Background and Objectives: The inflammatory cells released after intracranial hemorrhage, such as monocytes, macrophages, and neutrophils, activate the inflammatory system. These parameters can be used to evaluate the clinical course of diseases. This study aims to evaluate these parameters as possible predictors for evaluating the development of brain death. Materials and Methods: Patients with a Glasgow coma scale score below 7 were assigned to Group BD (patients with brain death) and Group ICH . The neutrophil, lymphocyte, platelet, monocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-neutrophil ratio (PNR) were measured at admission. Results: A high WBC count, neutrophil count, NLR, and PLR and a low lymphocyte count, LMR, and PNR were found to be significant for determining brain death. The area under the curve (AUC) values of NLR, PNR, PLR, and LMR to discriminate brain death were 0.63, 0.61, 0.56, and 0.61, respectively. Conclusion: NLR, PNR, PLR, and LMR are easily accessible and reliable parameters that can be used to predict the development of brain death and can be estimated by a simple complete blood count test. The diagnosis of brain death is carried out by clinical and radiological confirmation of irreversible damage to all brain functions. Neurological tests demonstrating the absence of brain stem functions, intracranial pathology that may cause coma, and apnea test positivity are required to establish the diagnosis of brain death . MechaniA stroke is defined as a loss of brain functions due to an abnormal blood supply. An ischemic stroke is a cerebrovascular accident resulting from impaired blood supply to the brain, while intracranial hemorrhage is defined as bleeding into the brain parenchyma ,4. Post-The evaluation of post-stroke inflammatory parameters can be used to predict the clinical course of patients. A complete blood count is a simple method frequently used in the monitoring of inflammatory parameters. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) assessed using a complete blood count have been shown to be a predictive value for determining the prognosis of stroke patients ,8.Brain-dead patients are potential donor candidates for organ transplantation. Therefore, these patients should be followed up meticulously for imminent brain death and should be evaluated early in order to increase the quality of organ perfusion during the process. The aim of this study is to investigate whether NLR, LMR, PLR, and platelet-to-neutrophil ratio (PNR) have an early predictive value for evaluating imminent brain death.2 of 35 to 45 mm Hg and PaO2 of >200 mm Hg. The apnea test was considered positive if spontaneous breathing was absent despite a PaCO2 value ≥60 mm Hg and/or an increase in PaCO2 of 20 mm Hg or more from baseline at the end of the test. The patients underwent cerebral CT angiography to confirm brain death and to detect the absence of intracranial blood flow. The patients without intracranial blood flow were considered brain dead [After obtaining the approval of Uludağ University Faculty of Medicine Non-Interventional Research Ethics Committee (decision no: 2011-KAEK-26/165), the study included patients admitted to the anesthesia intensive care unit of Private Medicabil hospital for intracranial bleeding with a Glasgow coma score below 7 between 01 January 2019 and 01 February 2022. The patients were divided into two separate groups: Group BD (patients with brain death) and Group ICH . In Group BD, according to the Ministry of Health regulation for organ and tissue transplantation, the absence of brainstem reflexes, a coma status that has been confirmed not to be induced by hypothermia or drugs, and a positive apnea test result were evaluated in favor of the diagnosis of brain death. To perform the apnea test, the patient was disconnected from the mechanical ventilator and administered intratracheal oxygen to prevent the auto-triggering of cardiac origin after providing normothermia, normotension, normovolemia, and PaCOThe Shapiro–Wilk test was used to check whether continuous variables followed a normal distribution. The continuous variables were expressed with median (minimum: maximum) values, while the categorical variables were expressed as n (%). For continuous variables, the Mann–Whitney U test was used to compare groups. The categorical variables were analyzed using the chi-square test, Fisher’s exact chi-square, and Fisher-Freeman-Halton tests. The receiver operator characteristic (ROC) curve analyses were carried out to estimate the sensitivity and specificity of white blood cell (WBC), neutrophil, lymphocyte counts, NLR, PNR, PLR, and LMR for predicting brain death. SPSS software  was used for statistical analysis, and the type I error rate was set at 5%.p = 0.820)  .p = 0.002, p = 0.004). The median lymphocyte count was higher in Group ICH (p = 0.021). There was no difference between the groups in terms of PLT and monocyte count . The median NLR and median PLR were higher in Group BD . The median LMR and median PNR were higher in Group ICH  (The median WBC and neutrophil count were higher in Group BD (= 0.002) .3  and a WBC count >13,760 cells/mm3 was significantly associated with an increased risk of brain death ; a neutrophil count >12,270 cells/µL was significantly associated with an increased risk of brain death.The ROC analysis performed to estimate the sensitivity and specificity of neutrophil count for predicting brain death  showed ap = 0.021); a lymphocyte count ≤810 cells/µL was significantly associated with an increased risk of brain death ; a NLR >12.9 was significantly associated with an increased risk of brain death ; a PNR ≤22.27 was significantly associated with an increased risk of brain death ; a PLR >287.36 was significantly associated with an increased risk of brain death ; a LMR ≤2.63 was significantly associated with an increased risk of brain death , which are similar to those reported in the literature.Neuroendocrine substances released after intracranial hemorrhage induce an increase in the leukocyte count. There are studies showing the association of leukocytosis with severe disability, poor neurological outcomes, and mortality ,10,11. TIt has been shown that high NLR values after intracranial hemorrhage are associated with poor prognosis and in-hospital mortality. A study of 1000 patients reported high NLR in patients who died in the hospital with a diagnosis of intracranial hemorrhage . A study3, the AUC value was measured as 0.67 [3 and a lymphocyte count <810 cells/mm3 increase the risk of brain death. Our study revealed similar results to those reported in the literature.The neutrophil, lymphocyte, and platelet values measured at admission after subarachnoid hemorrhage increase the risk of in-hospital mortality . In case as 0.67 . In the  as 0.67 ,17. In oHigh PLR and low PNR after aneurysmal hemorrhage have been shown to be associated with poor neurological outcomes . High PLOur study has some limitations. First, patients are admitted to our intensive care unit from other centers through the emergency referral unit, so the admitted patients may not reflect the general population. Second, the data of the patients were not followed up dynamically because the study had a retrospective design. It may be possible to obtain different results in further studies for the determined values.In conclusion, NLR, PNR, PLR, and LMR are easily accessible and reliable parameters that can be used to predict the development of brain death and can be calculated by performing a simple complete blood count test.


Annona genus: araticum tree (Annona crassiflora Mart.), graviola tree (Annona muricata), atemoya tree (Annona cherimolia Mill × Annona squamosa L.), pinha tree (Annona squamosa), bananinha tree , and marolinho tree (Annona coriacea). Only articles published between the years 2016 to 2021 that answered the guiding question were considered, in order to obtain recent data. Then, search strategies were designated for each database used: Science Direct, CAPES Periodicals, and Scielo. Most of the studies retrieved from the databases are related to fruits. The results showed that the number of flavonoids identified varies according to the analytical methodology used to identify and quantify the compounds. Quercetin was the most commonly found compound in all fruits of the Annona genus studied, and epicatechin, rutin, and kaempferol were also found to a lesser extent. The presence of these compounds in Annona makes the fruit promising, with potential applicability in the pharmaceutical and food industry.The Annonaceae family is widely distributed in subtropical and tropical regions. Several species of this family are known for their pharmacological and beneficial properties to human health, mainly attributed to flavonoids. The objective of this work was to carry out an integrative review in order to identify the main flavonoids found in some plant parts belonging to the  The Annonaceae family is widely distributed in subtropical and tropical regions. This family comprises a great diversity , with 18The botanical characteristics of the Annonaceae family may differ from species to species, depending on the origin, climate, and topography. This diversity can range from trees to shrubs to perennial vines, with elongated cylindrical intracellular resin channels and a broad and well-developed septate pith in the stems. The aromatic flowers bloom before they are fully developed. They are axillary, singular or grouped, hermaphroditic, and regular in shape. The fruits are made up of bunches of berries and are widely consumed due to their high nutritional value ,3.Annonaceae are very famous due to their wide use in traditional medicine. Several pharmacological studies have been conducted related to the medicinal use of the Annonaceae family, such as its use against pain, arthritis, rheumatism, and neuralgia, and in weight loss , anthelmAnnona [This family also stands out for its wide variety of chemical constituents belonging to various phytochemical groups. Studies report the presence of cyclopeptides , flavonoAnnona . Among tAnnona , araticuAnnona , marolinAnnona , and banAnnona .Annona crassiflora Mart.) (Araticunzeiro plants are heterogeneous in terms of stem diameter (10.4 cm), plant height (3.7 m), and production (average of six fruits per plant), with production being the most variable characteristic . The trea Mart.)  is a fruA. muricata leaves are related to their content of bioactive compounds, and these leaves are considered a rich source of bioactive compounds with potential uses in the formulation of therapeutic drugs or nutraceutical foods [Annona muricata) also known as soursop  are the subjects of numerous research works due to their content of potentially bioactive compounds . The bioal foods . The fru soursop , is a naA. cherimola Mill.) and pinha (A. squamosa L.) [Annona cherimola Mill. × Annona squamosa L.) (The atemoya tree a hybrid plant resulting from the cross between cherimoya (mosa L.)  maintainmosa L.)  has a smAnnona squamosa) is characterized by its small size, pivoting roots, and elongated leaves. These features also have several ramifications. The height of this plant varies from three to six meters, its flowers are small and can be isolated or in the form of a bunch, and its fruits are flat, ovoid, or heart-shaped [Annona squamosa L. fruit 2 lignans; (C6-C3-C6)2 diflavonoids; (C6)n plant melanins; (C6-C3)n lignins; (C6-C1)n atemoya tannins; (C6-C3-C6)n condensed tannins. Annona genus, the most common flavonoid classes are quercetin-3-O-rhamnoside, luteolin-7-O-glucoside, kaempferol-3-O-galactoside, and their derivatives [Flavonoids are part of the most relevant and diversified group of phenolic compounds among natural products  and are ivatives .These compounds belong to an important class of secondary metabolites , in addiAnnona genus.Therefore, it is essential to know which flavonoids are present in