CA-125), cancer antigen-19-9 (CA-19-9), interleukin-6 (IL-6), anti-endometrial antibodies (AEA); however, all of them are associated with advanced endometriosis and not applicable to the early stages of the disease ,10. TherOf great scientific interest are studies of the complex etiopathogenesis of endometriosis, involving genetic, immunological, and environmental factors. Key pathogenetic mechanisms include the inflammatory immune response and dysregulation of immune surveillance, which promotes the growth of ectopic endometrial foci ,11,12. ISeveral studies in endometriosis patients have demonstrated decreased activity of cells that inhibit endometrial implantation, such as natural killer (NK) cells and CD4+/CD8+ T lymphocytes. There is also an increase in immunosuppressor cells, particularly regulatory T lymphocytes, Th2 cells, and MDSCs (suppressor cells of myeloid origin), which may contribute to endometrial cell implantation and endometriosis progression .Endometriosis has overlapping similarities with autoimmune diseases such as polyclonal B-cell activation, abnormalities in T- and B-lymphocyte function, high levels of cytokines, clinical response to immunomodulators, involvement and damage to many organs and tissues, hereditary and family nature of the disease, and combination with other autoimmune disorders . EndometA large number of studies hypothesize the involvement of B-lymphocytes producing anti-endometrial (AEA), antiphospholipid (aPL), antinuclear (ANA), and anti-DNA autoantibodies, typical for other autoimmune diseases, in the pathogenesis of endometriosis ,19. In aUsing a two-dimensional proteomic approach to study the serum of endometriosis patients positive for AEA, target endometrial antigens were identified in the range from 30 kDa to 45 kDa , particuThe study of autoantibodies to molecules that play an important role in the pathophysiology of endometriosis, in particular to specific endometrial antigens , the glycolytic enzyme α-enolase 1 (ENO) involved in endometrial cell invasion, as well as to steroids (estradiol (E2), progesterone (PG)) and gonadotropins, in various forms of endometriosis, may contribute to a deeper understanding of the immune aspects of the pathophysiology of endometriosis, identifying promising diagnostic biomarkers and proposing new treatment strategies . In connAll study groups were comparable in terms of the mean age of the patients . In Group < 0.0001; p = 0.022). Patients in both subgroups equally often had pelvic adhesions (p = 0.789). Subgroups 1a and 1b did not differ by the rates of infertility (p = 0.745), uterine fibroids (p = 0.893), as well as parity, induced abortions, and spontaneous miscarriages.In Subgroup 1a, ovarian endometriomas were combined with DIE in 67.9% of patients (36/53). In Subgroup 1b, where all patients had DIE, there was a higher incidence of bowel and bladder endometriosis and adenomyosis compared with Subgroup 1a (p < 0.025). In a pairwise comparison of Subgroups 1a and 1b with Group 2, the patients with OEM had higher levels of IgM antibodies to TPM, PG, E2, and hCG and IgG antibodies to TMOD, ENO, E2, and hCG (p < 0.025). Notably, in Subgroup 1a, median autoantibody levels did not differ between patients with and without DIE (p > 0.05). At the same time, in the patients of Subgroup 2b with DIE without ovarian lesions, only increased levels of IgM antibodies to TPM and hCG were observed . When comparing Subgroups 1a and 1b, patients in Subgroup 1a had higher levels of IgG antibodies to E2 and TMOD than patients in Subgroup 1b .Serum levels of autoantibodies in patients with and without endometriosis are presented in Increased levels of antiphospholipid and antinuclear antibodies were detected only in 2/53 (3.8%) patients with OEM.p < 0.001)  . In addip < 0,001), while r > 0.9 was obtained when comparing IgM to E2 and PG, TPM and TMOD. Moreover, a direct correlation was found between IgG antibodies to TPM and TMOD , and between IgG antibodies to E2 and ENO  or TMOD , to PG and ENO .In DIE, a direct correlation was also found between IgM antibodies to hormones E2, PG, and hCG, as well as between IgM to TPM, TMOD and E2, and PG   had high diagnostic significance for ovarian endometriomas, confirmed by high values of the area under the ROC-curve  . Determip < 0.0001) and hCG (AUC 0.736 (0.587–0.854); p = 0.0013) had the high diagnostic value. According to logistic regression analysis, when determining IgM antibodies to TPM, the diagnostic accuracy for DIE was the maximum and reached 83.8%. The number of DIE patients with a level of IgM antibodies to hCG and TPM exceeding the cutoff values was 4.0 and 8.8 times greater than in the group without endometriosis.In DIE without ovarian lesions, only IgM antibodies to TPM (AUC 0.844 (0.708–0.933); The present study examined the serum autoantibody profile, including anti-endometrial, antiphospholipid, antinuclear antibodies, as well as antibodies to α-enolase and hormones, namely estradiol, progesterone, and human chorionic gonadotropin, in patients with different forms of endometriosis (ovarian endometrioma and deep infiltrative endometriosis), and in the comparison group without endometriosis. It should be noted that the possible influence on the study results of systemic autoimmune, oncological, infectious, inflammatory, and endocrine diseases, metabolic syndrome, as well as the use of hormonal and anti-inflammatory drugs in patients was excluded.The groups were formed according to laparoscopic surgery findings and histological confirmation of the diagnosis. Subgroup 1a included the patients with ovarian endometriomas, which in most cases were associated with DIE, and, less often with bowel and bladder endometriosis, as well as adenomyosis. In Subgroup 1b, bowel endometriosis and adenomyosis was found significantly more often than in Subgroup 1a. Patients of both subgroups were comparable in age and did not differ by the rates of pregnancy and childbirth, induced abortions, or spontaneous miscarriages.Pelvic adhesions and infertility were frequently observed in both subgroups. Endometriosis-associated pelvic adhesions often result from pro-inflammatory changes in the peritoneal media and tissues. Endometriosis can cause adhesions in up to 60% of cases . HoweverThe pathophysiology of endometriosis is not fully studied; there still are many theories about the pathogenesis of this disease. There is no consensus on whether different forms of endometriosis have a common pathogenesis, and whether one type can cause another. It is believed that deep endometriosis may be more likely to be of embryological origin; therefore, the immune system plays a minor role in its development . SuperfiEndometriosis is characterized by polyclonal activation of B lymphocytes, dysfunction of T (Th1) and B lymphocytes, impaired apoptosis and NK cell activity, imbalance of Th1/Th2 and increased Th2-dependent response, induction and translocation of T regulatory cells, release of immunological and inflammatory factors such as cytokines, and increased production of autoantibodies ,14. PeriThe results of the present study demonstrated a wide spectrum of serum autoantibodies in endometriosis, including antibodies to endometrial antigens , steroid and gonadotropic hormones , and α-enolase enzyme. Patients with endometriosis had higher levels of IgM antibodies to TPM, PG, E2, hCG, and of IgG antibodies to E2 and TMOD, compared to women without endometriosis. In endometriosis, these antibodies were more common than antiphospholipid and antinuclear antibodies.Patients with OEM had a wide spectrum and higher levels of serum autoantibodies of different specificities, in particular IgM antibodies to TPM, E2, PG, and hCG, as well as IgG antibodies to TMOD, ENO, E2, and hCG, compared to women without endometriosis. At the same time, in patients with DIE without ovarian lesions, only the levels of IgM antibodies to TPM and hCG were significantly increased. In addition, the levels of IgG antibodies to E2 and TMOD were significantly higher in patients with OEM than in patients with DIE. More frequent detection of high levels of IgM antibodies to endometrial and hormonal antigens may be associated with the progressive course of endometriosis and the increased content of these proteins, especially TPM, in proliferating endometrial cells in ectopic foci and active secretion of hormones.Our results are consistent with a systematic review , showingIn patients with OEM, a strong direct correlation was found between the levels of IgM and IgG antibodies to E2 and PG, IgM antibodies to TPM and TMOD (r > 0.7), while weaker direct correlation was observed between IgM antibodies of other specificities (r < 0.7). In DIE, a correlation was found between IgM antibodies to hormones, including hCG, as well as to endometrial antigens and steroid hormones (r > 0.7), while the highest r value was obtained when comparing IgM levels to E2 and PG, TPM and TMOD (r >0.9). A direct correlation between the levels of these autoantibodies may result from polyclonal activation of B lymphocytes to hormonal and endometrial antigens, the levels of which are significantly increased in endometriosis. The obtained data on specific patterns of correlation expand the understanding of the pathophysiology of endometriosis and may be useful in creating a diagnostic panel of autoantibodies.The results of the present study are consistent with the data of R. Gajbhiye et al., who revealed a high rate (60%) of anti-endometrial antibodies  detection in