This study explores the social network types of older Korean men and women, and the relationship of those networks to depressive symptoms. A population of 4608 older adults who participated in the Living Profiles of Older People Survey (LPOPS) were included in the study. Seven criterion variables—marital status, living arrangements, frequency of contact with children, close friends, and close relatives, participation in social activities, and total network size—were included in a K-means cluster analysis. Multivariable logistic regression analysis of the impact of social network type on depressive symptoms was conducted. We identified two “diverse type” social networks (diverse-married and diverse-unmarried) in women, and one diverse type and one “social-activity-focused type” network in men. Family focused type and two “restricted type” social networks  were identified in both men and women. The restricted-unmarried and restricted-couple-focused networks were associated with more depressive symptoms in both men and women. However, the family focused type was associated with more depressive symptoms only in women. The results indicated that social network types, and their impact on depressive symptoms, differ by gender. There is a need for further research on gender differences in the social network types of older adults across diverse cultures. A social network can be conceived of as a web of social relationships  allowingIndividuals are embedded within social networks ; this haPark et al.  found twThe gendered nature of social roles influences social network characteristics such as relationship with children, friends, and relatives, social participation, and so on. Women tend to have more sources of support, such as children, friends, and neighbors, and to benefit more from them. Women generally take the lead in child-rearing, which is associated with participation in new types of social networks centered around childcare facilities, playgroups, and other informal associations. Thus, women tend to maintain social ties and friendships in their later years. Older women living alone are not at risk for increased mental health or for isolation from social network and social engagement when there are no financial difficulties ,17. In cBased on evidence from the Western and Asian countries, we could infer that social network types and the relationship between mental health and social networks differs according to cultural values, social circumstances, and gender. However, to our knowledge, little research has been conducted on social network types and its impact on mental health by gender among older adults in South Korea. Therefore, the current study investigated this issue in a large, nationally representative sample of older Koreans. We hypothesized that social network types would differ by gender, as would their association with mental health. The goal was to improve our understanding of the link between social network types and mental health in old age.n = 216) were excluded. This was due to concerns that mobility and cognitive function may influence the ability to maintain social networks [Data from the Living Profiles of Older People Survey (LPOPS), conducted by the Korean Ministry of Health and Welfare in 2017, were analyzed in this study. The LPOPS used a two-stage stratified cluster sampling method; older residents were selected from households in 25 metropolitans and provincial  regions. After receiving approval, trained research staff visited participants in their homes and obtained informed consent. A total of 10,299 participants completed in-person interviews. Older adults with cognitive impairment (1394 men and 3316 women), physical dependence (733 men and 2169 women), or interviews completed by proxy  was used to measure depressive symptoms. The SGDS was developed by Yesavage and Sheik  and tranSocioeconomic and health variables were the covariates in this study. The socioeconomic variables included age, education level, and equivalent household income, while SRH was the health variable. Education level was classified as elementary school or below, middle school, high school, and college or above. Equivalent household income was calculated as the total household income divided by the square root of the number of household members. These scores were then divided into tertiles. Self-rated health (SRH) was measured with a single question “How would you rate your health in general?”  and then coded dichotomously .K-means cluster analysis) were applied to the network types of men and women. Seven criterion variables were used in cluster analysis: marital status, living arrangements, frequency of contact with children, close friends, and close relatives, participation in social activities, and total network size. Before cluster analysis, the criterion variables were standardized to rule out any effect of the use of different scales [K-means cluster analysis was performed. In this analysis, initial cluster centers are assigned to each of the criterion variables, and the iteration of cluster centers is repeated until the prescribed number of optimal clusters is achieved based on distances between these cluster centers. After network clusters were derived, the distribution of criterion variables across clusters was assessed to determine the differences among the clusters and evaluate the validity of them [Distributions and descriptive statistics were calculated for socioeconomic and health variables, as well as the variables used to distinguish network types. Two clustering techniques , but other variables were uncorrelated.n = 190) were in a diverse network, which was thus the least prevalent of the five network types. In total, 22.7% of men (n = 542) were in a social-activity-focused network. Individuals in this group had the highest frequency of participation in social activities. The frequency of contact with close friends was moderate, while that with children and close relatives was low. The total network size of these individuals was smaller than that of the other men. These individuals were typically married (97.4%), and few lived alone (0.6%). In total, 32.0% of the men (n = 762) were in a family focused network, making it the dominant network type in Korean older men of this study. The majority of these individuals were married (96.7%) and none lived alone. The individuals in this type of network had the most contact with their children and close relatives, although their level of participation in social activities was low.The social network types of the older men were classified as diverse, social-activity-focused, or family focused, and there were also two restricted network subtypes: restricted-couple-focused and restricted-unmarried. The diverse network type was dominant in the total network size and the frequency of contacts with close friends. Individuals in this group engaged in a moderate amount of social activity and had relatively frequent contact with close relatives and children. The majority of individuals in this type of network were married (93.7%), and few lived alone (3.7%). Only 8.0% of the men (n = 654) of the men were in a restricted-couple-focused network, making it the second most common network type, none of whom in this group lived alone. Individuals in a restricted-couple network were in moderately frequent contact with their children, but had the least contact with close friends and relatives, and the lowest level of participation in social activities and total network size. In total, 9.9% (n = 236) of the men were in a restricted-unmarried network; 93.2% of these men lived alone and 95.3% were unmarried. They had the least amount of contact with their children and, similar to those in a restricted-couple-focused network, also exhibited low scores for frequency of contact with close friends and relatives and frequency of participation in social activities. However, the individuals in the former type of network tended to have more social contact overall, except with their children than in a restricted-couple-focused type.In total, 27.4% , a family focused and two restricted subtypes .n = 310) of the women were in a diverse-married type network. The majority of the individuals in this type of network were married (96.1%) and a few lived alone (0.3%). They had the most contact with close friends and relatives, the highest rate of participation in social activities, and the largest total network size; the frequency of contact with children was also high. In total, 12.8% (n = 285) of the women were in a diverse-unmarried network, and 99.3% of women lived alone. The frequency of participation in social activities among the women in a diverse-unmarried network was as high as that of those in a diverse-married network. The frequency of contact with close friends and relatives was relatively high among individuals in the former type of