these plants to appreciate these species better. Therefore, the objective of this work was to carry out an integrative review to identify which flavonoids are mostly found in plant parts belonging to the Annona plants selected for the present work, associated or not with the term “flavonoid”, according to each database.The definition of the guiding question led to the designation of search strategies for each database used, namely Science Direct, Periódicos CAPES, and Scielo. The descriptors were used as a search strategy that approached the popular and scientific names of the six Annona genus using AND/OR search operators. The pre-selection was based on the relationship of guiding questions and reading both the abstract and the title of the works. The search strategy used for the Science Direct database resulted in 113 studies, while 63 articles were found in Periódicos Capes and 41 studies were selected in the Scielo platform. Of the 217 works retrieved, 8 were removed because they appeared twice in the databases. In total, 209 works were selected for the next stage  to Annona crassiflora Mart., 18.75% (3) to Annona coriacea, and 6.25% (1) to Annona cherimolia Mill × Annona squamosa L. It is worth mentioning that one of the studies recovered was related to more than one (graviola and araticum). Studies related to A. squamosa and A. leptopetala were not included due to the lack of studies returned in the survey that answered the guiding question.A. crassiflora Mart.) were epicatechin, quercetin, and rutin. Among the flavonoids identified in graviola (A. muricata), rutin, quercetin, and kaempferol stand out. Regarding the compounds isolated from marolinho (A. coriacea), quercetin was the most abundant  and transfer of hydrogen atoms  . SimilarOn the other hand, Prado et al. found a higher flavonoid content in the peel than in the seed in a quantitative investigation of flavonoids in different fruit parts . AccordiA. muricata leaves due to an interest in the neuroactive properties of its flavonoids in mice [Concerning graviola, Souza et al. worked with a hydroalcoholic extract of  in mice . An HPLCO-rutinoside and quercetin-3-O-rutinoside in a graviola leaf extract, in addition to demonstrating the ability of soursop leaves to boost immunity [A. muricata.Lee and colleagues, who also evaluated graviola leaves, found that in addition to quercetin and some of its derivatives, there was also the presence of aponarin, epicatechin, and glabridin . These cimmunity . Similarimmunity . Thus, iA study by Nam et al. focused on comparing the antioxidant activity of different extracts and parts  of graviola . The 80%Research by Justino et al. evaluated the antidiabetic potential of graviola leaves and performed an ethanolic extraction followed by a liquid–liquid partition of the ethanolic extract . As a reIn addition to the most consumed parts of the fruits, such as pulp and leaves, large amounts of waste such as seeds are discarded during fruit processing, generating a deficit of information on the exploitation of these by-products . In thisA. squamosa × A. cherimola), Mannino and colleagues, in a 2020 study, evaluated the chemical profile of this fruit and observed that among the compounds identified, six were from the flavonoid class [A. cherimola leaves to prepare dietary supplements to promote the physiological redox balance that plays an essential role in preventing several chronic diseases [When exploring the nutraceutical potential of atemoya , emphasizing quercetin-3-O-gentiobioside and quercetin-3-O-robinobioside in a similar way to the previous study, and also for rutin [Annona.Using traditional UV spectroscopy techniques, Novaes et al. identified in hamnetin . In 2019or rutin . AccordiAnnona. Therefore, these studies emphasize the importance of these species, since they can bring several health benefits and have a wide application in the food and pharmaceutical industry, especially Annona crassiflora Mart. (araticum), Annona muricata (graviola), Annona cherimolia Mill × Annona squamosa L. (atemoya), and Annona coriacea (marolinho).In general, the Annonaceae family, especially the fruits discussed in the present study, have a great prominence of compounds such as quercetin, rutin, and kaempferol, since these compounds were present in 93.75% of the included studies. Concomitantly, it can be inferred that even carrying out the research of these components through different methodologies and technologies, flavonoids are always present in species of the genus Annona genus were established: araticum (Annona crassiflora Mart.), graviola (Annona muricata), atemoya (Annona cherimolia Mill × Annona squamosa L.), pinha (Annona squamosa), bananinha , and marolinho (Annona coriacea), defined in light of the previous research about them.Articles published between the years 2016 to 2021 were considered, to obtain recent data, and the searches were performed using three databases, namely: Science Direct, Periódicos CAPES, and Scielo. Initially, six plants belonging to the Annona genus?”. In the second stage, searches were carried out, based on predetermined strategies  . The firrategies , for artAnnona genus mentioned above. There was no restriction regarding the language of the articles, and only scientific articles were used. Exclusion criteria were applied to those articles that did not answer the guiding question initially asked and those that were not published within the stipulated period. Other types of works returned by the databases were also excluded, such as theses, dissertations, and book chapters. The exclusion criteria were also applied for those articles that did not have free access.Inclusion criteria were studies published between 2016 and 2021 that identified flavonoids present in plant parts of the In the third stage, the pre-selection of scientific works was carried out. Both the title and the abstract of each article were read according to the established criteria of inclusion and exclusion. Thus, the complete reading of the pre-selected manuscripts in the previous step was carried out in the next step. As a fifth and final step, the results were interpreted. Only those works which answered the initial guiding question and could aid in developing its answer remained.Annona muricata). The selected works also identified flavonoids in araticum (Annona crassiflora Mart), marolo (Annona coriacea), and atemoya (Annona cherimolia Mill × Annona squamosa L.). According to the studies selected in this review, it is noticeable that quercetin is the most recurrent flavonoid in all plants of the Annona genus addressed in this study. In addition to quercetin, epicatechin, rutin, and kaempferol were reported in most of the studies addressed. The presence of these compounds makes these fruits promising and with potential applicability in the pharmaceutical and food industry due to the different properties they present.Among the six plants surveyed, the majority that answered the guiding question were related to the fruit, and the plant with the highest number of works was graviola (


Excessive Internet use is related to behavioral and cognitive dysfunctions, but little is known about the relationship between them in young elementary school children. This study examined the longitudinal relationship between children's Internet use for entertainment purposes, executive function problems, and maternal control. Differences by children's Internet addiction status in their associations were also examined. Data from Wave 9 (2016) to Wave 11 (2018) of 1,463 children and mothers who participated in the Panel Study on Korean Children (PSKC) were used. The children's ages were 8 (grade 2), 9 (grade 3), and 10 years (grade 4) at Waves 9, 10, and 11, respectively. Associations between the variables were analyzed using autoregressive cross-lagged model estimations and multi-group analysis. The results showed the longitudinal stability of each of children's Internet use, executive function problems, and maternal control over the 3 years. Mutual associations between maternal control and children's Internet use were found especially in the low-risk group. In addition, children's executive function problems positively predicted Internet use, and negative associations from executive function problems to maternal control were significant over the years. However, some of these associations were significant only in the high-risk group. Discussions have focused on the protective role of maternal control and cognitive intervention, which could reduce children's excessive Internet use. Excessive Internet use by young children has been a social issue in South Korea for many years. These days, children use the Internet almost every day for learning, interpersonal interaction, and entertainment , 2. HoweExecutive function comprises a set of components that are necessarily involved in cognitive and behavioral control and problem solving, such as working memory and attentive control, inhibition and shifting, planning and organizing, and mental reasoning –12. LackFirst, it is difficult to define “excessive Internet usage” by children resulting in executive function problems. It is also difficult to prove that normal Internet usage by children does not cause executive function problems and that only Internet addiction results in such problems. In particular, researchers , 18 haveIt would be noted that it is more common for mothers to care for children in Korea, and <10% of fathers substantially participated in childrearing in contemporary Korean society , 21. AltSecond, the direction of influence between excessive Internet use and executive function problems is not well understood. It is unclear whether one variable influences the other, or whether the two variables influence each other. For example, children at high risk for Internet addiction do not always show problems across all subcomponents of executive function, even though it is true that children with excessive Internet use report difficulty in inhibiting their needs when doing something or switching to something else . By contThird, since children's cognitive and self-regulatory abilities increase with age , 25, it Fourth, supervised Internet use by parents is considered key to protecting children from Internet addiction, and its importance is well documented across studies , 32, 33.On the basis of the four issues discussed above, this study aimed to examine the longitudinal relationship between children's Internet use, executive function problems, and maternal control in school-age children. For this purpose, the hypothesized model in The second aim was to examine longitudinal directionality between the three research variables. Previous findings indicated that time of Internet use positively predicted difficulty in attention and cognition processes , 16 and Finally, this study aimed to examine differences in the Internet addiction status (low-risk vs. high-risk) in the longitudinal relationship between children's Internet use, executive function problems, and maternal control. It is important to note that children's use of the Internet is not always a problem, and that severe dysfunction in cognition and behaviors is observed mostly in children with severe Internet addiction. In particular, clinical attention is mainly given to children who have shown Internet addiction for years, not to those who temporarily overuse the Internet. Therefore, this study classified children who showed excessive Internet use during all three waves as a high-risk group, and hypothesized that the longitudinal associations between the three variables would differ between children in the high-risk group and those who were not. Although it is expected that the association of children's executive function problems with other variables would be salient in the high-risk group, examination of Internet addiction status as a moderating variable was exploratory without hypothesizing a specific direction