patients with endometriosis, including OEM . Later, Anti-endometrial antibodies studied by R. Gajbhiye et al.  had showIn the present study, we examined the blood sera of patients with OEM and DIE stages II–IV, collected during the follicular phase of the menstrual cycle, using modified ELISA methods. Three types of autoantibodies of different specificity have been identified, including not only anti-endometrial (IgM to TPM), but also anti-hormonal antibodies (IgM to hCG and E2), which have shown high sensitivity (≥60%) and specificity (≥80%) and accuracy (up to 83.8%) for OEM diagnosis. At the same time, IgM antibodies to PG and IgG antibodies to E2 and ENO showed sensitivity from 52.8% to 58.2% and specificity >80% for OEM. Notably, only IgM antibodies to TPM and hCG showed a high diagnostic value for DIE without ovarian lesions: sensitivity 70% and 50%, specificity 81.5% and 85.2%, respectively. Of particular note is the high diagnostic value of antibodies to TPM in both forms of endometriosis. In addition to anti-endometrial antibodies, in our opinion, antibodies to steroid and gonadotropic hormones can be proposed as biomarkers of endometriosis.The autoantibodies are believed to be involved in the pathophysiology and development of endometriosis by stimulating the immune system and maintaining inflammation. Autoantibodies can bind to cell surface antigens and form immune complexes with soluble antigens, thus enhancing inflammation and tissue damage by recruiting neutrophils and other myeloid and lymphoid cells to the lesions . AnotherWhile immune infiltration and a persistent inflammatory environment favor the development of endometriosis, the greatest pathological consequences arise from aberrant complement activation . Thus, aProduction of autoantibodies to gonadotropic and steroid hormones in endometriosis may be associated with endocrine disorders characteristic of endometriosis, leading to increased levels of hormones in the blood, as well as with the use of hormonal therapy. Intensive production of antibodies to steroid hormones in patients with endometriosis may be promoted by excessive production of estrogens in the ovaries, ectopic endometrium, peripheral adipose tissue, and by increased production of progesterone by stromal cells in endometriotic heterotopia . In addiEndometriosis is characterized by altered PG signaling in the endometrium, which disrupts decidualization and leads to the development of ectopic lesions . It is kOf special interest is the detection of antibodies to endometrial antigens  and ENO, which are involved in important mechanisms of endometriosis pathogenesis associated with cell motility and migration, adhesion and invasion at the ectopic sites, cytoskeletal dynamics, conversion to stationary state, apoptosis, and necrosis ,38,39. IThe increased expression of these molecules in endometriotic cells seems to stimulate the formation of relevant antibodies. This assumption is supported by the study of the proteins of endometrial tissue lysates obtained from superficial and deep endometriotic lesions , which dAltered cellular and humoral immune responses in endometriosis, including increased production of pro-inflammatory cytokines and autoantibodies, can potentially affect women’s fertility. High levels of certain autoantibodies, especially anti-endometrial and anti-hormonal, can lead to a decrease in endometrial receptivity and the quality of oocytes and embryos and impaired embryo implantation and finally result in subfertility and even infertility. Therefore, screening for the mentioned autoantibodies, in addition to antiphospholipid, antinuclear, antithyroid, and antiovarian antibodies, seems to be a necessary part of investigation of endometriosis-associated infertility.The limitations of present investigation were: small size of the study and control groups, restricted by laparoscopic confirmation of the diagnosis; the absence of patients with stage I endometriosis in the study group; the presence of gynecological and somatic diseases in patients of the comparison group. Moreover, not all endogenous mechanisms triggering autoantibody production and not all possible confounders were taken into account in this study.This study project was approved by the Ethics Committee of the National Medical Research Center for Obstetrics, Gynecology, and Perinatology. The patients signed informed consent to participate in the study and to have their biological material tested. All patients underwent laparoscopic surgery in the Department of Surgery of the National Medical Research Center for Obstetrics, Gynecology and Perinatology between January 2019 and June 2021.The study group (Group 1) included 74 women with endometriosis aged 20 to 40 years. Endometriosis was diagnosed in all patients by laparoscopic identification of endometriotic lesions and subsequent histopathologic examination of the resected tissues. All patients with endometriosis were categorized by stage according to the rASRM. The study group was divided into two subgroups: Subgroup 1a comprised 53 patients with stage II–IV OEM, Subgroup 1b comprised 21 patients with stage III–IV DIE without ovarian lesions. The comparison group (Group 2) included 27 women with no endometriosis at diagnostic laparoscopy.Patients with oncologic and systemic autoimmune diseases and contraindications for surgical treatment were not included in the study. Exclusion criteria were: infectious, inflammatory, endocrine diseases, metabolic syndrome, hormonal and anti-inflammatory therapy during the last three months before the study.Blood for serum autoantibody profile evaluation was collected from women in the follicular phase of the menstrual cycle on day 10.2 ± 3.2 after fasting and immediately before laparoscopic surgery on an empty stomach. Blood serum samples were processed according to standard operating procedure, including centrifugation at 3000 rpm for 10 min at 4 °C, and stored at −80 °C in the centralized Biobank of the National Medical Research Center for Obstetrics, Gynecology, and Perinatology until testing within 2.5 years after collection. The entire set of samples was examined simultaneously and was not subjected to repeated freeze-thaw cycles.w/v]) bovin serum albumin (BSA) and 1.5% w/v gelatin in Tris-buffered solution, pH 7.4, the 1% w/v BSA in 100 mmol/L phosphate-buffered saline (PBS), pH 7.4, was used and incubated for 1.5 h at room temperature (20 ± 2 °C). The blood serum samples were analyzed at a 1:100 dilution in 0.5% (w/v) BSA-PBS containing 0.05% (v/v) Tween-20 in the duplicate, incubated at room temperature on a shaker at 200 rpm for 1 h. Antibodies  to chorionic gonadotropin were analyzed by ELISA method described elsewhere [Detection of antibodies  to steroid hormones, namely progesterone (PG) and estradiol (E2), was performed by means of modified ELISA described previously , using Tlsewhere , using aw/v BSA in 100 mmol/L PBS, pH 7.4, was used instead of 1% w/v gelatin. Serum samples diluted 1:100 were incubated at room temperature on a shaker for 1 h as described above. Optical density (OD) was measured on an Infinite F50 automated enzyme immunoassay analyzer  at a wavelength of 450 nm. The inter- and intra-assay variances in these ELISA methods were <15% and <10%, respectively.Antibodies to endometrial antigens  and ENO enzyme were identified by modified ELISA methods described elsewhere ,43, withAntiphospholipid antibodies (aPL) of M and G classes to cardiolipin (CL) and β2-glycoprotein-I (β2-GP-I) and antinuclear IgG antibodies (ANA) were detected in the serum using immunoenzyme kits .p < 0.05.The obtained data were analyzed using applied statistical software packages Microsoft Office Excel 2010 (14) and Statistica 10 . Normality of distribution of values in the samples was assessed using the Shapiro–Wilk W-test and the Kolmogorov–Smirnov test. In case of deviation from normal distribution, quantitative data were represented by median value (Me) with interquartile range between 25th percentile (Q1) and 75th percentile (Q3). Quantitative data were analyzed using non-parametric statistical methods. Data in two groups were compared using Mann–Whitney U-test, while in three groups the data were compared using Kruskal–Wallis test and Bonferroni correction for multiple comparisons. Qualitative data were represented by absolute (n) and relative values (%); the differences were evaluated using the χ2 test. Correlation between the variables was assessed by calculating the Spearman’s Rank correlation coefficient. Differences were considered statistically significant at The results of this study demonstrated that endometriosis is associated with the presence of serum autoantibodies to endometrial antigens, α-enolase, and to steroid and gonadotropic hormones, showing different autoantibody profiles in ovarian endometrioma and deep infiltrative endometriosis. Anti-endometrial and anti-hormonal autoantibodies have high diagnostic value for these forms of endometriosis, and also a potential pathogenetic significance in the progression of endometriosis and the development of endometriosis-associated infertility.We believe that further studies involving large cohorts of patients with various forms and early stages of endometriosis, and women without the disease, are required to extend obtained data, to investigate the dynamics of the levels of autoantibodies after treatment and during the relapse of the disease, and to evaluate the effectiveness of new methods of treatment, including immunotherapy.