network, but the frequency of contact with children was as low as that of individuals in a restricted-couple-focused network. The total network size (7.08 ± 3.09) of the women in a diverse-unmarried network was smaller only than that of those in a diverse-married network (9.47 ± 2.86), and thus was also higher than the average among females (5.75 ± 2.88).In total, 13.9% (n = 427) of the women were in a family focused network; all of these women were married and lived with others, and their frequency of contact with children was highest among the network types. Most of these individuals lived with adult children (99.8%). However, aside from frequency of contact with children, these women tended to have less social contact overall than those in other network types.In total, 19.2% (n = 826). Women in this type of network had low scores for frequency of contact with children, close friends, and relatives, and for participation in social activities. The total network size was also below average. The restricted-unmarried network type was the least well-represented among the women . All individuals in this type of network were unmarried and most of them lived alone (98.1%); they also had the lowest scores for contact with children, close friends, and relatives, and participation in social activities.The restricted-couple-focused network was dominant among the women  and social-activity-focused (23.6%) networks had higher education (college or above); the proportion of such men was lowest for the restricted-couple-focused network type (18.6%). About fifty percent of older men in the restricted-unmarried network were included in lowest equivalent household income. More men in the restricted-couple-focused and the restricted-unmarried networks had poor SRH  than in the other network types.The proportion of women with higher education (college or above) was highest in the diverse-married type network (9.1%) and lowest in the restricted-unmarried type network (4.0%). The proportion of poor SHR (68.9%) was largest among the women in the restricted-unmarried network, and lowest among those in the diverse-married network (48.1%). Regarding equivalent household income, the proportion of women in the lowest income category was very large in the restricted-unmarried network (62.8%) and lowest in family focused network (11.5%).ß = 0.14, ß = 0.19 respectively). Restricted-couple-focused networks was significantly associated with depressive symptoms in men (ß = 0.14) and women (ß = 0.11). Family focused network was associated with depressive symptoms in women (ß = 0.14) but not in men.All of the restricted type networks were significantly associated with a higher risk of depressive symptoms in both men and women. Men and women in the restricted-unmarried networks, respectively, were more likely to experience depressive symptoms  were also most prevalent for both older men and women in Korea, which is opposite to those previously reported in other Asian countries  ,13. ThisSpecifically, we found differences in dominant network type between older men and women. The couple-focused network was dominant for older women (37.1%), while in older men, family focused type was (32.0%). Despite women’s superior ability to maintain more relationships and diverse social connections, in this study more women (54.0%) belonged to a restricted network (restricted-couple-focused or restricted-unmarried) than men . This is in line with previous Korean studies, in which men were more likely to have diverse or family centered networks ,15,38, aThe social-activity-focused network identified in this study for some of the older men is novel, and is characterized by a high level of participation in various social activities, such as education programs for seniors, volunteer work, and religious meetings. Older men in a social-activity-focused network tended to have a higher level of education (college or above) and higher economic status than those in restricted networks, including the family focused subtype. Older adults with active social lives are more likely to be male , and areConsistent with several previous studies reporting an association between limited social ties and poorer health ,14,42, tAnother interesting finding was that older women in the diverse-unmarried type network reported better mental health than those in restricted-couple-focused and family focused networks, even though they lived alone and had lower educational and income levels, as well as poorer SRH. Moreover, compared to men in the family focused network, women in the family focused network were more likely to exhibit depressive symptoms. This accords with a previous study  reportinThis study had some limitations. First, we used a cross-sectional design, so the relationship of social network type with mental health should be interpreted with caution. Longitudinal data should be analyzed to clarify this association in older adults, stratified by gender. Second, all of the criterion variables were specifically concerned with structural aspects of social relationships, although social network function and quality also contribute significantly to well-being in old age. Further studies are therefore needed. Last, we identified different network types in older men and women in this study, but did not examine the gender differences among social network types. Further research would be needed to test whether network types are different from one another across genders. Despite these limitations, our study also had some important strengths. To our knowledge, it is the first study to identify social network topologies by gender among older adults in South Korea. Network typology can be a useful and practical instrument for identifying older adults at risk in community. The findings contribute to understanding of social network types of older men and women in later life and their implications for health and wellbeing. The results suggest that there are differences in those with poor networks by gender, and interventions for them should be different by gender. Moreover, we analyzed weighted data from a nationally representative sample, ensuring the generalizability of the findings. In addition, we controlled for various factors that may influence the maintenance of social relations, such as functional limitations and cognitive impairment.This study provides evidence that social network types, and their impact on mental health, differ between men and women. Additional empirical studies conducted in other cultural settings should be performed to validate our findings.


Background/Objective: Brachial artery aneurysm (BAA) is a serious complication in patients with previous arterio-venous fistula (AVF), renal transplantation (RT), and immunosuppressive regimens. Until now, there has been no standard of care for these patients, especially for patients undergoing chronic dialysis and immunosuppressive treatment. The aim of this study was to investigate data from the literature regarding these patients and to suggest recommendations for the best approach to their treatment. Methods: A review of the literature was performed by searching the PubMed database in the English language. The review was accompanied by two case reports. A total of 24 articles with different variables—demographics, renal transplantation, aneurysm size, and type of surgery—were subjected to the review. In addition, two cases are reported. Conclusion: This review suggests that the best treatment for these patients is open surgery, with aneurysmectomy and graft interposition. Results: All patients had RT. The age of patients ranged from 26–77 yo, with a male predominance. The majority had an AVF ligated after RT. The main clinical symptoms were pain, swelling, and pulsatile mass (66%). All patients, except one, were treated through open surgery. The first option for treatment was reversed saphenous vein graft interposition (36%), followed by ePTFE graft (16%). Upper-extremity peripheral aneurysms are rare and account for less than 1% of all peripheral artery aneurysms. The brachial artery is involved around 0.5% of cases, with 0.17% being true aneurysms [Brachial artery aneurysm (BAA) in patients with previously ligated arterio-venous fistula (AVF) for hemodialysis and renal transplantation (RT) is rare and few cases are presented in the literature .The number of patients that require RT is increasing worldwide. In 2017, there were 90,306 RTs worldwide, both from live and deceased donors ,5.This complication is extremely challenging, mostly due to the general profile of the patient, especially for patients on chronic dialysis and immunosuppressive regimens.BAA is associated with rare complications, such as distal limb ischemia, aneurysm rupture, nerve compression, and upper limb swelling .In this study, we present a literature review and two case reports of BAA, with the aim of evaluating the treatment modalities used for these patients.Two cases of giant BAA in patients with chronic kidney disease (CKD) and RT are presented below. The patients treated gave their informed consent for the use of their personal data. The article has the approval of the Ethics Committee of the “Pius Brânzeu” Clinical County Emergency Hospital no. 188/4 May 2020. Both patients gave their consent for publication.A literature review was performed by searching the PubMed database. The terms used for the search were brachial artery aneurysm, AVF ligation, and RT. The search was limited to any reported cases of brachial artery aneurysm formation in patients with RT and previous AVF ligation. The reports were selected according to the PRISMA guidelines. In the end, we selected 26 articles that matched all our keywords.The variables included in our search were related to the age of the AVF at the time of ligation, the duration from the ligation until aneurysm development, the type of clinical presentation, treatment choice, and type of immunosuppressive treatment.