or pattern.2 (1) = 7.99, p < 0.01), but no significant difference was found in family economic status (χ2 (1) = 0.59, p = 0.44). Of the 1,463 families included in this study, children's ages were 8 (grade 2), 9 (grade 3), and 10 years (grade 4) at Wave 9, 10, and 11, respectively, and about 51 % (n = 748) were boys, and 49 % (n = 715) were girls. The mothers' mean age was 31.21 years (SD = 3.65), and 70.8 % of the mothers graduated from college at the initial wave. Only 3.6 % (n = 49) of the families received financial assistance from the government.This study used data from Wave 9 (2016) to Wave 11 (2018) of 1,463 children and parents who participated in the Panel Study on Korean Children (PSKC). The PSKC is a nationwide longitudinal study conducted by the Korea Institute of Child Care and Education (KICCE), followed by developmental outcomes, family mental health, school adjustment, and other variables of 2,150 children and families since 2008 (at childbirth). The participants were recruited using a stratified multi-stage sampling method. First, 30 hospitals were recruited nationally. Among the families of newborns in these hospitals, 2,150 agreed to participate in the initial study, and continued to participate in annual follow-ups. Data were obtained from the children, parents, and teachers using questionnaires, web-based interviews, observations, and tests. The annual sample attrition from 2008 (Wave 1) to 2016 (Wave 9) was approximately 3 % on average. Of 1,556 families, data from 93 families, who were not present in two or more rounds of the survey on the research variables from Wave 9 to Wave 11, were excluded. Children and mothers who were excluded were compared with 1,463 participants, who remained in this study, but no critical differences were found. The excluded cases reported a lower percentage of college education  . The EFDnever  to alway , and web surfing. A high score indicates a high level of Internet use for entertainment purposes.not likely at all  and high-risk for Internet addiction. First, children who used the Internet for more than 2.5 h every day from Wave 9 to Wave 11 were identified by maternal report . In addition, at Wave 11, children were assessed using 15 items of a revised Korean version of the diagnostic scale for Internet overdependence  developed by the National Information Society Agency . Items oy likely . On the SPSS version 27.0 was used for the analyses of the descriptive statistics and bivariate correlations, and AMOS was used for the hypothesized cross-lagged panel model (CLPM) analysis. A CLPM is the statistical model which allows the examination of longitudinal sequential associations between variables . Typicaln = 168), maternal control (n = 157), and Internet use (n = 101) from Wave 9 to Wave 11. Regression imputation was applied for the missing values. A CLPM analysis with Maximum Likelihood Estimation (MLE) was performed. Model fit was assessed using Comparative Fit Index (CFI), Tucker–Lewis Index (TLI), and Root Mean Square Error of Approximation (RMSEA). CFI and TLI ≥ 0.90 and RMSEA < 0.08 indicate an acceptable fit  of the chi-square indicates that the coefficients in one group are different from those in another. Separate estimates of the predictive paths for the two groups were compared.Differences between high-risk and low-risk groups in the CLPM were then tested by multi-group analysis to estimates moderating effects of Internet addiction status. A nested model comparison test was performed to examine whether the estimated coefficients of CLPM varied depending on Internet addiction status. For nested model comparisons, a chi-square test was used. A significant t = −3.06–−2.07, p < 0.05, d = 0.15–0.22). In addition, maternal control was significantly higher in the low-risk group than in the high-risk group at Wave 10 and Wave 11 ., p < 0.001) and Wave 11 , respectively. The children's executive function problems  and maternal control  at Wave 10 and 11 were also predicted by the same variable in the previous waves. With regard to the cross-lagged paths, children's executive function problems at Wave 9 significantly predicted children's Internet use  and maternal control  at Wave 10. Maternal control at Wave 9 negatively predicted children's Internet use at Wave 10 . In addition, maternal control at Wave 11 was negatively predicted by children's Internet use  and executive function problems  at Wave 10. The results also indicate that contemporaneous correlations  among the study variables were significant across the waves.The results of the CLPM analysis examining the longitudinal stability and directionality between variables with the total sample are presented in 2 = 45.70 . p < 0.05), but not in the high-risk group. In addition, the paths from maternal control at Wave 9 to children's executive function problems at Wave 10 , and from children's executive function problems at Wave 10 to Internet use at Wave 11  were significant only in the high-risk group.A multi-group analysis for the CLPM split by Internet addiction status (low-risk vs. high-risk) was also performed, and the results of the chi-square difference test for nested model comparison indicated significant moderating effects of the Internet addiction status, χThis study examined the longitudinal stability, directionality, and cross-variable influence of children's Internet use, executive function problems, and maternal control using panel data of children aged 8–10 years. Differences in the associations between the three research variables caused by Internet addiction status were also examined using multi-group analysis. Hypothesized autoregressive cross-lagged paths were tested with the total sample, and then with each of the low-risk and high-risk groups for Internet addiction. The major findings of this study are as follows.As expected in the first hypothesis, the results of this study provide evidence of longitudinal stability of the three research variables. Maternal control and children's executive function problems tended to be stable in the lower grades of elementary school years. In particular, children's Internet usage continued in line with development during this period. For example, Internet usage time for 10-year-old children can be predicted by usage time a year before. Excessive Internet use and general Internet usage at a younger age are likely to continue. For example, children who used the Internet for more than 2.5 h per day at 8 years showed similar usage at 9 years. These findings are somewhat consistent with a previous study by Shek and Yu , in whicSecondly, this study hypothesized cross-lagged causality and found significant cross-variable relationship between children's Internet use, executive function problems, and maternal control with the total sample. Specifically, there were mutually negative associations between maternal control and children's Internet use across waves. This finding shows that maternal control consistently contributed to reducing children's time spent using the Internet for entertainment purposes. This result is consistent with the findings of other studies in which maternal control or monitoring was a protective factor for children's excessive Internet use , 36. It With regard to cross-relations between children's Internet use and executive function problems, i hypothesized bidirectional interactions between the two. However, the causal direction was found only in the pathway from children's executive function problems at Wave 9 to Internet use at Wave 10. This result is consistent with the findings of previous studies, in which children with low attention and impaired cognitive functioning were more likely to be addicted to the Internet , 53. In In addition, associations between children's executive function problems and maternal control were significant in only one direction in the total sample. Children's executive function problems negatively predicted maternal control. However, there is no plausible explanation for this result. It is only assumed that maternal control may not be frequently delivered to children when the children show cognition-related problems due to a lack of central executive functioning. Parenting strategies other than maternal control may be more appropriate for dealing with children's executive function problems. Further investigation is required to determine this possibility.As expected in the third hypothesis, differences between the low- and high-risk groups in the CLPM were found. With regard to Internet addiction status, mutual associations between children's Internet use and maternal control were found only in the low-risk group. None of the same paths were significant in the high-risk group. In contrast to previous studies , 58 suggChildren's executive function problems were positively associated with their Internet use only in the high-risk group. As mentioned above, low executive functioning in children is a risk factor for Internet addiction. In addition, a noticeable group difference was revealed in the association between maternal control and children's executive function problems. Contrary to the direction of these two variables in the total sample, maternal control negatively affected children's executive function problems only in the high-risk group. Executive function problems often involve impulsiveness and behavioral dysregulation, which can cause parents to be stressed and agitated . Thus, iIn light of the findings discussed here, this study has implications for interventions for problematic Internet use. Most importantly, controlled and supervised Internet use by mothers was found to be a protective factor against excessive Internet use in young school-age children. However, mothers' involvement in controlling Internet usage time at home may not be fully effective for children who need therapeutic intervention for Internet addiction. It is important to note that there was a causal association between maternal control and children's executive function problems, especially in the high-risk group in this study. Therefore, combining cognitive training with maternal involvement to increase executive functioning may be an effective strategy for the treatment of Internet addiction in young children. Moreover, identifying children's executive function problems as early as possible may be an important component for prevention and intervention for Internet addiction.This study is significant in that it conducted a longitudinal investigation to determine causal directions based on a considerably large number of samples in typical and Internet-addicted groups of children. Furthermore, it explains children's Internet usage and related variables during lower grades in primary school, a relatively less studied age group. Nevertheless, it also has certain limitations that should be addressed for future studies. First, although lower executive functioning was found to be a possible cause of problematic Internet use, it is unclear whether this relationship can be applied to clinical settings. For instance, the levels and patterns of executive function problems in children with ADHD or other cognitive impairments differ from those in healthy children. Therefore, future studies should consider children with cognitive mental disorders and examine their neurological impairments in executive functioning. Second, this study was limited in controlling or analyzing demographics because the variations in these variables were not fully extensive. Overall, the participants in this study represented a middle-class population. However, many previous studies on Internet addiction and maternal behaviors have reported differences in children's gender and family economic status. Therefore, the potential influence of demographics should be controlled or analyzed in future studies. Third, despite using a representative sample, this study is not completely free from the limitations of panel data, such as endogeneity or autocorrelations. In addition, children's Internet use and executive function problems were measured only on the basis of mothers' reports. Although the scales had a satisfactory level of reliability, there may be a gap in the children's behaviors in mothers' reports and those in real settings. Therefore, measures that include observations need to be taken to address the issue of ecological validity in future studies. Fourth, the parental controls reported by fathers were not included in this study. Since it is more common for mothers or women to care for children in Korean families, fathers rarely monitor their children's Internet use during the daytime. However, children who show excessive Internet use may have conflicts with both their mothers and fathers. Most importantly, the discipline of fathers, which is more intermittent but more intense than that of mothers, is also likely to affect children's Internet use. Composite patterns of paternal and maternal control and their interactions should be considered in future studies. Finally, parental control in the dimension of general parenting also involves psychological ways of exacerbating children's negative emotional outcomes. Consequently, the follow-up of this study will examine the influence of both mothers and fathers on their children's Internet use at a more elaborated level of behavioral and psychological control.https://panel.kicce.re.kr/pskc/module/rawDataManage/index.do?menu_idx=56.Publicly available datasets were analyzed in this study. This data can be found here: Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.HS contributed entirely to all procedures for conceptualization, hypothesis, analysis, writing, and revision.