Decent living standards (DLS) provide a framework toestimate apractical threshold for the energy, GHG, and material consumptionrequired to alleviate poverty. Currently, most research has focusedon estimating the energy required to provide the DLS. However, noattempt has been made to estimate the material consumption neededto provide the DLS. Thus, we ask the following questions: First, whatis the amount of materials in stocks and flows needed to provide aDLS? Second, which lifestyle and technology choices are effectivein providing a DLS without creating an excessive demand for additionalmaterials? To provide a DLS, a material footprint (MF) of 6 t/(cap*yr)with a lower and upper bound between 3 and 14 t/(cap*yr) is required.The direct and indirect in-use stocks required are estimated at 32t/cap and 11 t/cap, respectively. Nutrition (39%) and mobility (26%)contribute the most to total MF. Buildings account for 98% of directstocks, while the construction sector accounts for 61% of indirectstocks. We extend the coverage of the DLS by including the collectiveservice dimension and link the material stock-flow-service nexus andlife cycle assessment to compute the MF and in-use stocks needed toprovide the DLS. Littleresearch has been devoted to understanding the nexusbetween decent living standards (DLS) and material consumption. Weestimate for the first time the material flows and stocks needed toprovide the DLS. These services can beinterpreted as the minimum requirements that enable a decent livingstandard (DLS). The DLS offers a simple but efficient bottom-up approachto understand the tradeoffs between poverty and climate change, aswell as a framework to estimate the demand for energy and materialsrequired to achieve the SDGs , zero hunger(SDG 2), good health and well-being (SDG 3), quality education (SDG4), and reduced inequalities (SDG 10)).5To overcome this gap and to indicate universal determinants ofhuman well-being, Rao & Min6 estimate that by 2050, the energydemand necessary to provide a DLS is in the range of 10.1–20.9GJ/(cap*yr). More broadly, Millward-Hopkins et al.7 estimate that the global average energy requirements tofulfill a DLS by 2050 is around 15.3 GJ/(cap*yr). Alternatively, Kikstraet al.8 estimate that by 2040 at the regionallevel, between 9 and 36 GJ/(capita*yr) of energy is needed to fillthe gap between current multidimensional poverty and the DLS.In this respect, DLS research has focused on estimating theenergynecessary to supply the DLS in various social–cultural contexts.Focusing on the global South , Raoet al.9 and is responsible for morethan 90% of biodiversity loss and water stress.10 Additionally, the consumption of materials is increasingat unsustainable rates (23-fold throughout the 20th century).11 A trend that likely will continue to grow as the transition to cleanenergies and more efficient products requires a massive amount ofmaterials; e.g., photovoltaic and wind power plants require between6 and 40 times more copper than conventional fossil fuel technologies.12 These material–environment links arethe foundation of an ongoing debate on the need for establishing acap on material consumption.13These findings provide valuable information about the DLS in low-energydemand scenarios in line with temperature targets of 1.5–2°C; however, they do not address the link between DLS and otherenvironmental impact categories, such as material consumption. Thelink to materials, in particular, is relevant because materials suchas steel, wood, and concrete form an important link between poverty-relatedand environmental SDGs. On the one hand, poverty eradication requiresaccess to basic services, which require functioning products and materialstocks for their provision. On the other hand, material productionis a major contributor to greenhouse gas (GHG) emissions 1.2This paper aims to answertwo questions: What is the amount of materials, in-use stocks, andextraction flows needed to provide a DLS and which lifestyles andbundles of efficiency strategies are effective in providing a DLSwithout creating excessive demand for additional resources?14 and ecoinvent, a widely used databasefor LCA analysis, to compute the material footprint (MF), in-use stocks,and industrial material stocks needed to deliver the DLS, previouslyunseen in the literature.To answer these questions, we made two method improvements. First,we extend the coverage of the DLS by including the collective servicedimension by including the building space associated with wholesaleand retail, offices, hotels and restaurants, sports facilities, andothers. Second, we provide a link between the material stock-flow-servicesnexusOutside of our scope is the regionalizationof the DLS and theeffect of efficiency strategies and policy targets, i.e., reboundeffects on the provisioning of the DLS mainly because such analysisrequires additional data and assumptions.22.14 DLS framework and thequantitative energy thresholds for each DLS dimension from Millward-Hopkinset al.7 with the stock-flow-service nexus14 and the energy service cascade concepts,15 both key concepts to link material flow analysisto social and environmental sustainability aspects.This study integratesthe Rao & Min2.2The method to estimatethe DLS MF consists of four steps. First, we compile a list of servicesrequired by each DLS dimension and link them to their respective provisioningsystems as seen in 14 We compile a bundle of services and associatedin-use stocks needed to provide a DLS in each dimension based on Rao& Min4 and Millward-Hopkins et al.7 We use the global average population for theyear 2023 from the UN7 as a reference forour analysis. For shelter, we assume a four-person household witha space floor of 15 m2/cap. Similarly, for education, healthcare,and collective services, a space floor of 2.48, 1.6 , and 4.7 m2/cap, respectively, was considered. For communication, eachperson over the age of 10 yrs requires a phone, while one laptop andone router are required per household. For mobility, approximately8300 passengers-kilometers (pkm) are assumed. For nutrition, about2100 kcal/(day*cap) is required. Additionally, for hygiene, 50 L/(day*cap)of water is required and 0.74 kg of waste/(cap*day) is generated.Finally, for clothing, 2.4 kg of clothes/(cap*yr) are required (see Supporting Information SI1).In the second step, the reference flows for thedifferent provisioningsystems are calculated from the stock-flow-service nexus.In the third step, the indirect stocks in the formof industrialcapital  are estimated. Finally, the reference flows are linkedto their respective environmental flows.SI1 and SI2).As each DLS dimensioncan be fulfilled by several sets of goodsand services, we perform a scenario analysis to account for individualchoices and technological options. For example, in the case of nutrition,a daily intake of 2,100 kcal/cap can be met by different diets, e.g.,carnivorous, vegetarian, or vegan. These differences in lifestyleslead to differences in MF. Thus, we construct a total of 6441 differentscenarios .Moreover, we conduct 5 additional scenarios to understand what effecthas different electricity grids in providing a DLS .To estimate the DLS MF, we use a process-based life cycle assessment(P-LCA) and the ecoinvent 3.8 database. Particularly, we utilize thesystem model “allocation, cut-off by classification”which means the environmental burdens are the responsibility of theproducers and are not allocated to recyclable products, thereforeincentivizing the use of recyclable products.18 for an overview). First, P-LCAhas a greater product and service resolution than EEIO models, allowingus to account for the bundles of flows and in-use stocks needed toprovide the DLS. In other words, with P-LCA, it is possible to distinguishbetween the different types of technologies within a particular sector,such as between electric (EV) and combustion vehicles (ICEV), andbetween residential and nonresidential buildings, while in most EEIOmodels, industries are represented by one aggregated product . Second, the products and services required to fulfilla certain need, such as shelter or transport, are provided in physicalunits, e.g., m2 or pkm, while in EEIO data are presentedin monetary units. The former is more directly related to lifestylesand daily needs and activities. These two properties allow us to estimatethe DLS MF with a high level of technological detail.P-LCA has two desired features that make it a more suitableapproach to estimate the MF of providing a DLS compared to other methodssuch as environmentally extended input–output analysis (EEIO) and energy consumptionfor several building archetypes and regions (see SI1).Data forbuildings  are takenfrom the RECC database.20 We consider the two impacts, as both are usedin different contexts. We provide results and discussion for the TMR(hereafter MF), while the results for RMI without discussion are presentedin SI3-4 as ancillary data.The MFs were calculated using the characterizationfactors (CFs)(the impact intensity of a substance relative to a common reference),for the total material requirement and the raw material input  provided by Pauliuk.3The findings represent theprovisioning of a DLS with a globalaverage coverage for a single person in the hypothetical case of absoluteor abject poverty, i.e., zero or scarce access to any provisioningservices. The flows and in-use stocks are estimated based on the thresholdsfor the DLS presented in 3.1Providing a DLSrequires an MF of about 6 t/(cap*yr) of which the dimension of nutrition(38%) and mobility (26%) are the categories that contribute the mostto the total see 2A. The hLooking at services, transport by car (19%) andelectricity (17%)are the most significant contributors to the total MF, while foodproducts contribute with around 37% of the total footprint, milk provisionbeing the most significant contributor see 2B. CompaTheenvironmental flows  that most contribute to the MF are biomass (20%), gravel (16%),and hard coal (11%), while 14% of the total footprint comes from metalores such as gangue and iron. Similarly, phosphorus and shale  contribute with 9% of the total MF see 2C. In adWhen lookingat the types of materials, non-metallic minerals  and fossil fuels are responsiblefor around 34 and 28% of the total footprint, respectively, whilemetal ores contribute with 18% of the total impacts see 2D.SI3.10). Similarly, by the type ofMF, the fossil fuels (45%) contribute with the most impact, whilethe non-metallic minerals, metal ores, and biomass contribute withthe remaining 27, 18, and 10%, respectively (see SI3.21).Collectiveservices have an MF of 0.4 t/(cap*yr). In this dimension,electricity and gas consumption represent 59 and 4% of the total impacts,respectively, while 8 and 29% of the impacts are attributed to thelamps needed for illumination and the materials that make up the building(bricks (4%), wood (9%), steel (4%), and concrete (13%)), respectively(see SI1).The DLS dimension that contributes less tothe MF is communication(0.1 t/(cap*yr)) in this dimension; electricity consumption (364 kWh/(cap*yr))accounts for 83% of the total impacts. This is mainly due to the useof Wi-Fi and networks (212 and 355 kWh/year)  and 89% (router) of the total materials. The latterrepresents between 9% (router) and 61% (laptop) of the total materials.Similarly, the material composition of the transport stocks is mainlybasic metals (between 71% for scooter and 85% for bicycle) and chemicals,rubber, and plastics (between 10% for bus and 29% for scooter).The indirect material stocks in industrial assets associated withDLS are ∼11 t/cap see 4A. The dThe collective service dimension contributes witharound 3% ofthe total indirect stocks. In this category, non-metallic mineralproducts account for 79% of the total impacts, while basic metals,wood products, and chemicals and rubber contribute with the remaining14, 5, and 2%, respectively.Looking at the types of indirectstocks, it can be seen that 61%arise from the construction sector, in particular civil engineeringprojects (ISIC 42) such as roads, railways, tunnels, and bridges,utility projects , and engineering projects . Furthermore,the remaining 37 and 2% of indirect stocks come from the constructionof buildings (ISIC 41)  and other sectors (ISIC 26 to 31 and 43)such as the manufacture of machinery and equipment and others, respectivelysee 4B. Inge3.3Lifestyles andefficiency measures significantly influence the MF. The findings suggestthat the DLS can be provided with an MF in the range of 3–14t/(cap*yr) see 5A.SI1). Alternatively,a DLS with an MF of 14 t/(cap*yr) can be achieved through a residentialtower building (shelter), a diet based on meat and rice as a staple(nutrition), standard buildings , and the provision