®  at 1 g/dosage for infection prevention. An aneurysmectomy and reversed saphenous vein graft interposition, end-to-end anastomosis with 6.0 Prolene®  continuous sutures were performed under general anesthesia. The postoperative evolution was without complications  and the patient was discharged 10 days after surgery . After the RT, the AVF on the left side was closed. The patient was currently undergoing chronic RT rejection and hemodialysis three times per week. A CT-Angio of the left arm showed a brachial artery aneurysm of 12.73/7.68 cm, partially thrombosed. Aneurysm resection and vascular reconstruction with spatulated end-to-end anastomosis were performed [ surgery .®  at 1 g/dosage for infection prevention. Aneurysm resection and reconstruction with a collagen-impregnated woven nylon graft  of 10 mm in diameter and end-to-end anastomosis with 6.0 Prolene®  continuous sutures were performed under general anesthesia. This vascular graft was chosen due to the arterial diameter (more than 10 mm), arterial wall thickness (approximately 2 mm and anfractuous structure), and because the saphenous vein of the patient was not fit for the procedure . The postoperative evolution was without complications on the surgical site . A week after the vascular reconstruction, the patient developed constrictive pericarditis and needed a pericardial window. Two months after surgery, the patient developed a chronic rejection of the transplanted kidney and required nephrectomy. The status of the patient deteriorated rapidly, and he died 3 months after reconstruction . He underwent a CT-Angio investigation that showed a brachial artery aneurysm of 14.69/6.49 cm. The patient did not require hemodialysis after the investigation because the level of creatinine was constant at 4 mg/dL at 48 and 72 h after the investigation, respectively. Furthermore, for this patient, aneurysm resection and vascular reconstruction were performed. The patient received preoperatively an adjusted dose of Vancomycintruction .Both patients underwent preventive management of contrast-induced nephropathy according to the KDIGO Clinical Practice Guidelines for acute kidney injury ,9.Both patients were on a full association of antihypertensive drugs .The incision was made along the aneurysm projection to the skin. A drainage was left in place and it was removed after 24 h. The skin was closed with skin staples.After arterial reconstruction, the patients were treated with antiplatelets, aspirin (case 1) and clopidogrel (case 2) at 75 mg daily, respectively.In both patients, the one-month follow-up showed no pain or neurological deficits , and the surgical site incision healed, and the distal radial and ulnar pulses were palpable.BAA is defined as an arterial enlargement of more than 50% of the normal diameter. For the brachial artery, the normal diameter ranges from 3.5 to 4.3 mm in women and 4.1 to 4.8 mm in men, respectively .Fifty-six BAA cases were reported in the literature ,32,33,34The age of AVF was not mentioned in all cases but, when mentioned, it ranged from 12 to 354 months (with a mean age of 99.13 months). Of all AVFs, seven were not ligated, in 25 cases the duration after the ligation was not mentioned, and the mean duration of the ligation was 93 months, ranging from 6 to 252 months. The common presentation was with pain, swelling, and a pulsatile mass (66.66%—34 patients), followed by nerve compression (seven patients—13.72%), and ischemia (four patients—7.84%). It was also observed that most of the aneurysms were in the left arm, probably because the AVF was made on the non-dominant arm.The surgical conduit was as follows: reversed saphenous vein—20 patients (35.71%), ePTFE graft—eight patients (15.6%), end-to-end reconstruction—six patients (11.76%), reversed cephalic/basilic vein—eight patients (15.68%), other interventions .An immunosuppressive regimen was present in all patients, but not specified in 38 cases; other immunosuppressive regimens included methylprednisolone, azathioprine, tacrolimus, and mycophenolate mofetil.In this review, a male preponderance for BAA was found, but the reason for this is still unknown .The first physician who described a proximal dilatation after the ligation of an AVF fistula was William Hunter in 1757 .In the studied cases, there were 18 patients with reversed saphenous graft interposition (36%), eight patients with ePTFE (16%), six with end-end reconstruction (12%), four with inversed basilic veins (8%), three with inverted cephalic veins (6%), one with an allograft reconstruction, one with a cadaveric brachial artery, one with a devalvulated saphenous vein, and one with femoral artery transposition.The first case was fit for reconstruction with a saphenous vein but, in the second case, a synthetic graft was preferred because of the diameter of the artery  and because the patient did not have a suitably large saphenous vein, as seen on the ultrasound examination.Another treatment method is the endovascular approach, with the placement of a stent graft, but the risk of contrast-induced nephropathy in these patients is very high. The placement of a stent graft is a challenging technique for the treatment of a BAA. First of all, it is associated with a high risk of embolization and a superficial position of the brachial artery that can be easily compressed by extrinsic factors and arm movements  and stent damage. There is also discussion of the remnant arterial aneurysm that can compress the nervous structures of the arm, especially in case of a large aneurysm . FurtherThere are several known mechanisms that can be involved in arterial degeneration: the arterial wall stress, the long-term use of immunosuppressive agents, and the chronic inflammation caused by various factors .The stress on the arterial wall is mediated by the production of free oxygen radicals. They combine with NO, lead to the production of peroxide nitrates, and mediate vessel dilatation. Consequently, the arterial wall exceeds its adaptive capacity, thus leading to an inflammatory response which promotes smooth muscle cell differentiation, proliferation, and migration, and subsequent wall thickness .Chung et al. demonstrated that the degradation of elastic fibees extends to all layers of the arterial wall, and also stated that a longer duration of dialysis leads to a higher amount of calcium and phosphate deposition .The long-term use of immunosuppressive agents leads to vascular remodeling on each of the three layers of the artery. This phenomenon is mediated by an inflammatory process activated by cytokines ,41.There are also other mechanisms by which the arterial wall is subject to chronic inflammation: first of all, through hemodialysis itself, followed by diabetes, hyperlipidemia, arterial hypertension, infection, and repetitive trauma .®  without spiral support because we did not pass the elbow joint.This type of complication of the vascular access for hemodialysis in RT patients is a challenging one due to the patient profile, especially in relation to CKD and the immunosuppressive regimen. Considering these issues, a vein conduit is the first choice, followed by an ePTFE graft. In our case we chose DacronThe pathogenesis involved in the formation of BAA in patients with RT, immunosuppressive regimens, and AVF ligation consists of an association of arterial wall stress, the action of immunosuppression  and chronic inflammation.In patients with a giant BAA, RT, and an immunosuppressive regimen, the gold standard for aneurysm repair remains open surgery with aneurysm excision and arterial reconstruction. The role of endovascular therapy is yet to be determined.We also recommend periodic ultrasound follow-up on patients with a previous ligation of an AVF and immunosuppressive treatment in order to catch this complication in its early stages.