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Human breastmilk, the ideal food for healthy infants, naturally contains a high concentration of medium-chain fatty acids . MCFAs are an important energy source for infants due to their unique digestive and metabolic properties. MCFA-enriched oils are widely used in an infant formula, especially the formula produced for preterm infants. Recently, there has been a growing interest in the triglyceride structure of MCFAs in human milk, their metabolism, and their effects on infant health. This study summarized the MCFA composition and structure in both human milk and infant formula. Recent studies on the nutritional effects of MCFAs on infant gut microbiota have been reviewed. Special attention was given to the MCFAs digestion and metabolism in the infants. This paper aims to provide insights into the optimization of formulations to fulfill infant nutritional requirements. Dietary nutrition is vital for the metabolic outcome and development of infants. Human milk is the optimal source of nutrition for infants. Fat is an important component of milk, supplying ∼50% of energy for infants . Human mde novo FA synthesis, and the presence of an acyl thioester-hydrolase limits FA synthesis to more than 16  and milk fat , 6. Typi than 16 , 12; thevia the portal vein and rapidly transferred independently of the carnitine shuttle system to the mitochondria  account for 7–23% of the total FAs in human milk, and 12:0 and 14:0 are predominant, accounting for approximately 5% and 6%, followed by 10:0 and 8:0 . It was 4:0 accouy glands , resultiy glands , 28, 29.y glands . AdditioMedium-chain fatty acids account for a small portion of human milk; however, recent studies have shown that approximately half of the TAG molecule species in human milk contain at least one MCFA , 32. TabHuman milk fat is well-known as the best nutrition for infants and is generally considered the reference standard for the development of an infant formula. Our group has recently analyzed the FA and TAG composition of 180 commercial infant formulas on the Chinese market , 39. As The main TAGs containing MCFAs were 12:0/12:0/12:0 (LaLaLa) and 12:0/12:0/14:0 (LaLaM) in the plant oil-based infant formulas. Short- and medium-chain TAGs, such as 4:0/12:0/16:0 (BuLaP), 4:0/14:0/16:0 (BuMP), and 6:0/14:0/16:0 (CoMP), were predominant in the cow milk or goat milk-based infant formulas . These cThe digestion of lipids begins in the stomach, where the FAs are released by gastric lipase, which is present from the 11th week of gestation and reaches adult activity levels at birth . It has Ingested fat is digested and absorbed primarily in the small intestine, where TAGs are mainly hydrolyzed by pancreatic lipase to form the primary products 2-monoacylglycerol and free FAs . SubsequWith MCFAs being absorbed easier and faster than LCFAs, it is expected that adding MCTs to formulas would promote the higher absorption of fat . Some stin vivo mammalian neonate model  being easily oxidized is the effects on body fat accumulation and obesity, which have been well demonstrated in animal and clinical trials –69. MCFAAcetyl CoA can also be converted into ketone bodies, such as acetoacetate, 3-hydroxybutyrate (β-HB), and acetone, in the liver mitochondria . ExtraheBesides an increased metabolic rate, MCFAs are associated with increased lipogenesis in the liver , 75. MCTAlthough the impact of MLCT on infant health remains unclear, numerous clinical studies have demonstrated that, compared with a physical mixture of MCT and LCT, MLCT exerted some favorable effects on nutrition status in surgical patients, in particular lipid metabolism and liver function , 80. HenMilk fat is naturally rich in MCFAs, which are very important to the growth and development of infants. Although the consensus is that MCFAs have a unique advantage in absorption and metabolism in infants, the benefits of MCT on the growth performance of infants are not clearly shown in clinical trials. It is necessary to determine how the TAG structure of MCFAs influences lipid digestion and absorption and causes the observed outcome. Moreover, the effects of different MCFAs  on lipid metabolism warrant further investigation. Additionally, the distinct metabolic effects on infants resulting from the differences in the composition of TAGs containing MCFAs between an infant formula and human milk have not been fully addressed. The molecular species of TAGs containing MCFAs in natural fats, their metabolic processing, and the potential health benefits for infants are of great interest. We present a summary of recent studies on MCFA composition in human milk and an appraisal of the function and roles of MCFAs on long-term metabolism in infants, which will be conducive to the development of infant formulas.WW and JL designed the review. TY wrote the original manuscript. WW, LW, JJ, LM, JP, ZL, JG, CS, QJ, and XW reviewed and edited the manuscript. All authors read, discussed, and agreed to the published version of the manuscript.LM, JP, and JL were employed by Inner Mongolia Mengniu Dairy (Group) Co., Ltd. ZL was employed by Yashili International Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The issue of HIV/AIDS is prevalent around the world and in Ethiopia as well. The aim of this study was to determine the prevalence and risk factors of HIV/AIDS infection among sexually active women in Ethiopia.  For this study, data were obtained from the Ethiopia Demographic and Health Survey conducted in 2016. This study contains 11,729 women who have had at least one episode of sexual intercourse in their lifetime. Interviewers for voluntary HIV testing collected finger-prick blood specimens from women who agreed to be tested for HIV. Based on factors at the individual and community levels, a multilevel logistic regression model was used.  The study found that 2% of 11,729 sexually active women tested positive for HIV from all regions who received voluntary counseling and testing. The intraclass correlation coefficient findings showed that 32.844% of HIV/AIDS transmission among sexually active women was the result of community-level factors. Variables at the individual level were women of age 16–24 , women of age 25–34 , women with primary education level , more than one sexual accomplice , and women's age at first sexual intercourse between 25 and 34 ; these were the most significant determinants of HIV/AIDS infection. According to community-level factors, there was a lower HIV prevalence rate among rural women , and women in the Gambela region  also had higher HIV prevalence rates.  The prevalence of HIV infection among sexually active women varies by region, with urban women more likely to contract the virus. Women who had more than one regular sexual partner and had their first sexual encounter at a younger age are at an increased risk of contracting HIV/AIDS. According to the study, the government should focus more support on high-risk clusters, mainly in urban areas, as well as on regions with high rates of HIV/AIDS infection. Globally, over seventy-six million humans have been abscessed with the human immunodeficiency virus (HIV), and HIV infection has triggered more than 35 million deaths since its inception . HIV/AIDHIV/AIDS is a major public health concern and a leading cause of death in many African countries. Despite accounting for about 15.2% of the world's population, Africans accounted for more than two-thirds of the total infected worldwide, with 35 million infected, 15 million of who have already died . The youIn sub-Saharan Africa, Ethiopia has the highest number of people living with HIV/AIDS. It is an essential part of emerging nations' health systems , 8. HIV In Ethiopia, the general pattern of the pervasiveness rate fluctuates from one year to another and from one locale to another. A pattern investigation of the country from 1982 to 2011 shows a consistent progressive ascent in HIV/AIDS pervasiveness until the last part of the 1990s, trailed by a consistent downfall after 2000 . NonetheEthiopia has gained ground in lessening the quantity of HIV/AIDS cases in the nation, yet the changes observed are deficient in contrast with the ideal objectives of the reaction to the pestilence , 14. GivThe study used the nationally set of representative cross-sectional data extracted from the EDHS 2016. The Central Statistical Agency (CSA) conducted the 2016 Ethiopia Demographic and Health Survey (2016 EDHS) from January 18, 2016, to June 27, 2016. Ethiopia's demographic and health survey 2016 select a total of 18,008 households for the sample, of which 17,067 were occupied. Of the occupied, 16,650 were successfully interviewed, yielding a response rate of 98%. The total household size was 16,650, and of these, 15,683 were eligible women. In the sample of interviewed women, 15,683 responded correctly . Our stuThe dependent variable is dichotomous “HIV status of the women in Ethiopia” .Individual-level covariates associated with HIV status in Ethiopian women were classified as the women's background, socioeconomic status, and demographic characteristics: age, education, sex, and wealth index; HIV/AIDS awareness, which includes general knowledge, transmission modality, and methods of infection prevention. As a result, it can be divided into two categories: no and yes. In addition, marital union status, age at first sex, and multiple sexual partners are all factors in sexual behavior .Region and urban rural residence were considered community-level factors incur directly from the EDHS.In this study, data were extracted and decoded using SPSS software version 23, and the decoded data were analyzed using STATA version 14. To characterize the study participants, descriptive statistics such as frequencies and percentages were used. A multilevel study design does not consider individual women to be independent of one another. In this study, patients are nested by cluster (enumeration areas). In this case, the conventional regression model is meaningless. Because of this, a multilevel logistic regression model was developed to determine the prevalence of the HIV/AIDS pandemic among women who are sexually active.nd model (model I) was set by including all