of mobility by electric vehicles (see SI1 and SI5).A DLS with an MF of 3 t/(cap*yr) can be achievedthrough a multifamilyresidential household constructed with wood and little concrete andsteel (shelter), a vegan diet with potatoes as a staple (nutrition),non-residential buildings with more wood , and a scenario in which the use of private carsis reduced by 27% and short distances are covered by walking (mobility) if electricity is provided withrenewable energies. Having a grid with high shares of wind (36%) (Denmark)may reduce the MF by 5%. Alternatively, an electricity grid with hydroas the main energy source (93%) (Norway) may bring 14% savings. Thehighest amount of nuclear power (71%) (France) translates into 6%of the savings. The high shares of renewable sources without nuclearsources (Uruguay) translate into 13% of the potential savings in providinga DLS. However, a mix of high shares of fossil fuels (43%) and solarresources (13%) (German) will increase the MF by 1%. This is mainlybecause although the German mix has more solar (13%) and wind (18%)sources than the global mix ,the former has less hydro (4%) than the global mix (17%).44.121 Similarly, Bringezu22 suggests that a potential target for achieving sustainable consumptionof natural resources is an MF in the range of 8–14 t/(cap*yr).Additionally, Lettenmeier et al.23 suggesta material cap of 8 t/(cap*yr) in Finland to ensure sustainable consumptionof materials in the household sector.The MF (3–14 t/(cap*yr)) to provide a DLS is in line withthe suggestions for a sustainable consumption of materials by 2050found in the literature. Specifically, the International ResourcePanel (IRP) suggests that an MF of 6–8 t/(cap*yr) is requiredto decouple economic growth from the use of natural resources.24 for additional MF for differentEU countries for a timespan between 1993 and 2000). Furthermore, Wiedmannet al.100 provided information for theRMI for 186 nations for the year 2008. These results cannot be comparedwith the values presented in Supporting results in SI3.Compared with currentmaterial consumption patterns, the DLS is much lower. For example,MFs associated with consumption in the US, Germany, and China arearound 85, 72, and 37 t/(cap*yr), respectively  and not theactual stock dynamics and associated impacts that have a differentdevelopment over time than the service consumption. Additionally,individual countries may have a much longer lifetime for stocks thanwhat we have used here, while other countries recently have expanded and close-to-saturated  stocksso that there are lower maintenance and replacement requirements inthe coming decades, leading to lower MFs even for high living standards.4.225 Taking the reference scenario for the shelter(a single-family building) as an example, increasing the amount ofwood (from ∼52 to ∼120 kg/m2 or 131%) wouldreduce the MF by 26%. Similarly, a lighter building using less concrete(from ∼1.2 ton/m2 to ∼886 kg/m2 or 28%) and steel (from ∼71 to ∼55 kg/m2 or 22%) would reduce the MF by 17%. Combining the two alternatives(more wood and less concrete and steel) will reduce the MF by 28%.Alternatively, switching to a multifamily household (standard buildingtypes) reduces the MF by 25%, while changing to a residential towerwill increase the MF by 67%. Finally, moving to a lighter, wood-basedmultifamily building would reduce the MF by 43%. Similar trends canbe observed for nonresidential buildings (see SI5.2).Buildings make up a large proportion of directstocks  since their construction is highly material-intensiveand has a longer lifespan (≥80 yrs) than other stocks, suchas cars (∼15 yrs). Therefore, alternative construction processessuch as changing the materials or making the construction lighterare necessary to provide a DLS with low material intensity.11 This implies that on average, in developing countries, stocks needto build up to provide a DLS. Results from Krausmann et al.11 differ methodologically from ours, as the formerare based on historical data of accumulated stocks across the years, and ours are based on a product system model,where, to provide any particular service, stocks are built up fromzero (LCA perspective).In general, the total stocks (direct and indirect)required to provide a DLS (∼42 t/cap) are significantly lowerthan those reported for developed countries (335 t/cap), China (136t/cap) and the world average (115 t/cap), while for developing countries(38 t/cap), our results are slightly higher.26 This result may belower if electricity grids with high amounts of renewable energy areused. For example, using the mix from Norway that is mainly basedon hydro  reduces the MF for providing aDLS to 5.2 t/(cap*yr) or 14%. Alternatively, using the German mixwith fewer fossil fuels  and hydro  but more solar  comparedto the global average technology used will slightly increase the DLSMF by 1% (see The mix of electricity chosen to providea DLS has direct implicationsfor the MF (1.0 t/(cap*yr) or 17% of total impacts). We use a globalaverage technology mix with a share of 63% fossil fuels, 17% hydro,11% nuclear, 4% wind, and 5% others .y 1% see 5C.In general, electricity mixes with high shares of renewables help to provide a DLS with a lower MF, in contrast to whatone might expect due to the fossil fuel–metal ore linkage.4.327 and second, the amount of fertilizer  used per kg of potatoes (∼0.04kg fertilizers/kg) is lower than that required for rice (∼0.06kg fertilizers/kg) or wheat (∼0.08 fertilizers/kg) (own estimationsbased on fertilizer recommendations from FAO28). Furthermore, switching to more efficient cooking appliances (80%compared to reference) will reduce the MF by 2%, while cooking withelectricity instead of gas will increase the MF by 10%.Different lifestyles and efficiency measuressignificantly change the MF of providing a DLS. Taking nutrition asan example, reducing meat consumption by half or switching to a vegetarianor vegan diet, leaving all of the other parameters constant, reducesthe MF of nutrition by 9, 24, and 35%, respectively. Alternatively,switching the consumption of staples to wheat or rice (potato referencescenario), assuming that the consumption in gr/day is the same regardlessof the type of staple, will increase the MF between 22 and 34% respectively,mainly due to two factors. First, the yields for potatoes (21 t/ha)are between 4- and 5-fold bigger than for rice or wheat, respectively,29 and other parameters such as energy provision and consumption remainsimilar, the MF for the nutrition dimension in regions where riceis consumed as a staple, such as Asia (77.5 kg/cap), will be highercompared to the rest of the world (between 6.6 and 55 kg/cap).30 However, diets must be adjusted to meet HGDrecommendations. The global average diet is ∼2950 kcal/(day*cap)with values ranging between ∼3370 kcal/(day*cap) (South andNorth America) and ∼2600 kcal/(day*cap) (Africa).31Assumingthat by 2030 the regions will adjust their daily diet to meet thehealthy global diets (HGD) recommendations32 Active mobility measures such as walking andcycling and reducing the use of private vehicles reduce MF. Coveringshort distances by walking instead of cycling (reference scenario)leads to 3% savings. Alternatively, if 23–27%  of thedemand for private vehicles (2806 pkm/(cap*yr)) is shifted to publictransport (train and bus), 10% savings can be anticipated.Similarly, the MF of mobility is highlydependent on the transportmodes  and their powertrain (combustionor electric engine) used to meet the service demand. Compared to thereference scenario, a transition to electric vehicles would increasethe mobility MF by 26%. This is mainly because EVs require betweenone and four times more metals and minerals than ICEVs.4.43 Rao & Min4 argue that public space prevents overcrowding,fosters a sense of freedom, enables the pursuit of leisure activities,and allows a space to congregate for political and social activities.These needs are addressed, among others, in SDG 9.1 , SDG 10.2 ,and SDG 11.7 . However, so far, no attempts have been madeto measure this dimension, primarily because no guidance is availablein the literature for the minimum amount of space required to meetthese needs.4 Thus, to approach this issue,we include information on additional non-residential buildings requiredto support human activities (see SI2).We found that the public space requirements (4.7 m2/cap)for a decent living standard have an MF of 454 kg/(cap*yr) .Providing a DLS not only requires basic needs at the householdlevel but also the provisioning of important human activities, suchas recreation, social relations, and participation in society andpolitical processes.4.51 Providing a DLS for these people will requirea massive political effort mainly because it is not only a matterof income or even the services provided, but it is also about therequired in-use stocks (direct and indirect) and the connected supplychains and environmental impacts associated. By simply scaling ourresults, we find that providing these people with a DLS requires anMF of about 7.2 Pg/yr and around 51.6 Pg stocks (direct and indirect).Currently, around 1.2 billion people live in multidimensionalpoverty .In the second step, the DLS requirements need to be detailed forspecific regions, e.g., global South and North, or even more granular,to accurately consider the stage of development, the level of urbanization,transport infrastructure, and sociocultural factors such as populationsize, age distribution, housing, diets, and social values that determinewhat a region perceives as a DLS.33 However, there is a lack of articulation of what human developmentmeans under climate constraints in political debates. The DLS mayserve as a baseline for defining such rights because they link humandevelopment with energy and material use and the associated climateimpact and mitigation potential.6The Paris agreement acknowledgesthe necessity of setting climategoals that safeguard development rights.4.62 of space, but do not have information regarding the constructionor end of life (EoL) phase. Second, we only account for the buildingsthat are representative for each DLS dimension but do not includeadditional stocks needed to deliver the service in each DLS dimension,e.g., beds and medical instruments for healthcare, desks, boards,and educational equipment for education, and chairs, tables, computers,and sports and office equipment needed for collective services. Similarly,the infrastructure required to support communications, i.e., clouds,servers, and networks, is missing; thus, the MF of these dimensionsmay be underestimated. Similar constraints apply to the remainingdimensions (see SI2).The major constraintof this study is the ambiguity of the service levels needed for eachDLS dimension and the regional and future efficiency/technology options.Hence, the values proposed here and in other literature should beseen as first indications of DLS levels, which must to be adaptedto regional cultural and climate contexts. In addition, ecoinventhas limited coverage of several stocks such as infrastructure, buildings,and machinery relevant to the DLS. Therefore, some dimensions aremore accurately represented than others. For example, data for residentialand non-residential buildings are missing, meaning that the MF for the dimensions of shelter, education,healthcare, and collective services may be underestimated. This ismainly for two reasons. First, the data from the RECC model used tomodel the buildings only have information on the main material requirements,i.e., how much steel, concrete, and wood are needed per mSecond, ecoinventhas a wide geographical coverage for key processes such as electricitybut is lacking for regional data for food products, water, naturalgas, and many others. This implies that the analyses done at the regionallevel, even in the generalized form, i.e., the global South and theglobal North, will be based on proxy processes, mainly from Europe,that do not represent the geographical and technological conditionsof the regions. These proxy may not be determinant for some DLS dimensions,such as clothing or mobility, mainly because textiles and transporttechnologies do not differ across regions, but they may be relevantfor DLS dimensions, such as nutrition, and those that are representedby buildings, that is, shelter, healthcare, and education mainly becausethe geographical conditions of each region directly affect the energyconsumed in the buildings either for heating or cooling and the impactsassociated with food production.34 the assumption of linearity, i.e., for any process, doublingthe demand is associated with doubling the emissions,35 and temporal boundaries are present in this study. Thelatter particularly does not allow us to easily develop future scenariosfor providing the DLS with more efficient technologies, as the processesin ecoinvent are modeled in the best case with modern technology.An alternative to tackle these issues is to conduct regionalized LCAsto customize regional processes36 and prospectiveLCAs37 to analyze technologies in earlydevelopment stages.Additionally, the methodologicalconstraints of P-LCA, i.e., truncationerrors by setting subjective system boundaries,38 and Giljum et al.39 who used satellite image interpretation to identify regional miningtradeoff with deforestation, and Virág et al.40 who quantify the amount of stocks associated with mobilityinfrastructure).Furthermore, the presented MF indicatesthe total mass extractedfrom the natural environment (TMR) and processed (RMI), which is onlya rough indication of the environmental impacts of materials use,such as land degradation and energy demand for material processing.Therefore, it cannot replace more specific impact assessments, suchas toxicity, eutrophication, and carbon footprint. These impacts needto be broken down into individual materials (which we do in 4.7SI, and the LCA approach, owncompositions of “DLS baskets” by region/country arepossible. Moreover, effort should be made in estimating the amountof materials and stocks needed to close the gap between the DLS andthe actual poverty as done for energy by Kikstra et al.8Future efforts should focuson disaggregating the results into regions. With our results, theextensive