The hippocampus, which engages in the process of consolidating long-term memories and learning, shows active development during childhood and adolescence. The hippocampus also functionally influences attention. Based on the influence of hippocampal function on attention, it was expected that the volume of the hippocampus would be associated with the difference in attention during childhood and adolescence, in which the brain develops actively. Thus, this study examined the association between hippocampal volume and attention metrics measured by the continuous performance test (CPT) in 115 children and adolescents . In association studies with both auditory and visual attention, we found that the bilateral hippocampal volumes showed negative relationships with auditory omission errors. A smaller volume of the left hippocampus also led to a longer auditory response time. However, visual attention did not show any significant relationship with the hippocampal volume. These findings were consistent even after adjusting for the effects of the related covariates . Taken together, this study suggested that the increase in hippocampal volume during childhood and adolescence was associated significantly with better auditory attention. During childhood and adolescence, the brain develops substantially. The white matter volumes in brain regions of children and adolescents increase with their age  based on task goals. The other type of attention is reflective attention, which is also known as internal attention. Reflective attention selects, sustains, and processes the information derived from the working and the long-term memories. In other words, perceptual attention engages in the encoding stage, and reflective attention engages in the retrieval stage during the memory consolidation process. Reflective attention is involved in the memory process through processing internal representations such as thoughts and memories without corresponding external stimuli or situations, and perceptual attention is involved in the memory process by processing external sensory stimuli  is a typical disorder associated with attention, there have been inconsistencies between the findings regarding the changes in hippocampal volume in children and adolescents who were diagnosed with ADHD , this study evaluated visual attention and auditory attention, which are closer to perceptual attention. Factors that plausibly influenced hippocampal volume  were also considered.via a flier posted in schools and libraries in Seoul and Gyeonggi-do Province. Initially, a total of 150 participants were recruited  for the study. All the participants who were engaged in this study met the following criteria: (i) they were capable of understanding and following the instructions and descriptions fully in the present study; (ii) they had no possibility of pregnancy for female before the study; (iii) they were taking no medications that could significantly influence their waking and sleep conditions; and (iv) they had no predicted problems in neuroimaging and psychological tests. Participants with any clear neuropsychiatric history of psychiatric disorders , developmental disorders , learning disabilities, language impairments, uncorrected sensory impairments, neurological disorders (convulsive disorder), or acquired brain injury  were excluded from the analyses .This study was approved by the Institutional Review Board (IRB) for Human Subjects at the Seoul National University Hospital (No. C-1412-081-633) and was conducted in accordance with the 1964 Declaration of Helsinki. All the participants and their parents or legal guardians completed the written informed consent.The KEDI-WISC is a modified version of the revised Wechsler Intelligence Scale for Children .A threshold false discovery rate (FDR) = 0.2 was determined to be significant for addressing multiple comparison issues  . All the participants were assessed for IQ, CDI, ISI, and CPT, and a brain MRI was performed. Then, we measured the bilateral hippocampal volume through VBM analysis with the obtained brain images. Participants were classified by sex and age (based on 12 years), and clinical characteristics were analyzed for this study .P < 0.012). After adjusting for age, the differences in clinical characteristics between male and female were not significant except for IQ (P < 0.019), visual ATA (ATAv) (P < 0.045), and ATAv_omission errors (OE) (P < 0.008).When participants were divided by sex , the female participants showed better performance on the IQ test (n = 44), age ≥ 12 (n = 71)], the CDI score showed a high score in the age group of 12 years and older (P < 0.0001). In the auditory attention evaluation, participants above 12 years had lower results in ATAa_comission errors (CE) (P = 0.026), but had slower results in ATAa_RT (mean of response time) (P < 0.0001) than the other group. In the visual attention evaluation, participants above 12 years showed lower ATAv (P = 0.006), ATAv_OE (P < 0.0001), ATAv_CE (P = 0.03) and ATAv_Response Time variability (ATAv_RTv) scores (P = 0.007). On the contrary, the participants under 12 years had faster results in ATAv_RT (P = 0.032). After adjusting for sex, all the results were significant.When the analysis was conducted by subgrouping children and adolescents [based on 12 years, age < 12  between variables related to attention and regional GMV.Analysis of children and adolescents based on 12-year-old showed that the left hippocampal volume of participants under 12 years was negatively correlated with auditory ATA_RT score and visual ATA_detectability (d). This means that the left hippocampal volume is large and the mean response time is faster, but the detectability for visual ATA is low, which means that it is difficult to distinguish the target stimulus from the non-target stimulus.For the participants aged 12 years or older, the right hippocampal volume was negatively correlated with visual ATA_OE and showed positive correlations with visual ATA_d(detectability). The volume of the right hippocampus affects visual ATA_OE performance. The larger the right hippocampal volume is, the better the stimuli can be distinguished in the visual ATA .P = 0.6210, right HP: P = 0.4485). We represented all partial correlation values and the significant values, including both uncorrected and FDR-adjusted p-values, in The mean hippocampal volume between boys and girls was adjusted for age, TIV, and IQ. This adjustment did not change the results  and depression-related scales (CDIs) by including those covariates in the partial correlation analyses. This adjustment did not significantly change the results shown in An additional adjustment for age, which involved separate analyses of children (12-year-old or younger) and adolescents (13 years or older), also did not change the results.This study aimed to examine the association of hippocampal volume with visual and auditory attention in children and adolescents. These findings suggest that larger bilateral hippocampal volumes performed better by showing fewer omission errors in response to auditory stimuli. In addition, the larger volume in the left hippocampus responded more quickly to auditory stimuli presented in the ATA after factors that seemed to influence the volume of the hippocampus, such as sleep, depressive symptoms, age, IQ, sex, and TIV . Although female were found to show a larger volume in the hippocampus than male between the ages of 8 and 15 years , perirhinal cortex (PRc) and entorhinal cortex (ERc) in the presentation of visual stimuli, whether the hippocampus is involved in the activation of attention in response to visual stimuli is not known  for Human Subjects at Seoul National University Hospital (No. C-1412-081-633). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.M-HP designed the study and wrote the protocol. EC, HK, S-YK, YK, B-NK and SP managed the literature searches and analyses. BP and S-YK undertook the statistical analysis, and T-HK, HK, K-IJ, M-HP, and BP wrote the first draft of the manuscript. All the authors contributed to and approved the final manuscript.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.