individual-level variables. This step evaluates the significance of each individual-level explanatory variable, the significance of each predictor, and changes in the first- and second-level variance terms. By incorporating all community-level variables, the third model (Model II) was developed. Individual-level and community-level factors were included in the 4th model (model III) [The null model (model I) is the first of four successive multilevel model analyses, and it is equipped with no explanatory variable at the individual and community levels to recognize the presence of a potential contextual result. The 2del III) , 19.i and j are the level 1 and level 2 units, respectively; X mention to individual-level factors and Z mention to the community-level variable; πij denotes to the probability of HIV/AIDS status for the ith women in the jth community; and the β bespeak the fixed coefficients. In the absence of predictor influence, the intercept-the effect on the probability of HIV/AIDS status among sexually active women is mentioned by β0; uj demonstrate the random effect , Akaike's information criterion (AIC), and Bayesian's information criterion (BIC) were used to compare models [P-value ≤0.05 is well thought out statistically significant. To measure the degree of variation between enumeration areas, the measures of variation were summarized using the ICC, MOR, and PCV. The following formula was used to compute the ICC: ICC=VA/VA+(π2/3)=VA/VA+3.29, where, in each model described elsewhere, VA represents the variance estimation. The total variation attributed to individual or community-level factors was calculated using PCV at each model: PCV=(VA − VB)/VA, where VA is the initial model's variance and VBs the model's variance with more terms [VA represents the variance at the community level, and MOR is always≥ 1. There is no difference between clusters if the MOR is 1 [Because of the data's hierarchical nature, multilevel logistic regression fashions were used to determine factors related to HIV/AIDS status among women . A two-le models . As the re terms . The MORMOR is 1 , 20.x2-value = 3.4, P-value = 0.337), there is a significant association between all sociodemographic characteristics , age between 25 and 34 , women with primary education , more than one sexual accomplice preceding to the survey , and women's age at first sexual intercourse between 25 and 34  were the most significant .Women in rural areas were less likely to be HIV positive  than urban women. Women found in the Somalia region  and Gambela region  were the most significant determinant factors of HIV/AIDS infection among women who are sexually active .The prevalence of the HIV/AIDS pandemic among sexually active women varied across communities . AccordiUsing data from the Ethiopian Demographic and Health Survey 2016 , the purWomen's residence had a significant impact on the prevalence of HIV/AIDS infection. This finding is consistent with the findings of an Ethiopian study , 11, 22 HIV infection is more common in educated women than in women with no or only preschool education. HIV infection is 1.8 times more likely in sexually active women with primary level education than in women with no education or preschool level education. This means that sexually active women with primary school education are more likely to be abscessed with HIV than those with no education or only preschool education. This study was coinciding with other studies , 28, 29.In sexually active women between 16–24 and 25–34 years, the probability of HIV infection was 0.8 and 0.733 times lower than that in women under 15 years old. This result is similar to a previous study, which found that the disease is especially prevalent in young women and adolescent girls between 15 and 24 years old , 30. ThiThis study uses a nationally representative survey dataset, which enhances inferences for the entire country level. The major strength was that interaction effects were examined in the study. In the survey, participants were asked to recall events from five years ago, and some details may have been forgotten. The cross-sectional nature of the data also prevents causal relationships between outcome and exposure variables from being identified. Due to these limitations, estimates for specific countries may change over time as a result of the self-reported data and should be considered cautiously since they are based on self-reported values from a nationally representative survey. As a national representative dataset, the EDHS is designed and deployed rigorously by the Centers for Disease Control and Prevention. Despite these limitations, this allows the results to be generalized across the country. It will also be possible to compare the results internationally due to the use of similar instruments across countries.In the path of HIV prevention, treatment, care, and backing administrations, HIV testing is essential. This research was undertaken to identify demographic, socioeconomic, HIV/AIDS awareness, and sexual behavior factors related to HIV/AIDS among women who are sexually active. The chances of contracting HIV increased for women in the country's urban communities, regardless of how the prevalence of the disease varies by region. Women with more schooling are more likely to contract HIV than women without any instruction or just a preschool education. HIV disease is more likely to occur in women who have had more than one sexual partner and who had their first sexual experience at a younger age. The findings of this study suggest that the government should provide more assistance and focus on regions with high rates of HIV/AIDS infection. Furthermore, prevention efforts should concentrate on gatherings with high risks, especially in urban areas and among women with a low level of education.


Cerebral small vessel disease (CSVD) is prevalent in the elderly and leads to an increased risk of cognitive impairment and dementia. The volume of white matter hyperintensities (WMHs) increases with age, which affects cognition.To explore the relationship between WMH volume and cognitive decline in patients with CSVD.We performed a systematic search of PubMed, Embase, and the Web of Science databases from their respective creation dates to the 5 May 2022 to identify all the clinical studies on either mild cognitive impairment (MCI) or dementia in regards to WMH volume in CSVD.n = 2,278) and a 49% increased risk  of progression to dementia . In a subgroup analysis, a follow-up period of over 5 years increased the risk of MCI by 40%  and dementia by 48% .White matter hyperintensities was associated with the risk of both the MCI and dementia, with a 35% increased risk  of progression from cognitively unimpaired (CU) to MCI (six studies, White matter hyperintensities was found to be substantially correlated with the risk of cognitive impairment. Furthermore, cognitive decline was found to be a chronic process, such that WMH predicted the rate of cognitive decline in CSVD beyond 5 years. The cognitive decline observed in patients with WMH may, therefore, be minimized by early intervention. Cerebrovascular small vessel disease (CSVD) is an age-related microvascular disease affecting the cerebral small arteries, small veins, and capillaries. The incidence of CSVD is related to the slow accumulation of tissue damage, which primarily manifests as static focal cerebrovascular diseases such as static lacunar infarction (LI), cerebral microbleeds (CMBs), local leukoaraiosis, and progressive cognitive dysfunction . We analyzed data from 14 studies on the impact of brain WMH volume on the risk of cognitive impairment to investigate whether there exists a link between WMH volume and cognitive impairment in CSVD.This meta-analysis was conducted on literature obtained from the databases such as PubMed, Embase, and the Web of Science. To assess the interactions between WMH volume and cognition, the literature search was conducted using the keywords such as “cognition,” “dementias,” and “mild cognitive impairment” in combination with either “white matter hyperintensities volume” or “WMH.” We searched all the entries published up until 5 May 2022. All the searches were conducted by combining the Medical Subject Headings (MeSHs) terms and free text. We also screened any relevant references, including related review articles that were referred to in each publication.We included both the observational cohort and case–control studies. The included studies determined brain WMH by MRI and white matter hyperintensity volume was calculated by FSL, MATLAB, or other computer segmentation software. Patients were diagnosed as either cognitively unimpaired (CU) or mild cognitive impairment (MCI) based on both the clinical assessment of their functional status in daily life and neuropsychological testing. Participants were excluded if they had a history of dementia, stroke, or other neurological problems. For the analysis of the prevalence of cognitive impairment and dementia in patients with a high white matter signal in the context of CSVD, articles with unclear baseline cognitive levels, i.e., studies without a clear “CU” or “MCI” at baseline, were excluded. There were no differences in either the gender distribution or education level between groups. Reported odds ratios (ORs), relative risks (RRs), and hazard ratios (HRs) were covered, and literature containing only the correlation coefficient values β and SE was excluded. Additionally, this study excluded case reports, cross-sectional studies, animal studies, and reviews that did not contain the original data.The following data were extracted: authors, year of publication, sample size, study design, duration of follow-up, patient source, outcome measures, odds ratio (OR), relative risk (RR), hazards ratio (HR), and primary data. Effect estimates adjusted for covariates such as age, sex, and education were analyzed. If no OR, RR, or HR was reported, they were calculated from the original data. Studies were excluded if neither the raw data nor the OR/RR/HR was provided.Q statistic [a P-value assessed using I2 ]. If there was little evidence of heterogeneity between studies , the fixed effects models were used to pool effect estimates. If there was heterogeneity between studies, we used the random effects models and probed for sources of heterogeneity through sensitivity analysis. Subgroup analyses were performed in accordance with the baseline cognitive level of subjects and their follow-up progression of cognitive impairment. We assessed publication bias using Egger's test. If statistically significant publication bias was found, the “trim-and-fill” method was utilized to adjust for the bias. The methods and results reported in this meta-analysis have been based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)   Stang,  was usedA total of 6,177 literature entries from PubMed, Embase, and the Web of Science were retrieved. A total of 134 reports remained after the initial screening by removing duplicate literature items, old literature, reviews, animal experiments, etc., that failed to meet the inclusion criteria. Finally, leaving 14 items of literature are to be included for full-text reading and analysis . Six of A total of 10,444 enrolled patients participated. It was determined that 999 of the 10,444 (10%) participants developed a change in their cognitive diagnosis from baseline to follow-up. Of these patients, 7,474 patients were CU at baseline, 367 patients were patients with MCI, and 2,603 patients were CU- and MCI-promiscuous enrollees. Among them, 335 (4.48%) participants had incident MCI, while 368 (4.92%) participants had incident dementia , the latter of which was comprised of 189 patients with CU, 103 patients with MCI, and 76 patients with CU + MCI.The 14 cognition-related studies differed in their approaches used for cognitive testing. Nine studies used the Mini-Mental State Examination (MMSE), while four studies