Metabolic syndrome (MetS) is a constellation of several associated cardiometabolic risk factors that increase the risk of developing type 2 diabetes mellitus (T2DM), cardiovascular diseases, and mortality. The role of hormonal factors in the development of MetS is assumed. In women, an insulin-resistant state that is associated with polycystic ovarian syndrome and increased deposition of intra-abdominal adipose tissue promotes the development of MetS and increases cardiovascular risk. The neuroendocrine hormone melatonin is secreted mainly at night under the regulatory action of the suprachiasmatic nucleus in the hypothalamus. Melatonin secretion is influenced by exogenous factors such as light and seasons and endogenous factors such as age, sex, and body weight. At present, the role of melatonin in metabolic disorders in humans is not fully understood. In this review, we set out to analyze the relationship of melatonin with the main features of MetS in women. Data from experimental and clinical studies on the role of melatonin in glucose metabolism and on the involvement of melatonin in lipid disturbances in MetS are reviewed. The complex influence of melatonin on hypertension is discussed. The changes in melatonin, leptin, and ghrelin and their relation to various metabolic processes and vascular dysfunction are discussed. According to the modern concepts, MetS is a constellation of several inter-related cardiometabolic risk factors such as abdominal obesity, hyperglycemia, atherogenic dyslipidemia, increased blood pressure, and prothrombotic and proinflammatory conditions. These factors increase the risk of developing type 2 diabetes, cardiovascular disease, and mortality . The rolp = 0.021) and 2.2% among men (p = 0.0831), and it is mainly due to hypertriglyceridemia and high blood pressure among women [n = 2334), He, Y. et al. [There are data that show that about 47 million US residents live with MetS, and the prevalence of MetS differed slightly among men (24%) and women (23.4%) . When thng women . Studiesn p = 0.031, and ing women ,10, otheng women ,12,13, ang women . Gender-ng women  found a ng women  have ind. et al. . The pre1 and MT2), one cytoplasmic quinone reductase receptor (MT3), and one nuclear retinoid-related orphan receptor (RZR/RORα) [1 is encoded on chromosome 4, contains 351 amino acids, and inhibits adenylate cyclase, while MT2 is encoded on chromosome 11 and consists of 363 amino acids, inhibiting adenylate cyclase and guanylyl cyclase. Melatonin receptors MT1 and MT2 are widely represented in the pituitary gland, in structures of the central nervous system , in the cardiovascular system , in the gastrointestinal tract , in the digestive system , and in various cells  [3 is localized in the liver, kidney, heart, lung, small intestine, muscle, and brown adipose tissue and has predominantly antioxidant effects [1X) is also known, which probably supports melatonin binding to MT1.Melatonin is a neuroendocrine hormone that is synthesized in the principal cells of the pineal gland, namely, pinealocytes, from the amino acid tryptophan . This prZR/RORα) ,20,21. MMelatonin is secreted mainly at night under the regulatory action of the suprachiasmatic nucleus ,23. The In the present literature review, we aimed to analyze the inter-relationship of melatonin with some MetS risk factors such as dysglycemia, dyslipidemia, and hypertension in women. Changes in melatonin, leptin, and ghrelin concentration and their relationship with various metabolic processes and vascular dysfunction are discussed. Data for the review were collected by using Scopus, PubMed, ScienceDirect, and Google Scholar databases, published between 2000 and 2022. The following keywords were used: “metabolic syndrome”, “melatonin”, “women”, “ghrelin”, and “leptin”. In total, 254 studies were found, then 62 of them were selected for this systematic review.It is believed that the disturbed rhythm of melatonin secretion leads to changes in carbohydrate metabolism, affecting the secretory activity of pancreatic islet cells, glucose metabolism in the liver, and insulin sensitivity of target tissues . Accordi2), that melatonin administration impaired glucose tolerance, regardless of the timing of its administration [p = 0.15), triglycerides (p = 0.17), HDL cholesterol (p = 0.59), and systolic blood pressure (p = 0.013) but resulted in a slight, non-significant worsening in fasting plasma glucose (p = 0.29) [In the last 10–15 years, researchers have noticed an increased interest in studying the role of melatonin in glucose metabolism as a risk factor for the development of T2 DM or in its treatment in humans . Despitestration . An opin = 0.29) ,36.2 (MTNR1B) and glucose tolerance. In healthy female carriers of the mutation, melatonin administration decreased glucose tolerance [2 receptor on glucose uptake and transport in the trophoblast. The study revealed that this variant is significantly associated with GDM, elevated fasting plasma glucose, and 1 h and 2 h plasma glucose. In a review article, Verteramo et al. [2 gen polymorphisms positively correlated with an increased risk of glycemic disorders.An interesting relationship was established between a mutation in the gene encoding the melatonin receptor MTolerance . The effolerance  also invo et al.  tried to1c), microalbuminuria, and lipid profile in 30 patients with T2DM who received oral melatonin 3 mg/day for 3 months. They found that elevated total serum cholesterol decreased significantly after the 60th day from the start of therapy , and after 90 days of treatment, it reached values lower than those of healthy controls; LDL-cholesterol also decreased on day 60  and reached a 46% decrease after day 90; triglycerides showed a 22% decrease after day 90, which was non-significant compared to baseline values. They found a significant increase in HDL-cholesterol on the 30th day from the start of therapy ; on the 90th day, the increase was 30%. Plasma malondialdehyde (as an indicator of lipid peroxidation) decreased significantly after the 60th day of melatonin administration, and glucose and HbA1c decreased significantly after the 90th day. In a study in Iraq, a double-blind, placebo-controlled trial was conducted on 20 women with MetS treated with metformin and melatonin (10 mg daily at bedtime) for 3 months and 15 women with MetS treated with metformin and placebo [In addition to maintaining carbohydrate metabolism, it is believed that melatonin is likely to be an essential factor in lipid regulation. A number of experimental and clinical studies support the beneficial effect of melatonin on lipid profile parameters. In pinealectomized rats, there was a significant increase in the plasma concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-cholesterol), and very-low-density lipoprotein cholesterol (VLDL-cholesterol), and a decrease in high-density lipoprotein cholesterol (HDL-cholesterol), and the administration of melatonin (5 mg/kg for 28 days) improved the concentrations of these indicators . Other e placebo . Based on = 554) aged 25 to 42 years who were followed for 8 years. Women with low morning melatonin excretion (n = 125) were found to have hypertensive episodes. It is hypothesized that low nocturnal melatonin concentrations may be a pathophysiological factor in the development of hypertension. A recent clinical study compared salivary melatonin at different times of the day  in pregnant women (n = 58) with hypertension or impaired glucose metabolism with that of healthy pregnant women (n = 40), also assessing sleep quality and sleep–wake cycle [n = 64, 53% women) and healthy controls (n = 111. 64% women) and experimental models with and without pulmonary hypertension. No statistically significant sex-related difference in melatonin was found in controls and patients with untreated pulmonary hypertension. Compared with healthy controls, untreated patients with pulmonary hypertension have elevated diurnal plasma melatonin. The pathophysiological mechanism of this increase is currently unclear. According to data from this study, high melatonin concentrations are an independent risk factor for pulmonary hypertension, and low melatonin is associated with poor long-term patient survival. A strong correlation was found between melatonin and heart rate in subjects with pulmonary hypertension, whereas in controls, melatonin correlated with systolic blood pressure.Currently, the mechanisms by which melatonin affects blood pressure are thought to be complex and incompletely understood . In thiske cycle . Women wke cycle  from 202p = 0.0423), diastolic (p = 0.0153), and mean arterial pressure (p = 0.013) was found at night, resulting in an improved day–night blood pressure rhythm. Możdżan et al. [Several scientific studies have analyzed the influence of exogenous melatonin on systolic and diastolic blood pressure values. In a placebo-controlled study, 18 women  received slow-release melatonin 3 mg/day for 3 weeks or a placebo . The resn et al.  evaluaten et al. . A commen et al.  discusseThe development of MetS and subsequent adverse complications directs researchers to search for new risk factors . A certaAccording to some studies, night-shift work affects circadian rhythms and is a risk factor for obesity and a number of chronic diseases . They foAdipose tissue produces various proinflammatory cytokines ) and adipokines (leptin and adiponectin), which induce the enhanced formation of reactive oxygen species and oxidative stress . In thisn = 43), women with MetS (n = 43) had statistically significantly lower serum concentrations for both proteins, which correlated negatively with triglycerides, fasting glucose, and HOMA-index and positively with HDL-cholesterol. The reason for the low ghrelin concentrations in women with MetS is not clear. According to one of the stated hypotheses, hyperinsulinemia and hyperglycemia probably suppress the secretion of ghrelin, but for now, the exact mechanism remains to be clarified.A study in Brazil investigated whether a combination of gonadotropins, sex hormones, metabolic risk factors, and inflammatory markers could distinguish obese from non-obese women of different menopausal statuses . It was The potential association of total, acylated, and non-acylated ghrelin with carotid artery atherosclerosis and gender in MetS patients was analyzed in a study by Zannetti et al. . Gender Metabolic syndrome is a significant risk factor for the development of cardiovascular disease and diabetes. The association of melatonin with several classic syndrome features  in women has been discussed in experimental and clinical studies. In recent years, more and more attention has been paid to the role of some new additional risk factors for the development of MetS, such as the hormones melatonin, leptin, and ghrelin. Clarifying the relationship between the primary and additional features of the syndrome in women is essential for the complex etiopathogenetic evaluation of MetS. The data given in this review can help to achieve a better understanding of the differences in the prevalence and components of MetS in women and to look at integrating them into appropriate guidelines for a future complex therapeutic approach toward the components of the syndrome in affected individuals.