Introduction: Measurement of reactive balance is critical for fall prevention but is severely underrepresented in the clinical setting due to the lack of valid assessments. The Stepping Threshold Test (STT) is a newly developed instrumented test for reactive balance on a movable platform, however, it has not yet been validated for fall-prone older adults. Furthermore, different schemes of observer-based evaluation seem possible. The aim of this study was to investigate validity with respect to fall risk, interpretability, and feasibility of the STT using two different evaluation strategies.Methods: This study involved 71 fall-prone older adults (aged ≥ 65) who underwent progressively increasing perturbations in four directions for the STT. Single and multiple-step thresholds for each perturbation direction were determined via two observer-based evaluation schemes, which are the 1) consideration of all steps  and 2) consideration of those steps that extend the base of support in the direction of perturbation . Established balance measures including global , proactive , and static balance , as well as fear of falling  and fall occurrence in the past year, served as reference measurements.Results: The sum scores of STT correlated moderately with the BriefBEST  and TUG  and low with the 8LBS  and Short FES-I . The sum scores did not distinguish between fallers and non-fallers. No floor/ceiling effects occurred for the STT sum score, but these effects occurred for specific STT thresholds for both ACE  and DSE . No severe adverse events occurred.Discussion: Correlations between the STT and other balance tests were in the expected magnitude, indicating convergent validity. However, the STT could not distinguish between fallers and non-fallers, referring to a need for further studies and prospective surveys of falls to validate the STT. Current results did not allow a definitive judgment on the advantage of using ACE or DSE. Study results represented a step toward a reactive balance assessment application in a clinical setting. Approximately every third person aged 65 and above experiences at least one fall annually  have been shown to be independent predictors of future falls in community-dwelling older adults  . As opposed to counting every step is taken . A sample of 71 community-dwelling adults aged 65 and older was recruited. We contacted 3,350 people creening . Eligiblcreening  to levelcreening . Other rDemographic characteristics and falls within the last 12 months (retrospective) were assessed and recorded during standardized interviews. For this purpose, a fall was operationally defined as an unexpected event in which a person walking, standing, sitting, or lying down involuntarily, suddenly, and uncontrollably comes to rest on the ground or another lower level  . The stuThe stepping behavior of the participants was evaluated for all 24 surface translations. In order to avoid injuries, the participants wore a safety harness that protected them from falling. The rope length was adjusted so that in the event of a fall, the knees of the participants would come to rest ~10 cm above the treadmill surface. In case of a fall or excessive fear by the participant, the test was terminated prematurely. The testing process was recorded on video from the thoracic spine of the participant downwards. The camera system  was placed at a distance of 2.1 m and an angle of 35° dorsolateral to the participant  and recoThe evaluation of the stepping behavior of the participants was assessed by video analysis. Stepping behavior was scored as no step, single step, or multiple stepping. For the ACE, we counted each step up to the point where the subject regained balance, based on the observational judgment of a static steady-state balance, i.e., maintaining a steady position while standing with a stable trunk. For this purpose, we defined a step as an observable change in the bipedal BoS. In the DSE, we specified a step as reaction behavior that leads to a sensible extension of the BoS in the opposite direction of the surface translation. To be counted as a single step, the BoS in the basic test position had to be extended by one step in the opposite direction to the surface translation. To be counted as a multiple-step, the actual BoS had to be additionally extended by one or more steps in the opposite direction to the surface translation. Subsequently, single-step and multiple stepping thresholds were determined for each direction of surface translation . In the increasing perturbation protocol, the single-step threshold was defined as the first perturbation displacement from which the subject needed to take a step to recover. The multiple stepping threshold was defined as the first perturbation displacement from which the subject needed to take multiple steps, i.e., at least two steps, to recover. To ensure that the threshold was reached, two successive perturbations in the same direction each had to result in a single step or multiple stepping for the threshold to be scored  step and stepping thresholds, anteroposterior (forward and backward) step and stepping thresholds, and the original thresholds for each  single-step and multiple stepping threshold.Statistical analyses were performed using IBM SPSS Statistics Version 26  and MS Excel 2010 . Hypotheses were two-sided evaluated at the alpha level at 2-Test for categorical variables, and by either the Mann-Whitney-U test or the independent t-test, as indicated, for continuous variables. Normal distribution was tested by means of the Shapiro-Wilk W test. For the estimation of convergent validity, we investigated the association of the STT with the TUG, BriefBEST, 8LBS, and the Short-FES-I applying the Spearman's rank correlation coefficient. Correlation coefficients of r = 0.1–0.29 indicate a small, r = 0.3–0.49 moderate and r ≥ 0.50 strong correlations  was included in the analysis (p = 0.007). No further significant differences were found in regards to age, gender, balance capacity, and fear of falling between non-fallers and fallers  and the TUG (r = −0.379). In addition, the STT sum score (ACE) correlated low with the 8LBS (r = 0.173) and the Short FES-I (r = 0.108) (r = 0.102 to |−0.297|) in 8 of 16 values, moderately in 6 values (r = 0.312 to |−0.433|), and did not correlate with the reference measures in 2 values (r = 0.107 to |−0.293|), moderately in 5 values (r = 0.300 to |−0.390|), and did not correlate in 3 values with the reference measures (r = 0.104 to |−0.292|), moderately in 1 value (r = 0.309), and did not show correlations with the reference measures in 3 values (The Stepping Threshold Test sum score (ACE) correlated moderately with the BriefBEST (= 0.108) . The Ste2 values . The sinmeasures . The mul3 values . Correla3 values .r = 0.388) and the TUG (r = −0.435). In addition, the STT sum score (DSE) correlated low with the 8LBS (r = 0.246) and Short FES-I (r = −0.104) and (r = |−0.104| to |−0.279|) in 7 of 16 values, moderately in 6 values (r = 0.305 to |−0.447|), and did not correlate with the reference measures in 3 values (r = |−0.105| to |−0.238|), moderately in 2 values (r = |−0.342| to 0.415), and did not correlate with the reference measures in 5 values (r =0.106 to |−0.267|), moderately in 1 value (r = |−0.318|), and did not show correlations with the reference measures in 2 values (The Stepping Threshold Test sum score (DSE) correlated moderately with the BriefBEST (104) and . The Ste3 values . The sin5 values . The mul2 values . Correla2 values .p = 0.034) (The Stepping Threshold Test sum score and subscores (ACE) showed no significant differences between fallers and non-fallers . Signifi= 0.034) .p = 0.015) with higher thresholds for the non-fallers compared with the fallers (The Stepping Threshold Test sum score and subscores (DSE) showed no significant differences  between  fallers . The subThe Stepping Threshold Test sum score of both ACE and DSE showed no floor (0%) or ceiling effect (0%). The subscores of both the ACE and DSE also revealed no