applied the Clinical Dementia Rating CDR; . CognitiAccording to the time of follow-up, we divided the included literature into two subgroups: more than 5 years and <5 years . StudiesP = 0.009], and that of dementia was 32% greater  increased risk of progression from CU to MCI and risk of dementia by 49% , but no increased risk of progression of dementia in patients with MCI  and dementia by 48% . No association between MCI and dementia progression was observed in subgroups with less than a 5-year period of follow-up [MCI: RR = 1.03; (95% CI: 0.99–1.06); dementia: RR = 1.08; (95% CI: 0.92–1.28); t = 6.94, df = 16, P-value < 0.0001). This was corrected by using the “trim-and-fill” method  because they have different clinical pathogenesis. Additionally, different methods used for reporting results were utilized between studies; some studies provided raw data from which OR, RR, or HR could be calculated, while other studies provided adjusted or unadjusted OR/RR/HR or other forms of statistical measurements. This variability created analytical compatibility issues and prevented some studies from being enrolled in the analysis due to a lack of obtainable data. Additionally, some studies controlled for covariates, while other studies that performed multivariate analyses differed in the covariates included, thus affecting this meta-analysis. Moreover, patients with other imaging markers of CSVD and WMH should be examined separately to determine their respective specific impacts on cognitive changes. This meta-analysis suggests that WMH volume increases the likelihood of cognitive alterations. However, heterogeneity between the included studies and patient populations, the small number of studies analyzed, and the differences in measurement methods prevent any conclusive conclusions from being established.This meta-analysis quantified a positive correlation between the WMH volume of CSVD and decreased cognition. WMH appears to increase the risk of cognitive impairment in patients with CSVD, and the cognitive decline is a chronic process, whereby WMH predicted the rate of cognitive decline in CSVD for at least 5 years. The results of this meta-analysis suggest that early intervention may prevent or delay the onset of clinical dementia, and minimize cognitive decline for at-risk patients with WMH.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.WG drew up the protocol, performed the search, extracted the data, did the meta-analysis, and drafted the manuscript. JS participated in data extraction, checking, editing and looking overall responsibility for the article, and supervised the management. All the authors were reviewed before the submission of the manuscript.This study was supported in part by the National Key Research and Development Program of China (Grant No. 2018YFC1704100), the National Natural Science Foundation of China (Grant No. 82074362), and the Fundamental Research Funds for the Central Universities (Grant No. 2019-JYB-TD-007).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Many observational studies have shown that obesity strongly affects skin and soft tissue infections (SSTIs). However, whether a causal genetic relationship exists between obesity and SSTIs is unclear.2 statistic, and horizontal pleiotropy was tested using the MR−Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO).A two-sample Mendelian randomization (MR) study was used to explore whether obesity is causally associated with SSTIs using a publicly released genome-wide association study (GWAS). An inverse-variance weighted (IVW) analysis was used as the primary analysis, and the results are reported as the odds ratios (ORs). Heterogeneity was tested using Cochran’s Q test and the IP= 5.86 × 10-18). After adjusting for the effect of type 2 diabetes (T2D) and peripheral vascular disease (PVD), the positive effect still existed. Then, we further assessed the effect of BMI on different types of SSTIs. The results showed that BMI caused an increased risk of impetigo, cutaneous abscess, furuncle and carbuncle, cellulitis, pilonidal cyst, and other local infections of skin and subcutaneous tissues, except for acute lymphadenitis. However, the associations disappeared after adjusting for the effect of T2D and PVD, and the associations between BMI and impetigo or cellulitis disappeared. Finally, we assessed the effects of several obesity-related characteristics on SSTIs. Waist circumference, hip circumference, body fat percentage, and whole-body fat mass, excluding waist-to-hip ratio, had a causal effect on an increased risk of SSTIs. However, the associations disappeared after adjusting for the effect of BMI.The results of the MR analysis showed a positive effect of BMI on SSTIs (OR 1.544, 95% CI 1.399-1.704, This study found that obesity had a positive causal effect on SSTIs. Reasonable weight control is a possible way to reduce the occurrence of SSTIs, especially in patients undergoing surgery. Obesity is an excess of body fat that is detrimental to health and is often assessed clinically by the body mass index (BMI) . ObesityA cohort study involving 171,322 adults from 2011 to 2016 found that increased BMI was associated with an increased risk of cellulitis and hospitalization for cellulitis, and that obesity was an independent risk factor for cellulitis, after adjusting for confounders . HoweverGenetic epidemiology is used to elucidate the determinants of disease because the inheritance of genetic variants is random and cannot be confounded by additional risk factors , 18. Menvia exposure factors  data were used to determine the causal relationship between obesity and SSTIs. Single nucleotide polymorphisms (SNPs) were instrumental variables for obesity. The BMI is often used to measure and assess obesity in the clinical practice . In addi factors Figure 1https://gwas.mrcieu.ac.uk/), which consists mainly of GWAS data that are currently publicly available for use in Mendelian randomization analyses  were obtained from the MRC IEU OpenGWAS database   . Finally2<0.001) .F statistic of each SNP as follows: F=R2×(N-2)/(1-R2) /(1-R2) . R2 deno)/(1-R2) . IVs wit)/(1-R2) .The inverse variance weighted (IVW) method was used as the main method to analyze the causal relationship between obesity and SSTIs. The causal effect of each SNP on the outcome was assessed by calculating the Wald ratio of each SNP, and the inverse variance of the SNP was used as the weight in a meta-analysis to evaluate the combined causal effect. In addition, we used MR−Egger, weighted median, sample mode, and weighted mode to assess the causal relationship between BMI and SSTIs. MR−Egger has low statistical power; thus, the focus is more on direction and effect , 33. The2 statistic to assess heterogeneity among the SNPs and the MR−Egger method to test for horizontal pleiotropy. In addition, the MR pleiotropy residual sum and outlier (MR-PRESSO) method was used to detect outliers in the analysis and assess the adjusted causal effects after excluding the outliers  software with the R packages “two-sample MR” and “MRPRESSO”. P= 5.86 × 10-18). The MR−Egger method  and weighted median  also showed consistent results. In the above analysis, Cochran’s Q and I2 tests did not detect heterogeneity, and the MR−Egger test did not detect horizontal pleiotropy . After adjusting for PVD, BMI was also causally associated with an increased risk of SSTIs . Finally, after we adjusted for T2D and PVD, an increase in BMI was still positively associated with an increased risk of SSTIs .Next, we assessed the effect of an adjusted BMI on SSTIs after excluding T2D and PVD, which often coexist with obesity Figure 2Finally, we also explored whether SSTIs had a causal effect on the BMI. The results of the IVW method showed no effect of SSTIs on the BMI. Due to the presence of heterogeneity . The resWe performed a stratified analysis of different types of SSTIs (according to ICD-Tenth Revision) to further assess the effect of BMI on different types of SSTIs Figure 3We investigated whether obesity-related characteristics  had a causal effect on SSTIs. The univariate MR analysis showed that the obesity-related characteristics of WC, HC, BF, and FM, excluding WHR, had a causal effect on the increased risk of SSTIs Figure 4Many previous clinical studies have noted that obesity is a risk factor for a variety of diseases, including SSTIs. However, due to the limitations of previous studies, these findings may be influenced by confounding factors and reverse causality. Our study was based on MR to explore the relationship between obesity and SSTIs. The results of the study found a positive causal effect of obesity on an increased risk of SSTIs. This positive causality persisted after adjusting for the effects of T2D and PVD.Our findings suggest that obesity increases the risk of SSTIs, which is similar to the results of previous studies . This fiIn chronic inflammation, immune cells are constantly stimulated by cytokines or chemokines and are activated, eventually causing immune cell depletion . In addiObesity also affects the function of immune cells, which leads to decreased immune function and promotes the development of infections. Macrophages are key mediators of inflammation in adipose tissue and are the most abundant immune cells . In the Obesity or high-fat diets modify the composition of the gut microbiota and increase intestinal permeability, leading to the passage of bacteria and bacterial products  across the intestinal barrier into the circulation, which can activate innate immune cells and immune signaling pathways and contribute to inflammation formation , 60–63. Overall, obesity leads to immune system dysregulation, a reduced cell-mediated immune response, and modified gut microbiota, representing possible reasons for the increased risk of infection associated with obesity , 71–73. We performed a stratified analysis of the types of SSTIs, and the findings showed that an increased BMI was positively associated with an increased risk of impetigo, CA-F-C, cellulitis, PC, and other local infections of skin and subcutaneous tissues. However, after adjusting for T2D and PVD, an increased BMI was not significantly associated with the development of cellulitis, which may be due to obesity-induced elevated blood glucose due to insulin resistance and PVD to further mediate the development of cellulitis , 77. In In addition, this study evaluated the relationship between several other obesity-related characteristics and the risk of SSTIs. Previous studies have found that obesity characteristics, such as WC and BF, are predictors of infection , 79. In To the best of our knowledge, this study is the first to use a two-sample MR analysis to assess the causal relationship between obesity and SSTIs. In addition, the genetic variants used as IVs were extracted from the largest GWAS. However, there are some limitations to this study. 1). The MR analysis conducted in this study was based on a European cohort, and whether there is a demographic effect on the results is unclear. 2). The genetic data of exposure and outcome were pooled data from a GWAS, and relevant data, such as disease prevalence and age specificity, are lacking. 3). This study focuses on the causal relationship between obesity and SSTIs, but whether a causal relationship exists between weight loss and SSTIs is unclear.This study shows that a positive causal relationship exists between a genetically predicted increase in BMI and an increased risk of SSTIs, further deepening our understanding of obesity causing SSTIs and providing guidance for prevention and treatment.https://gwas.mrcieu.ac.uk/datasets/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: HH and ML performed the study and wrote the manuscript. XW and HL revised the manuscript. JM wrote sections of the manuscript and performed the statistical analysis. GC designed the study. All authors contributed to the article and approved the submitted version.