Background: Vitamin B12 is one of the most important B-Vitamins that the human body needs on a daily basis, the lack of which can precipitate several neurological issues. Objectives: This systematic aimed to investigate the neurological implications of Vitamin B12 deficiency and the effects when B12 levels were corrected in susceptible individuals. Methods: The databases PubMed-MEDLINE, Web of Science, Cochrane, and Scopus were all searched using pertinent keywords, reference searches, and citation searches. The terms used to access the database were “Cognition”, “Dietary patterns”, “Neurology”, “Nutritional profile”, and “Vitamin B12”. Results: Vitamin B12 was shown to noticeably improve cognition and other neurological parameters in the short term in older adults and the short-to-medium term in children; however, there was no perceived increase/improvement when the Vitamin was administered in the longer term, either alone or in conjunction with other similar nutritional interventions. Conclusion: Vitamin B12’s role in the improvement of neurological functions over a long-term period remains somewhat inconclusive to date, as the majority of our selected control trials did not display much correlation between the two factors. However, Vitamin B12 did improve cognition levels in both children and older adults over a short course of administration. The sophisticated molecular molecule called B12 is water soluble. It is essential for the normal development of people, animals, and even a few microorganisms . Dairy gOther kinds of B12 include methylcobalamin, deoxyadenosylcobalamin, hydroxocobalamin, and cyanocobalamin. Methyl cobalamin, which is also present in dietary supplements, is the most active form of cobalamin discovered in human circulation. This form must be converted by the organism into either methyl cobalamin or 5-deoxyandenosylcobalamin in order to be absorbed . CobalamPeople of all ages, financial statuses, races, and sexes are susceptible to deficiency. It is the most common dietary deficiency in the United States . Early iThese days, people of all ages have psychiatric problems, acute anxiety, and sadness. Although these people are given expensive psychiatric medications, opioids, or benzodiazepines, in many instances, there is also the presence of an underlying moderate-to-severe level of Vitamin B12 deficiency . Hence, Orderly Reviews in Healthcare: Meta-Examination [This systematic review was performed as per the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA)  strategymination , with thThrough this systematic review, our primary objective was to review studies that were published in the neurological literature and discussed the effects of Vitamin B12 deficiency on the neurological parameters of individuals, such as cognition, overall health and/or any pre-existing neurological/systemic disorder.There were a total of 634 documents discovered after extensive search of the online journals, and 416 of the papers were selected initially. Following that, 362 similar/duplicate articles were eliminated, which resulted in 54 separate papers being available. The abstracts and titles of submissions were then reviewed, and a further 37 papers were eliminated. Finally, 17 documents that met the requisite inclusion and exclusion criteria were chosen; these primarily included in vitro studies, literature reviews and comparative assessments.Articles that contained relevant data for our review objectives were selected for full-text screening. Studies that reported clinical trials, in vitro studies, randomised/non-randomised studies, systematic/literature reviews containing substantial sample volume and detailed case reports were considered for inclusion in our review. We also monitored studies that possessed higher methodological quality.The following were excluded from the scope of our systematic review: incomplete data, seminar presentations, scholarly articles, placebo-controlled studies, and opinion articles.Since the literature available on this topic was quite scant in volume, we did not limit our search in terms of the time period in which the studies were published, i.e., we took into account all the papers that were published within the context of our topic (where the number of papers itself was found to be quite sparse in number). Additionally, literature reviews and cases published in languages other than English were excluded.Using relevant keywords, reference searches, and citation searches, the databases PubMed-MEDLINE, Web of Science, Cochrane, and Scopus were all searched. “Cognition”, “Dietary patterns”, “Neurology”, “Nutritional profile” and “Vitamin B12” were the search terms used to access the database.Two independent reviewers located the relevant papers by using the right keywords in various databases and online search tools. The chosen articles were compared, and a third reviewer was brought in if there was a dispute.After choosing the articles, the same two reviewers independently extracted the following data: author, year of publication, country, kind of publication, study topic, population demographics , outcome measure(s), relevant result(s), and conclusion(s). The data were compared and any differences were discussed with the third reviewer.The AMSTAR-2 technique  was usedAfter selecting data on the sample size, variables analyzed, and various elements of the investigations, the data were then entered into the Revman 5 programme for meta-analysis. Forest plots illustrating the risk ratio (RR), and risk difference (RD) for different study methodologies were obtained as part of the meta-analysis for our study, as shown in The AMSTAR-2  checklis2 = 140.20, df = 9 (p < 0.00001); I2 = 94%, indicating significant heterogeneity among the studies. The test for overall effect was conducted using Z = 12.19 (p < 0.00001), indicating a statistically significant effect of Vitamin B12 interventions on neurological outcomes. These findings suggest that Vitamin B12 supplementation may have a beneficial impact on neurological function in individuals with a deficiency. However, further research is needed to determine the optimal dosing and duration of Vitamin B12 interventions in this population.The meta-analysis of the included selected randomised control trials is represented in 2 = 157.23, df = 9 (p < 0.00001); I2 = 94%, indicating significant heterogeneity among the studies. The test for overall effect was conducted using Z = 12.68 (p < 0.00001), indicating a statistically significant effect of Vitamin B12 interventions on neurological outcomes. These findings suggest that Vitamin B12 supplementation may have a positive impact on neurological function in individuals with a deficiency. However, further research is required to determine the optimal dosage and duration of Vitamin B12 interventions in this population. The results of this meta-analysis provide evidence for the importance of adequate Vitamin B12 intake in maintaining neurological health.The meta-analysis included selected randomised control trials, and the forest plot depicted the RD of the studies ; I2 = 77%, indicating significant heterogeneity among the studies. The test for overall effect was conducted using Z = 8.14 (p < 0.00001), indicating a statistically significant effect of Vitamin B12 interventions on neurological outcomes. These findings suggest that Vitamin B12 supplementation may have a protective effect on neurological function in individuals with a deficiency. However, further research is needed to determine the optimal dosing and duration of Vitamin B12 interventions in this population. It is important to note that the studies included in this meta-analysis were observational in nature, and therefore, causality cannot be established. Overall, the results of this meta-analysis provide support for the importance of adequate Vitamin B12 intake in maintaining neurological health.2 = 19.72, df = 4 (p = 0.0006); I2 = 80%, indicating significant heterogeneity among the studies. The test for overall effect was conducted using Z = 8.60 (p < 0.00001), indicating the statistically significant effect of Vitamin B12 interventions on neurological outcomes. These findings suggest that Vitamin B12 supplementation may have a beneficial impact on neurological function in individuals with a deficiency. However, further research is needed to determine the optimal dosing and duration of Vitamin B12 interventions in this population. The results of this meta-analysis provide evidence for the importance of adequate Vitamin B12 intake in maintaining neurological health. It is important to note that the studies included in this meta-analysis were observational in nature, and therefore, causality cannot be established.The meta-analysis  of Vitamin B12 on the neurological parameters of individuals can be identified as another limitation of this review, but the fact that no such current investigation could be found in the literature warrants further research in this field so that a unified consensus can be reached with respect to the effect of Vitamin B12 in alleviating neurological decline in susceptible individuals.Despite the valuable insights provided by this systematic review and meta-analysis, there are some limitations to consider. Firstly, the studies included in the meta-analysis were heterogeneous in terms of study design, participant characteristics, dosages, and the duration of Vitamin B12 interventions. Secondly, the studies included were conducted in different populations with varying risk factors for Vitamin B12 deficiency. This could have introduced bias into the findings of the meta-analysis. Thirdly, the studies were conducted in different countries and settings, which could have influenced the results due to variations in dietary and lifestyle factors. Fourthly, the quality of the studies included in the meta-analysis varied, which could have affected the robustness of the findings. Lastly, the meta-analysis did not assess potential publication bias, which could have influenced the findings. Therefore, caution should be taken when interpreting the results of this meta-analysis, and further research is needed to address these limitations and provide more conclusive evidence regarding the role of Vitamin B12 in neurological health.Through this systematic review and subsequent meta-analysis, it was determined that the majority of the studies that were chosen did not find any advantages of daily Vitamin B12 supplementation over a long period of time (around 1 year or more) on neurologic or cognitive function in older people with moderate Vitamin B12 deficiency who were asymptomatic, nonanemic, and without anaemia. These findings are directly applicable to modern clinical practice, which has identified low Vitamin B12 status as a risk factor for neurologic and cognitive impairments, particularly in older adults. Further, the current study’s findings raise concerns about the usefulness of screening for mild Vitamin B12 deficiency in the absence of anaemia and signs of neurologic or cognitive impairment, and point to the need for stricter definitions of Vitamin B12 deficiency.