ceiling or floor effects (0–4.29%) . In bothSD = 2.7). In the ACE, 17 of these 18  subjects had already reached all single-step thresholds and 10 of these 18 subjects (55.55%) had already reached all multiple stepping thresholds. In the DSE, 9 of these 18  subjects had already reached all single-step thresholds and none of these 18 subjects (0%) had already reached all multiple stepping thresholds. Accordingly, 62 of 70 (88.57%) participants reached all thresholds in the ACE and 52 of 70 (75%) participants reached all stepping thresholds in the DSE during the testing procedure. For five participants (7.14 %), fall thresholds were documented , whereas the earliest fall appeared in perturbation number 18 and the latest in perturbation 23. We were able to include every participant but one due to technical problems (98.59%) in the analysis of both ACE and DSE using the calculated thresholds. There were no adverse events, but some participants reported high stress levels and anxiety during the higher intensities of the STT.In total, 1,593 of 1,680 (94.8 %) perturbations were applied. The test was terminated prematurely in 18 subjects (25%) with an average of 19.7 out of 25 applied perturbations , but this result was based on only a single study  and r = −0.435 (DSE) confirmed our hypothesis. Lower correlations in our study compared with the study of Handelzalts et al. . The study of Kiss et al.  and r = 0.246 (DSE) confirmed our hypothesis of a low to moderate the relationship between reactive and static balance measures.The study of Crenshaw et al.  exploreds et al.  includedr = −0.398 and multiple stepping threshold: −0.302) between the single-step and multiple stepping thresholds and the fear of falling. The study of Crenshaw et al. (r = 0.19–0.20) of single-step thresholds and moderate correlations (r = 0.39–0.40) of multiple stepping thresholds with activity-specific balance confidence, a construct which is similar to fear of falling. Accordingly, we hypothesized to find low to moderate correlations between the STT sum score and the Short FES-I. We determined lower correlation coefficients of r = −0.108 (ACE) and r = −0.104 (DSE), which are, however, within the expected range. Interestingly, anteroposterior subscores were higher (ACE: r = −0.195 and DSE: r = −0.249) and mediolateral subscore did not indicate any correlation (ACE: r = −0.008 and DSE: r = 0.085). These findings are in line with experiences gained during the testing procedure that AP perturbations seemed to be the most uncomfortable especially for anxious participants. Anteroposterior step and stepping thresholds might be closer related to fear of falling since backward perturbations require a particular fast step reaction  and the original single-step and multiple stepping thresholds . Due to the high numbers of variables in our secondary outcomes the possibility of type-I error must be considered here. However, only the primary outcome, i.e., the STT sum score, was considered in hypothesis testing and secondary outcomes do not affect the conclusion of this study. In summary, our hypothesis regarding the convergent validity of the STT with other assessments of balance and fall risk was confirmed.These results are supplemented by numerous correlations between the reference measures, the STT subscores  is capable of, ceiling effects in the multiple stepping thresholds appeared in the DSE in all directions except in the forward translations. This is surprising, since mediolateral reactive stepping strategies, such as the cross-over step are also very demanding for older adults . In this study, results for the Single-step subscore were similar or only slightly different to the STT sum score and the Multiple stepping subscore in both ACE and DSE. The study of Crenshaw et al.  found coSince the perturbation treadmill and the camera system we used are commercially available, the test application is also transferable to other settings. To increase feasibility, especially in the DSE, stress and anxiety levels should be reduced for example by more extensive familiarization with the test prior to the actual test administration. Further studies are needed to investigate the different areas of feasibility such as acceptability, practicality, and implementation  applied perturbations. This high frequency of differences in the evaluations confirmed the need for a differentiated view of these two observer-based evaluation methods. For both evaluation strategies, namely the ACE and DSE, we presented evidence for convergent validity. Based on discriminative validity, neither DSE nor ACE shows advantages over the other evaluation strategy. The total number of correlating thresholds was slightly higher in the ACE compared with the DSE, the subscores, and the original thresholds. There are tendencies that the ACE might be more valid in mediolateral single-step thresholds and the DSE be more valid in anterior multiple-stepping thresholds . FurtherA limitation of this study is the retrospective characterization of participants as fallers or non-fallers. The number of recurrent fallers in our sample was too small to conduct an analysis of such a subsample. While our STT protocol was unpredictable with respect to perturbation direction, the gradual increase of the perturbation intensity might have been predictable. While our results indicated convergent validity, future validation studies could use a specific reactive balance test as a reference measure.Finally, we would like to provide recommendations based on our findings and experiences during the study process:To avoid floor and ceiling effects, future studies should determine the optimal intensity in terms of magnitude, velocity, acceleration, duration of and the number of surface translations for each direction for different populations. In community-dwelling, fall-prone older adults this includes both higher and lower magnitudes than applied in this study. On the same note, care must be taken to avoid excessive demands and to ensure safety. Particular attention should be paid to the proper balance of mediolateral, anterior, and posterior perturbations intensities.In consideration of the floor effects that occurred only in anteroposterior perturbations as well as the described associations between anteroposterior step and stepping thresholds and fear of falling, we recommend either starting the STT with mediolateral perturbations or with a lower intensity.When using unexpected perturbations, participant anxiety and stress levels should be considered when planning studies. Future investigations should refrain from extending the duration of the test, e.g., by a higher number of applied perturbations, to avoid a further increase in the stress level and a resulting physical and psychological overload of the participants. In this context, we would like to point out psychological consequences of fall experiences such as post-fall anxiety syndrome  can be found below: The studies involving human participants were reviewed and approved by Ethics Committee of Heidelberg University (reference: AZ Schwe 2019 /1-2). The patients/participants provided their written informed consent to participate in this study.MA was involved in data analysis and interpretation and drafting of the manuscript. LB was involved in the conception, experimental design, data acquisition, data interpretation, and drafting of the manuscript. ML was involved in data interpretation and critical revision of the manuscript. MS was involved in the conception, data interpretation, and drafting of the manuscript. All authors contributed to the article and approved the submitted version.clinicaltrials.gov (study registry number: NCT04087512). The mentioned study is supported by the Klaus Tschira Foundation. The responsibility for the content of this paper lies with the authors. The funders did not take any part in this work.This study was embedded in the interventional study for disorder training registered at 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.