Data were collected among 752 social service workers in Poland. Structural equation modeling confirmed a slightly different effects of challenge and hindrance stressors (T1) on the two components of job burnout (T2) and depression (T2). Hindrance  stressors were related to high depression. Hindrance stressors intensified exhaustion and disengagement from work, while challenge stressors were only associated with high exhaustion. Exhaustion (but not disengagement from work) was related to depression. These findings support the mediation function of burnout in the health impairment process but only in relation to exhaustion. They also showed that the challenge–hindrance distinction is justified also in the JD-R model. The implications for theory and research on the mental health of employees, as well as for human management practice are discussed.The aim of the study was to better understand the health impairment process, postulated by Job Demands-Resources (JD-R) model. Previous studies on the process have not clearly explained which types of job demands  lead to depression and which burnout component (exhaustion or disengagement from work) mediates job demands—depression link. The direct and indirect (mediated  Depression is cited as one of the main causes of low work ability, with costs borne not only by the employees, but also by the organizations and society as a whole , 2. Studvia work engagement. According to the second ones, known as the health impairment process, prolonged job demands result in depleting job resources and job burnout, which in the long run leads to depression (The Job Demand-Resources (JD-R) theory attempts to explain these mechanisms by referring to the intermediary function of job burnout, perceived as a long-term effect of chronic work-related stress caused by excessive job demands . In thispression . The heapression –21, howepression , 23, litpression , 18, 24.One of the most interesting proposals of the typology of stressors in the work environment is offered by the Challenge-Hindrance Stress model . It posivia two components of job burnout—exhaustion and disengagement from work) effects of challenge and hindrance stressors on depression in employees involved in human service work in Poland. Many studies have documented that the risk of job burnout (and depression as its consequences) is particularly high among human service workers, whose work consists in establishing close relationships with other people based on providing help—e.g., doctors, nurses, caretakers or teachers  or the Canadian National Population Health Survey. In these projects, depression was diagnosed on the basis of both the subjective assessment of the participants and the opinion of specialist clinicians.The results of studies on the direct relations between psychosocial risks at work and depression are not consistent. A significant number of cross-sectional studies shows positive connections , 38, 39,day-to-day stress and low social support to be associated with depression, when measured after 1 year  enabled the prediction of the occurrence of depression after 2 years . Similarr 1 year . In the The JD-R model assumes that job burnout mediates the relationship between job demands and depression . In explSeveral cross-sectional , 46, 47 per se , but differently with motivation (β = 0.22 and −0.19), and performance (β = 0.21 and −0.27). In another ones (β = 0.10 and 0.25), however work engagement was related to higher level of CS and lower level of HS (β = 0.21 and −0.19). Similar regularities were observed by Podsakoff , commitment , turnover intentions , turnover , and withdrawal behaviors . In a more recent meta-analysis of 31 studies, Mazzola and Disselhorst  relationships with high exhaustion, they have differing relationships with cynicism and inefficacy . While tIn addition, previous studies have tested a single types of hindrance and challenge stressors. Therefore, based on the typology proposed by Cavanauugh , two aggH1: Depression is positively related to both of hindrance (H1a) and challenge (H1b) stressors.H2: Exhaustion mediates the effects of hindrance (H2a) and challenge (H2b) stressors on depression. Hindrance and challenge stressors lead to an increase in exhaustion, which in turn is related to higher depression.H3: Disengagement from work mediates the effects of hindrance and challenge stressors on depression in different way. Hindrance stressors lead to an increase in disengagement from work (H3a), which in turn is related to lower depression. Challenge stressors lead to a decrease (H3b) in disengagement from work, which is related to lower depression.(N = 752) were employees belonging to three occupational groups from the social service area: (1) teachers in juvenile correctional facilities and juvenile shelters (n = 236), personnel of social welfare homes for the chronically mentally ill, mentally disabled children and youth (n = 297), and medical personnel of psychiatric and addiction treatment wards for children and youth (n = 219). The selection criterion for the groups listed above was that the nature of the work consisted in direct and intense contact with other people, with the aim to deliver assistance in various options: saving life and health, and constant care for the sick or individuals experiencing social problems or in conflict with the law. A systematic reviews support that human service workers are very often subjected to the wide array of work stressors, which might even cause impairment in mental health, such as burnout and depression . One-way between subjects ANOVA showed no significant differences in the distribution of age, F = 2.53, p = 0.081, and the length of service in the three analyzed occupational groups F = 1.54, p = 0.215. The sample size was predetermined based on requirement of at least 200 participants for any structural equation modeling (SEM) analysis as minimum  and September–November 2018 (Time 2) by trained interviewers , at the premises of the facilities where the respondents worked. Respondents received financial rewards for participating in the research. Each participant was treated in accordance with the ethical guideline of the Helsinki Declaration. They received a hard copy of the questionnaires together with a letter explaining the aim of the study. Confidentiality of data and anonymity were provided. Participants were asked to reply to questionnaires and then to seal the questionnaires in envelopes which were then collected by the interviewers. In order to be able to match individual participants in both waves of the study, they received anonymizing identification codes. Out of 1,000 distributed questionnaires 751 (75%) returned in the first wave and 601 of them returned in the second wave of study . They were included in the data analysis. The final sample consisted of 486 women (81%) and 115 men (18%) aged 20–77 years . Work experience ranged from 1 to 47 years , values above 0.95 for CFI, values below 0.06–0.08 for RMSEA, values <0.06–0.08 for SRMR, and above 0.05 for PClose  was carried out. In the case of aggregated indices , their factor structure was also checked. The CFA was intended to confirm that the analyzed items related to job demands contain two factors: (1) challenge stressors including cognitive demands, emotional demands and quantitative demands, and (2) hindrance stressors including role conflict, low role clarity and job insecurity. Whenever it was necessary we were inspecting more closely modification indices in order to look for possible avenues of models' improvement . However, the main aim was to examine the models' fit without necessity to interfere with the scale structure . The model fit was assessed in regard to commonly used and accepted criteria. For example, by excellent parameters we considered the values between 1.00 and 3.00 for CMIN , hindrance stressors T1 , job burnout T2  and depression T2 were introduced into the model. The following were tested: (1) direct effects of CS/HS on depression; (2) indirect effects of JB on CS/HS—depression link.At first, we tested whether hindrance stressors and challenge stressors had a postulated structure. For example, we have examined whether hindrance stressors have a hierarchical structure consisting of three factors and whether the statements included in these three factors have a sufficient empirical basis to be gathered into one general index. In order to do so, we conducted a series of second-order confirmatory factor analysis (CFA). The results are presented in 2/df), values above 0.95 for CFI, values below 0.06–0.08 for RMSEA, values <0.06–0.08 for SRMR, and above 0.05 for PClose  and were high enough (above 0.32), according to the criteria proposed by Fidell and Tabachnick , p = 0.001]. The mediation of HS via disengagement from work was not statistically significant . The total effect of HS on depression, however, was significant: higher levels of HS were related to higher levels of depression (this confirms H1a), and higher HS were also related to higher levels of disengagement from work, but there was no significant relationship between disengagement from work and depression. These results correspond with the correlational matrix , and exhaustion was related to depression, but the total effect of CS on depression was not statistically significant (this does not confirm H1b). There was no mediational effect of disengagement from work in the CS—depression link (this does not confirm H3b), ab = 0.00, BCa 95% CI , p = 0.644. CS does not relate to high disengagement from work, and this, in turn, does not promote depression. Overall, the results support H1 partly and H2 partly, while H3 was not confirmed.Exhaustion was a significant and a full mediator of the relationship between CS and depression, The aim of the presented 1-year prospective study was to better understand the health impairment process, postulated by JD-R model . In linevia exhaustion and disengagement from work, but in different way. Specifically, while HS would lead to higher exhaustion and higher disengagement from work, CS would be related to higher exhaustion and lower disengagement. Depression, in turn will be associated with high exhaustion and low disengagement from work. The obtained results supported both the total effect of HS on depression with higher levels of HS related to higher levels of depression and different functions of the two job burnout components. We found that exhaustion (contrary to disengagement) mediates the undesirable impact of HS and CS on depressive symptoms. Although HS led to high disengagement from work, there was no relationship between disengagement and depression. These findings support health impairment process, postulated by JD-R model  and withdrawal  may be ways to conserve or rebuild stress-depleted job resources , 51 and The