Plant fibers are rich in dietary fiber and micronutrients but often exhibit poor functionality. Ultrasonication can affect the particle size of plant fiber, thereby influencing other techno-functional properties. Therefore, this study aimed to investigate the effects of high-intensity ultrasound on citrus, apple, oat, and pea fiber. Initially, solutions containing 1 wt% of plant fiber were homogenized using ultrasonication (amplitude 116 µm, t = 150 s, energy density = 225 kJ/L,  The processing of fruits, vegetables, and cereals generates large quantities of agricultural waste material yet contains highly nutritious components. Particularly regarding the increasing demand for food, it is of major interest to transform these by-products into valuable ingredients. Especially dietary fibers (DF), as the predominant nutrient in these by-products, are important for human health. Recent studies have shown that the fermentation of DF in the human intestine produces short-chain fatty acids, having a positive impact on common chronic conditions such as type 2 diabetes or coronary heart diseases . HoweverCommercial dietary fiber compounds  were received from Herbafood Ingredients GmbH . All other chemicals used in this study were purchased from Sigma-Aldrich  or Merck KGaA  unless stated otherwise.Samples were prepared, each containing 1 wt% of plant dietary fiber in a 200 mL volume. Various dietary fibers, including apple, pea, oat, and two distinct citrus fibers with differing levels of purification, were utilized. Following the mixing of the dietary fiber with tap water, the pH of the solution was adjusted to 7 and stirred for 10 min. To homogenize the solution, high-intensity ultrasound , Hielscher Ultrasonics GmbH, Berlin, Germany) was employed under the following conditions: amplitude = 116 µm, t = 150 s, energy density = 225 kJ/L, and v:v) and boiled for 10 min. Before adding 50 µL of m-hydroxybiphenyl solution, the samples were cooled down to room temperature in a water-ice bath. After 20 min of incubation, the absorbance was measured at 520 nm. 0.5% NaOH was used as a blank, and galacturonic acid monohydrate was used for the calibration curve.As an indicator of pectin content, the content of galacturonic acid  was determined. Initially, 100 mg of each plant fiber was suspended in 45 mL of a 0.5% suspension of Chelaplex III. The pH value was adjusted to 11.8 and the suspension was incubated at room temperature for 1 h. Afterwards, the pH value was decreased to 4.5, and 2 mL of a 1 v% enzyme solution was added, containing Vegazym M  and Celluclast , followed by another incubation at room temperature for 15 h. Finally, the liquid fraction was recovered by filtration and diluted appropriately for the determination of galacturonic acid, following the method of Blumenkrantz and Asboe-Hansen  with sliThe characterization of dietary fiber solutions regarding insoluble fractions (IF), alcohol-insoluble fractions (AIF), and soluble fractions (SF) was conducted by adapting the method of Morales-Medina et al. . IF reprAs a first step after mixing or sonicating the suspensions, the total volume was filtered through filtration bags . The insoluble residue was washed twice with 10 mL distilled water (preheated to 60 °C), and washings were collected in the filtrate. After that, the retentate was washed twice with each, 15 mL of ethanol (95 v%) and acetone. The washings were discarded, and the filtration bag containing the IF was dried overnight at 105 °C and weighed accurately. For AIF, 50 mL of the filtrate from step one was mixed with 200 mL of preheated ethanol  and allowed to stay for 1 h at room temperature. Again, the precipitate was then filtered through a filtration bag and washed twice with each: 15 mL of ethanol (78 v%), 15 mL of ethanol (95 v%), and 15 mL of acetone. This bag, containing AIF, was also dried overnight at 105 °C and weighed accurately. The SM was calculated using the following equation:g . The supernatants were discarded, and the tubes were placed upside down for a further 10 min, draining the unbound water. Then, 1 g of the remaining pellet was weighed accurately (±0.001 g) in dried glass cups, followed by drying in a drying oven  at 105 °C for 24 h. Finally, the glass cups containing dried pellets were weighed, and WBC was calculated as follows:The water binding capacity (WBC) of the examined plant fibers was measured before and after ultrasound treatment. Therefore, a 1 wt% fiber solution was prepared and sonicated according to the sample preparation parameters see . The untThe swelling capacity of plant fiber samples was examined in duplicate following the method published by Zhang et al. , with slThe investigation of the particle size distribution of the untreated and ultrasound-treated fiber suspensions was conducted following the method previously reported by Kalla-Bertholdt et al. . All susTo measure the rheological characteristics of the suspensions containing 1% fiber (UT/T), the methods of Huang et al.  and KallFor microstructural analysis, samples were analyzed following the method previously applied by Kalla-Bertholdt et al. .t-test was employed. Statistical significance was considered at p < 0.05. Microsoft Excel (Version 2307) was utilized for statistical analysis.All experiments were conducted in duplicate or as otherwise specified. Standard deviations and averages were calculated based on these measurements. To assess significant differences between untreated and treated samples, a student’s The galacturonic acid content  of the used plant dietary fiber was investigated as an indicator for pectin, which is the most abundant soluble dietary fiber (SDF) in fruits . GalA isIt was expected that CF Cl would exhibit high amounts of GalA because of the maximum amount of SDF detected among the plant DF used in this study. Additionally, the lowest amounts of GalA were anticipated for OF, as the most abundant SDF in oats is β-glucan, not pectin . β-glucaTo gain a deeper understanding of the effect of ultrasound treatment on dietary fiber, the insoluble fractions (IF), alcohol-insoluble fractions (AIF), and soluble fractions (SF) were determined . The IF In In All in all, the measurements of static light scattering for fiber particles should be taken with caution due to the underlying simplifications. Nevertheless, it can be concluded that high-intensity ultrasound influences particle sizes. This influence is dependent on sonication intensity and treatment time, the initial size of the fiber particles, as well as the nature and purity of the fiber compound. For the investigated fiber compounds, a particle size reduction was achieved for CF AQ, whereas for CF Cl, AF, and PF, an increase was observed. Particle sizes of oat fiber were unaffected.To investigate the effect of ultrasonication on the techno-functional properties of dietary fiber, the water binding capacity (WBC) and swelling capacity (SC) of the different fiber samples were examined. Both capacities represent important properties of dietary fiber because they represent key functionalities in food products as well as in human physiology. Water binding capacity refers to the amount of water retained by fibers under specific conditions. The binding of water can occur via hydrophilic groups of fiber or entrapment in porous areas within the molecular structure . In a prp < 0.05). After sonication, CF AQ more than doubled its WBC , and AF showed an increase of around 40% . These changes were attributed to cavitation-induced particle size reductions, resulting in a larger surface and therefore more hydrophilic and polar groups accessible for interactions with water [WBC is strongly correlated to the chemical structure of the fiber and the functional groups exposed. Functional groups, such as hydroxyl or carbonyl groups, interact with water through hydrogen bonding or dipole interactions, thereby affecting WBC . Additioth water ,19. For th water . As visiConsidering these investigations, WBC is not only dependent on fiber source, particle size, and SDF and IDF contents but also on the microstructure of fiber particles. Network formation does not necessarily imply improved interactions with water or an increase in water binding capacity.Swelling capacity measures the variation in the total volume of dietary fiber and water after a distinct period of time. Similar to WBC, this property is closely related to the temperature, origin, chemical structure, particle size, and porosity of the compound ,47. In gTo examine viscosity changes after ultrasound treatment, the flow curves of 1 wt% fiber solutions were recorded . In geneAll in all, these findings clarify that the determining factors for increased viscosities are not solely the amounts of included viscous components, such as pectin. Instead, particle sizes and particle-particle interactions also play significant roles.The microstructure of the untreated and ultrasound-treated fiber samples is shown in The study of the ultrasonication-induced functional and structural modifications in plant fiber has enhanced our understanding of the underlying mechanisms. Ultrasonication, mediated by cavitation effects, influenced key structural attributes such as particle size and the content of alcohol-insoluble fractions, which are an approximation for SDF. The ultrasound treatment caused the disintegration of fiber particles up to a certain threshold, beyond which no further fragmentation was observed. This suggests that ultrasonication predominantly disaggregates particles and does not cleave covalent bonds. However, this general hypothesis may not fully apply to highly purified and pectin-rich fiber compounds, specifically CF AQ and AF. Due to the harsh processing and extraction conditions employed during production, the fiber structure of these compounds may exhibit increased susceptibility to cavitation-induced shear forces, resulting in a transition from IDF to SDF. The SDF content exhibited a notable increase, rising from approximately 5.5% to 17% for CF AQ and from 8% to 17.6% for AF. The transformation of the fiber structure was visually confirmed through FE-SEM images. In the case of CF AQ and AF, the fiber structure evolved from the tube- or thread-like fragments into thin, nearly transparent layered sheets with attached single filaments, possibly indicating the defibrillation of cellulose macrofibrils into microfibrils. This structural alteration had a profound impact on the techno-functional properties, particularly viscosity, which was attributed to the increased SDF content and unique microstructure. Viscosity increased significantly, soaring from approximately 1.4 Pa·s to 84.4 Pa·s for CF AQ and from 1.34 Pa·s to 31.7 Pa·s for AF. In summary, the techno-functional properties of sonicated DF compounds are not solely determined by particle sizes, SDF, or pectin content. Greater emphasis should be placed on the origin of dietary fiber and, most importantly, its processing history. When these factors are considered, ultrasound as a green technology emerges as a promising method for tailoring the functional properties of commercial DF, presenting an interesting approach for the food industry, particularly in the context of clean-labeling purposes.