Despite a campaign of effective educational interventions targeting knowledge, attitudes, and prevention, Human Immunodeficiency-Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) continues to be a significant public health issue in India, with Mizoram reporting the highest HIV/AIDS cases in 2018–2019. In this study, we extracted Mizoram state from the National Family Health Survey Fourth Series (NFHS-4) 2015–2016 datasets and investigated factors associated with respondents’ knowledge, attitudes, and prevention towards HIV/AIDS. The sample included 3555 adults aged 15–49 years residing in Mizoram, North-east India. Respondents who reported having ever heard of HIV/AIDS was 98%. Multivariate analysis indicated that the probability of having inadequate knowledge of HIV/AIDS was higher among those with no schooling, who were illiterate, of non-Christian faiths, belonging to backward tribes or caste, from poor households, and those who lived in rural areas, not exposed to media. The odds of mother-to-child transmission (PMTCT) of HIV/AIDS transmission was high among females , respondents aged 35–39 years  and those belonging to other backward class. The HIV/AIDS knowledge of respondents was found to be encouraging as the majority (98%) were considered to have a good level of understanding of the condition. An educational intervention to reduce the number of adults 15–49 years infected with HIV/AIDS in Mizoram should target those from low socioeconomic groups, those from non-Christian religions, and those from other backward classes. Human Immunodeficiency Virus (HIV) continues to be a major global public health issue, with thousands of new HIV infections every year, a disease that has claimed almost 33 million lives so far . In 2019In 2019, around 69.22 thousand new infections and AIDS-related deaths were estimated at 4.43 per 100,000 population [The North-eastern state of Mizoram has the second-highest AIDS mortality in India at 23.34 per 100,000 population. While the new HIV infection incidence is declining in the country and other States, the State of Mizoram has seen an 18% increase in incidence from 2010 to 2017 , an alarIn 1992, the Government of Mizoram established the State AIDS Cell, and Mizoram State AIDS Control Society (MSACS) came into existence in 1998 under Health and Family Welfare. Since then, MSACS has promoted and implemented education and awareness programs to prevent and control HIV/AIDS in Mizoram. Despite the efforts made by MSACS in controlling the spread of HIV, the number of new infections is increasing; this causes an increased concern regarding the level of awareness, beliefs, and practices in HIV/AIDS in the general population.A recent study in India has indicated the effectiveness of education on improving the knowledge and attitudes of young women toward HIV . SeveralThere have been no studies that have assessed people’s knowledge, attitudes, and beliefs towards HIV/AIDS in Mizoram. A study in India has reported the urgent need for and efforts toward making people more caring and accepting towards PLHIV. This can be mainly achieved by raising knowledge about HIV and its modes of transmission . In the The study used data from the 2015–2016 National Family Health Survey Fourth Series (NFHS-4) . NFHS isFour survey questionnaires were administered that collected information on household data and interviewed eligible women and men and biomarkers. Two versions of questionnaires were used for women in NFHS-4. The first version (district module) questionnaire did not include questions on sexual behavior and HIV/AIDS. This version of the questionnaire was fielded in the entire sample of NFHS-4 households. In the second version of the questionnaire (state module), four additional topics, including sexual behavior and HIV/AIDS, were included. This second version was fielded from a 15 percent subsample of NFHS-4 households designated to provide information only at the state and national levels. Men had only one questionnaire ,13. InfoThe analyses were guided by previous studies ,14,15, eA wealth index was constructed from the data collected through the household questionnaire using the method recommended by the World Bank Poverty Network and United Nations Children’s Fund . The priThe four outcomes that were analyzed in this study can be broadly classified under the following headings.This included questions on those who have heard of HIV or AIDS.The questions included combining those that says ‘YES’ to all the four indicators “willingness to care for a relative with HIV/AIDS in own home”, “would they buy vegetables from a shopkeeper or vendor who has HIV/AIDS”, “female teacher who has HIV/AIDS but is not sick should be allowed to continue teaching”, “would not want to keep a secret that a family member got infected with HIV/AIDS”.These included questions on reducing the risk of getting HIV/AIDS combined with those that said ‘YES’ to (a) have 1 sex partner only, who has no other partners, and (b) always use condoms and 1 sex partner only, who has no other partners.These included questions on knowledge of prevention of HIV/AIDS from mother-to-child transmission (PMTCT) and that HIV/AIDS transmission from mother to her baby can occur (a) during pregnancy, (b) during delivery and, (c) by breastfeeding.All analyses were performed using “svy” commands in STATA v14.1 , and the binary form of the four outcome variables was noted as 1 for “Yes” and 0 for “No”. Preliminary analyses involved frequency tabulations of all selected characteristics, followed by the Taylor series linearization method  used in For selected indicator variables, the unadjusted factors were tested by odds ratios (OR) using univariate analyses that adjusted for cluster, and survey weights were presented as unadjusted OR (95% CI) for all explanatory variables. Then, multiple logistic regression analyses that adjusted for cluster and surveyed weights in a manual process stepwise backward regression model ,21 were Summarized in The 95% confidence intervals of 4 outcome variables across all explanatory variables were calculated. Results indicated that low levels of education, other backward class, poor household wealth index, belonging to a religion other than Christianity, not having regular exposure to media, being illiterate, and living in rural areas commonly reported significantly lower knowledge of HIV/AIDS, prevention towards HIV/AIDS, PMTCT and attitude towards HIV/AIDS , those from a non-Christian faith (p < 0.001), with no regular media exposure (p = 0.006), and those who lived in rural areas. Knowledge on the prevention of HIV/AIDS was lower among those of non-Christian faith (p < 0.001), no regular media exposure (p = 0.023), and those from other backward class (p = 0.03). Negative attitude towards HIV/AIDS was significant among those from a rich household wealth index (p = 0.02), those exposed to media (p = 0.028), and those from other backward class (p = 0.002).Only factors identified as significant were included in a multivariate analysis and are reported in This study examined the knowledge, attitude, and preventive behaviors towards HIV/AIDS among adults in Mizoram. It found that those who lived in rural areas, from poor households, who were illiterate, with no schooling, from a non-Christian faith, belonging to other backward classes, and who had no media exposure to be factors associated with HIV/AIDS for this population group. This was the first study that sought to understand HIV/AIDS and its associated factors among adults in Mizoram. This study has revealed their shortcomings towards HIV/AIDS literacy and has identified areas for information, education, and communication interventions that will modify the approach toward addressing HIV/AIDS in Mizoram.This study showed that the adult population in Mizoram had good overall HIV/AIDS knowledge, but that there were significant gaps among those who lived in rural areas, from poor households, who were illiterate, with no schooling, from a non-Christian faith, belonging to other backward class, and those who had no exposure to media. A similar study in Yemen  also fouThe study findings showed that respondents from other backward classes had low knowledge and prevention toward HIV/AIDS. The other backward classes of Mizoram are remotely isolated with limited access to media and health resources and have a high level of poverty and low level of education. A study among the rural tribal communities of Southern India  revealedThe findings from our study showed that respondents who did not have Christian