obtained research results only partially confirmed the different effects of HS and CS on the two components of job burnout. As expected, employees who experienced the high level of HS felt more exhausted and less engaged with the job after a year. However, it turned out that CS also leads to negative outcomes, admittedly only in relation to exhaustion (but not to disengagement from work). It can therefore be concluded that both stressors are job characteristics which in long run consume resources and therefore may be the source of exhaustion, however, CS other than HS also allow for potential resource gains, personal development and may keep engagement . The obtThe authors of the presented research are aware of some of its limitations. Although, on the basis of the results of prospective studies with double measurement of variables, one can conclude about the order of occurrence of the studied phenomena (and thus the direction of the relationship between the studied variables), it is not justified to draw conclusions about the cause-effect relationships . This reA polemical issue may be the arbitrariness of classifying stressors as challenge and hindrance, in our study. While building the aggregated indicators of challenge and hindrance stressors, we were guided by theoretical premises , howeverIn future studies, it would be worth investigating the role of personal and job resources. The authors of the JD-R model strongly emphasize the role of job resources as factors that may reduce job demands , are functional in achieving work goals, and stimulate personal growth, learning and development . TherefoOur results yield some practical implications for fostering employee's wellbeing in organization. With growing number of empirical evidence about benefits from investing in workers' happiness  it seemsSome practical remarks can also be made regarding challenge stressors, although they were not related to the level of depressive symptoms and to disengagement, the were associated with exhaustion. This implies that as long as the work requires high cognitive and emotional engagement it can potentially lead to depletion of resources and can be harmful to wellbeing , 23. TheThis 1-year prospective study has confirmed in part the health impairment process, postulated by JD-R and justified the distinction of stressors into challenge and hindrance. It found that the two groups of stressors had different impact both on depression and job burnout. Hindrance stressors  had the direct impact on depression. This direct effect was mediated by job burnout, but only in relation to exhaustion (not disengagement from work). Disengagement from work was not associated with depression. Although both types of stressors were related to higher exhaustion, only HS was related to disengagement from work. These findings are consistent with job stress models and some results of meta-analytical studies, in general.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.LB: conceptualization, methodology, investigation, resources, writing—original draft, supervision, and project administration. MP: methodology, investigation, formal analysis, resources, and writing—original draft. DJ: methodology, investigation, data curation, writing—original draft, and visualization. All authors contributed to the article and approved the submitted version.


Frailty index and vestibular disorders appear to be associated in observational studies, but causality of the association remains unclear.n = 175, 226), whereas the GWAS of vestibular disorders was the outcome . MR Steiger filtering method was conducted to investigate the causal effect of the frailty index on vestibular disorders. An inverse variance weighted (IVW) approach was used as the essential approach to examine the causality. Additionally, the MR-Egger methods, the simple mode analysis, the weighted median analysis, and the weighted mode analysis were used as supplementary methods. The MR-PRESSO analysis, the MR-Egger intercept analysis, and Cochran's Q statistical analysis also were used to detect the possible heterogeneity as well as directional pleiotropy. To evaluate this association, the odds ratio (OR) with 95% confidence intervals (CIs) was used. All statistical analyses were performed in R. The STROBE-MR checklist for the reporting of MR studies was used in this study.A two-sample Mendelian randomization (MR) study was implemented to explore the causal relationship between the frailty index and vestibular disorders in individuals of European descent. A genome-wide association study (GWAS) of frailty index was used as the exposure .In total, 14 single nucleotide polymorphisms (SNPs) were identified as effective instrumental variables (IVs) in the two sample MR analyses. The significant causal effect of the frailty index on vestibular disorders was demonstrated by IVW method [OR 1.008 , The MR study suggested that genetically predicted frailty index may be associated with an increased risk of vestibular disorders. Notably, considering the limitations of this study, the causal effects between frailty index and vestibular disorders need further investigation. These results support the importance of effectively managing frailty which may minimize vestibular disorders and improve the quality of life for those with vestibular disorders. In MR, genetic variants are used as instrumental variables (IVs) for assessing the causal effect between exposure and outcome. With MR, genotypes can be unbiasedly estimated as they are determined at conception and they are generally not confounded by other factors such as reverse causation . A detailed description of the exposures and outcomes of the GWAS used in the MR study can be found in The general design of this MR research can be found in https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90020053/). Notably, Atkins et al.  and Swedish Twin Gene participants . For UK Biobank and Twin Gene, frailty indexes were calculated using 49 or 44 self-reported items on symptoms, disabilities, and diagnosed diseases. The 49 self-reported baseline data variables were used to calculate the frailty index for UK Biobank. Physiological and mental health variables, including symptoms, disabilities, and diagnosed diseases, were reported by participants at baseline (see p < 5*10−8).The GWAS involving 175, 226 European ancestry individuals were used to generate the exposure dataset for frailty index. . The GWAS summary data for vestibular disorders was obtained from the MRC-IEU Open GWAS data infrastructure, available through the UK Biobank  of European ancestry   for frailty index were identified as IVs. Then, independent variants were identified using a clumping procedure implemented in R software, in which a linkage-disequilibrium threshold of r2 < 0.001 within a 10,000 kb window in the European 1,000 Genomes Project Phase 3 reference panel was set  and F statistic parameters to determine whether the identified IVs were powerful enough. Generally, IVs (SNPs) with F-statistic parameters <10 are considered weak instruments  IVs must be relevant to exposure ; (2) IVs must be independent of any confounding factor; and (3) IVs are associated with outcome  only p < 0.05 with two-tailed tests. An FDR correction based on Benjamini-Hochberg was implemented to correct for multiple comparisons . There were 14 SNPs involved in our analyses, as shown in p = 0.001] (shown in p = 0.466), suggesting a low level of heterogeneity and relative reliability of the causal effect. Additionally, weighted median analysis , simple mode analysis , weighted mode analysis , and MR-Egger analysis  also indicated comparable results (p = 0.544] (shown in p = 0.491). Based on the funnel plot results (shown in p < 0.001). The estimated causal effect of frailty index on vestibular disorders may be still significant after adjustment for BMI , CRP , IBD  and smoking  , shown in , 3. For  results . MR anal results . The horshown in . Furthershown in , there wshown in , 6. As aBased on the summary level data from large GWAS, we implemented the two-sample MR study with the purpose of investigating the causal association between frailty index and vestibular disorders. We found a causality between genetically predicted frailty index and vestibular disorders in our analysis. The sensitivity analyses showed consistent estimates, indicating that there was minimal horizontal pleiotropy and the association was robust. According to our knowledge, this is the first MR study to evaluate the potential causality of frailty index and vestibular disorders.Vestibular disorders are mainly characterized by dysfunction of the vestibular system, involving body posture and motion perception, eye movement control, posture, gait, and spatial positioning. According to the proposed structure of the international classification of vestibular disorders (ICVD), there are four layers about vestibular disorders: symptoms and signs; clinical syndromes; diseases/disorders; and pathophysiologic mechanisms. Four categories of vestibular symptoms are described by the ICVD: vertigo, dizziness, vestibulovisual symptoms, and postural symptoms  systems  was not evaluated in this study. The fourth limitation is that the GWAS data were compiled for individuals of European descent, which means that the population at large might not be fully represented by our results. Fifth, the two GWAS datasets are from European populations, there will be an overlap of samples. Over-fitting and instrument bias become more pronounced as overlap between samples increases, similar to those observed in one-sample MR. Last, the two European samples could differ substantially according to population characteristics such as socio-economic background, which also could affect the interpretation of causal estimates.In our study, we found that vestibular disorders may be causally related to frailty index. Notably, considering the limitations of this study, the causal effects between frailty index and vestibular disorders need further investigation. These results support the importance of effectively managing frailty which may minimize vestibular disorders and improve the quality of life for those with vestibular disorders.The original contributions presented in the study are included in the article/GX and CQ conceptualized and designed the study. GX, HW, and JH prepared and analyzed the data and drafted the manuscript. LL, TZ, MZ, and XL contributed to interpretation and editing of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (Grant Number 72074225), the Philosophy and Social Science Foundation of Hunan Province (Grant Number 19YBA351), and the Key R&D Plan of Hunan Province (Grant Number 2020SK2089). The funding sources played no role in conducting the research and preparing the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.