DIC in severe falciparum malaria and fatal malaria was 14.6%  and 82.2% . The estimates of DIC among severe malaria patients who had multi-organ dysfunction with bleeding, cerebral malaria, acute renal failure, and ≥2 complications were 79.6% , 11.9% , 16.7% , and 4.8% , respectively. The proportion estimates of DIC among the patients with malaria depended on the Plasmodium species, clinical severity, and types of severe complications. The information from this study provided useful information to guide the management of malaria patients. Future studies are needed to investigate the association between Plasmodium infection and DIC and to understand the mechanism of malaria-induced DIC.Disseminated intravascular coagulation (DIC) is a potentially life-threatening condition that causes systemic coagulation to be turned on and coagulation factors to be used up. However, the evidence for DIC in malaria patients is still not clear, and small case series and retrospective studies have shown varying results. This meta-analysis was intended for the evaluation of the evidence of DIC among malaria patients using a meta-analysis approach. The protocol for the systematic review was registered at PROSPERO as CRD42023392194. Studies that investigated DIC in patients with malaria were searched in Ovid, Scopus, Embase, PubMed, and MEDLINE. The pooled proportion with 95% confidence intervals (CI) of DIC among malaria patients was estimated using a random-effects model. A total of 1837 articles were identified, and 38 articles were included in the meta-analysis. The overall proportion of DIC in malaria was 11.6% (95% CI: 8.9%–14.3%, I Anopheles mosquitoes infected with Plasmodium species. It is one of the deadliest infectious diseases in humans, which is frequently found in tropical and subtropical areas. Additionally, international travelers and immigrants from endemic countries are a known source of malaria and distribution worldwide ) AND (((Disseminated Intravascular Coagulation) OR (Disseminated Intravascular Coagulation [MeSH Terms])) OR (Consumption Coagulopathy)) OR (Consumption Coagulopathy [MeSH Terms])”. The searches in other databases, including Ovid, Scopus, Embase, and MEDLINE, were slightly modified according to each database (The search strategy was created by using search terms with the Boolean operators “AND” and “OR” as follows: “(“Disseminated Intravascular Coagulation” OR “Disseminated Intravascular” OR “Disseminated Coagulation” OR “Disseminated Coagulations” OR “Consumption Coagulopathy” OR “Consumption Coagulopathies” OR “Intravascular Coagulation” OR “Intravascular Coagulations”) AND . The disagreement over selection between authors was finalized by discussion for consensus.The original studies that investigated the DIC in patients with malaria from inception to 7 January 2023 were included in the present study. Studies without full texts, non-human studies such as animal studies, and in vitro studies were excluded. Non-original articles such as reviews, case reports, letters, notes, and systematic reviews were also excluded. The retrieved studies from the database searches were imported into Endnote version 20.0  for reference management. Before selecting the studies, duplicates were removed by both the automation tool in the Endnote software and manually by the authors. The remaining studies were screened for titles and abstracts and non-relevant studies were excluded. The eligible studies were then examined for full texts against the pre-set criteria. Study selection was performed independently by two authors (TD and MK). The disagreement over selection between authors was resolved by discussion. After the study selection was finalized, the necessary data were extracted into a Microsoft Excel sheet, including information on the name of the first author, publication year, study design, study area, participants (and number), clinical status (complications), age groups, The studies were assessed for their reporting quality based on Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria for observational studies . The STR2-statistic) values of 0–40%, 30–60%, 50–90%, and 75–100% indicated unimportant, moderate, substantial, and considerable heterogeneity, respectively [Plasmodium spp., method for malaria detection, or clinical status, sub-group analyses were performed. The funnel plot and Egger’s test were employed to detect possible publication bias. All analyses were performed using the statistical software Stata Version 17.0 .The pooled proportion with 95% confidence intervals (CI) of DIC among malaria patients was estimated using a random-effects model as described previously by DerSimonian and Laird . Forest ectively . If the A total of 1837 articles were identified from Embase n = 418), MEDLINE n = 247), Ovid n = 576), PubMed (n = 193), and Scopus n = 403). After 793 duplicates had been removed, 1044 articles were screened for their titles and abstracts. Then, 986 non-relevant articles, such as articles that enrolled other diseases rather than malaria were excluded. The remaining 70 articles were further examined for eligibility, and 34 articles were excluded for the following reasons: no full-texts (n = 13), no records of articles (n = 8), unable to extract data (n = 6), non-English articles (n = 3), poster or conference abstracts (n = 2), reviews (n = 1), and an animal study (n = 1). A total of 37 studies [3. After 8, MEDLIN, Ovid  and more than half of them in adult participants (60.5%). More than half of the studies enrolled patients with severe malaria (57.9%), followed by severe and non-severe malaria (34.2%). Microscopy was the most used method for the detection of Plasmodium (65.8%). Details of the studies are shown in A summary of the included studies is shown in According to the STROBE criteria that assessed the study’s quality with an overall score of 22 items, two studies received high scores ,53. The Six studies investigated the evidence of DIC in patients with malaria but no DIC was found ,41,51,562: 93.2%, 38 studies, Plasmodium spp., method for malaria detection, and clinical status showed that the study design, clinical status, and types of complications were the probable sources of heterogeneity of the proportion estimates between the studies , 11.9% , 16.7% , and 4.8% , indicating the existence of a publication bias in the meta-analysis due to a small-study effect or the fact that some studies were missing from the meta-analysis.The funnel plot was asymmetrical  and the Plasmodium parasites, particularly those patients who developed severe malaria.Although the epidemiology of DIC in patients with malaria has been reported in the literature, the real evidence of DIC among malaria patients remains unclear. The present study intended to synthesize the evidence of DIC among malaria patients using data from the literature. The results showed that the pooled estimate of the number of patients with malaria who had DIC was 11.6%. The high proportion of DIC among the patients with malaria indicated a likelihood and a probability of bleeding tendency among the individuals who get infected with Plasmodium infection with an increased risk of mortality and it can be triggered by several pathological mechanisms, including parasite-derived factors, host immune responses, and endothelial damage that can lead to coagulation activation, coagulation inhibitor defect, and impaired fibrinolysis. Endothelial activation is considered a major pathophysiological feature of malarial infection, which is caused by the interaction of parasite-derived molecules with endothelial receptors, resulting in increased expression of adhesion molecules such as von Willebrand factor (vWF) and vWF propeptides [DIC usually occurs in severe peptides . Hollestpeptides . vWF plapeptides . Increaspeptides . In malapeptides . In addipeptides . The activation of the pro-coagulation stage may occur in mild and severe malaria infections caused by various mechanisms. Phosphatidylserine exposure on the infected red blood cell surface membrane triggers the formation of prothrombinase complex . Pro-infEndogenous anticoagulant proteins, including antithrombin, protein C, and protein S are decreased in malarial infection due to high consumption, leakage, and reduced hepatic production. Under normal physiological conditions, protein C is activated by thrombin and forms a complex with thrombomodulin on the endothelial cell surface leading to proteolytic cleavage of factors Va and VIIIa. However, during malarial infection, protein C is inhibited by inflammatory cytokines ,71. TissThe high proportion estimate of DIC among patients with malaria found in the present meta-analysis was due to the variability in the study design, clinical severity, and types of severe complications. In the subgroup meta-analysis of different study designs, the proportion estimate of DIC in malaria was highest in the cohort studies (21%). The high proportion estimate (79.6%) was found in the cohort study by Das et al.  but the P. falciparum infections showed that the highest proportion of DIC among the patients was demonstrated in fatal malaria cases (82.2%). The DIC related-death was reported by several studies and linked to P. falciparum [falciparum malaria, the proportion of DIC was lower than the fatal malaria cases by 14.6%. Moxon et al. showed that the patients with cerebral malaria had a high proportion of DIC (11.9%) [The meta-analysis involving different levels of severity of lciparum ,31,40,44 (11.9%) . Cerebra (11.9%) . The ass (11.9%) ,63,76,77 (11.9%) . The intKidney complication is a common cause of morbidity and mortality in severe malaria infection. The meta-analysis showed that the malarial patients with acute renal failure also had a high proportion of DIC (16.7%). The association between kidney injury and DIC was explained by several studies ,80,81,82Plasmodium species, the meta-analysis showed a higher overall proportion of DIC among the patients with P. falciparum malaria than those with P. vivax malaria (16% versus 3%). These results indicate that P. falciparum infection led to a higher probability of DIC development than P. vivax. The DIC due to P. vivax was scarcely reported in the literature, and mostly as case reports [In the different  reports ,84. Alth reports ,46,53. Plasmodium species. Finally, the information from this study would provide useful information to guide the management of malaria patients.The present study had several limitations. First, the limitation on the quality score of the included studies , may have an impact on the overall proportion estimated in the current study. Second, the heterogeneity of the proportion estimates between the included studies, which remained in the meta-analysis results though the meta-regression and subgroup analyses, indicated that other confounders or some other characteristics of the participants that were unavailable to be retrieved may be the sources of the heterogeneity, but these are still uninvestigated. Third, publication bias due to a small-study effect or because some studies were missing from the meta-analysis was found in the present meta-analysis and may have had an impact on the meta-analysis’s conclusion. More studies are needed to investigate the evidence, probable risk factors, and mechanism of DIC among patients infected with malaria with the different severity levels of malaria or Plasmodium species, and types of severe complications. The information from this study would provide useful information to guide the management of malaria patients. Future studies are needed to investigate the association between Plasmodium infection and DIC and to understand the mechanism of malaria-induced DIC.The present study demonstrated that the pooled proportion estimate of DIC among the patients with malaria was 11.6% and varied between 8.9% and 14.3%. The proportion estimates of DIC among the patients with malaria depended on the clinical severity,