faith had lower knowledge and prevention of HIV/AIDS. This is similar to a study done in Ghana  and LebaThe majority of respondents were willing to care for HIV-infected relatives and would buy vegetables from an HIV-positive vendor. This revealed that the majority of the respondents had a positive attitude towards people living with HIV. However, 37.4% of the respondents reported that HIV/AIDS should be kept a secret in the family. The reports are similar to other studies done in India ,30. In IRegarding sexual behavior, the majority of respondents in the study reported always using condoms during sex and having only one sex partner. This could be attributed to the efforts made by the government and social organizations in propagating the use of condoms to prevent HIV through media, posters, and pamphlets. However, other studies ,35 have Our study has several limitations. Data for our analysis were generated by self-report and thus may be subjected to presentation bias with respondents giving socially desirable answers rather than the truth. In addition, because our study was population-based, it did not differentiate high-risk groups such as female sex workers, injecting drug users, and men who have sex with men. Despite these limitations, this study has a very strong internal validity because this is a large sample-size population-based study, and the findings could help design and improve HIV/AIDS education and prevention programs in Mizoram.HIV/AIDS education and awareness programs need to be disseminated among socially and economically disadvantaged communities, rural communities, and those from non-Christian faiths. This study showed that those who were illiterate had inadequate knowledge and understanding of HIV/AIDS. However, posters and pamphlets may not produce the desired knowledge regarding HIV among these groups of people. Mass media has been one of the important strategies in disseminating HIV/AIDS knowledge and promotion of HIV testing . A studyThe church plays an influential role in the communities and reaches every corner of Mizoram . HIV/AIDThis study demonstrated that HIV/AIDS knowledge level is encouraging in the study population, with the majority of the respondents reported to had heard of HIV/AIDS and understood the route of transmission. Nevertheless, HIV/AIDS prevention and education intervention need to be targeted toward those from low socioeconomic groups, from non- Christian religions, and those from other backward classes. The inadequate knowledge exhibited by those from rural communities warrants urgent and appropriate interventions and education on HIV/AIDS and its transmission, prevention, and reduce stigmatization and discrimination. The majority of the respondents reported having regular media exposure, increased utilization of mass media such as television and radio are recommended to disseminate HIV/AIDS awareness and education so that it reaches all strata of educational levels, socioeconomic groups, and religions within Mizoram.


Endometrial cancer (EC) is one of the most common female reproductive system tumors, with close to 200,000 new cases each year. It accounts for approximately 7% of the total number of female cancers, but until now the cause of EC has remained unclear. Ferroptosis is regulated cell death that distinguishes apoptosis and caused by oxidative damage. The process has unique biological effects on metabolism and redox biology. In this study, we analyzed the relationship between EC and ferroptosis. According to the different expression levels of related genes, we first divided 544 EC samples into four clusters and found that most of the infiltrating immune cells were significantly different among the four groups. A differential gene expression analysis between Fe.cluster groups was performed, and the samples were again divided into three Fe.gene.cluster groups. The molecular characteristics and clinical characteristics of the groups were significantly different. Finally, 13 characteristic genes were selected as ferroptosis gene signatures, and the Fe.score was obtained by calculation. The Fe.score is closely related to the clinical and molecular characteristics of EC, and a low Fe.score has a significant survival advantage. The GDSC predicts that the IC50 of multiple chemotherapeutic drugs is also significantly different between the two groups. In conclusion, our research has explored the relationship between EC and ferroptosis in detail, provides comprehensive insights for ferroptosis-mediated EC mechanism research, and emphasizes the clinical application potential of Fe.score-based immunotherapy strategies. Analysis workflow chart. Endometrial cancer (EC) is one of the most common types of gynecological malignancies, and it affects the health of many women around the world. As the eighth leading cause of cancer-related deaths in women, the morbidity and mortality of EC are increasing rapidly . For patFerroptosis is a newly discovered iron-dependent cell death that is different from other forms of cell death, including apoptosis and necrosis. Ferroptosis involves three main metabolites, thiol, lipid, and iron, leading to iron-dependent lipid peroxidation and ultimately cell death . FerroptRAS family  are the most commonly mutated in all human cancers  , and isc cancers . The feror cells . KRAS-muroptosis ; in addiroptosis . Ferroptroptosis , hypoxiaroptosis , and improptosis in situ by delivering Fe2+ and Fe3+  conversion was performed. This data was used for subsequent analysis.The somatic mutation, transcriptome, CNV, and sample phenotype data of EC were downloaded from the TCGA xena database. Among them, there were 530 samples with somatic mutation data; there were two sets of CNV data, one of which consisted of the CNV results compiled by xena, showing CNV at the gene level, and the other was the sample DNA copy file downloaded from The gene sets of 23 infiltrating cells were obtained from a reference . The genggpubr was used to draw box plots to show the differences in the expression of these genes between tumor tissues and normal tissues. The CNV results of ferroptosis genes were extracted, the frequency of amplification and deletion was counted, and a dot plot was drawn. The R package maftools was used to import the maf files of somatic mutations in 530 EC samples and draw the somatic mutation spectrum. The R package RCircos was used to draw a circos map of 60 ferroptosis genes, showing the positions of the genes on the reference genome. The R package pca3d was used to perform principal component analysis (PCA) on the expression matrix of 60 ferroptosis genes and draw a three-dimensional PCA map.Using TCGA-EC RNA-Seq data, the expression values of 60 ferroptosis genes were extracted, and the R package ConsensusClusterPlus was used to perform unsupervised clustering with the following parameters: m (maximum number of categories) = 6, reps (repeated sampling) = 1,000, pItem (proportion of items selected each time) = 0.8, pFeature (the proportion of features selected each time) = 1, the clusterAlg  = “pam”, distance  = “spearman.” The output results were synthesized, the K values were filtered, and the classification of each sample was obtained.Using the expression matrix of ferroptosis genes in 544 EC samples as input files, the R package limma was used to analyze the differences in the gene sets, and the threshold was a BH-corrected p-value < 0.05. The top 20 differential gene sets were extracted, the R package ComplexHeatmap was used to draw the differential gene set heat map, and group labels were added.For Fe.cluster, grouped two by two, the expression matrix of all genes of the two samples was extracted, the c2.cp.kegg.v7.1.symbols gene set was combined as the input file, gene set variation analysis  was persurvival was used to perform single-factor Cox risk regression analysis to obtain the hazard ratio (HR) and p-values of differential cells, and then the R package forestplot was used to draw forest plots to visually display the prognostic effects of differential cells.The gene expression matrix of 544 tumor samples and the gene set of 23 infiltrating cells were used as the input files of the R package GSVA for single-sample GSEA (ssGSEA). Using the enrichment score as the content of each cell, a box plot was drawn using the R package ggpubr, and the Kruskal–Wallis rank sum test was performed to show the differences in the content of 23 infiltrating cells between the Fe.cluster groups. Differential cells were selected, the R package ggpubr was used to draw box plots, and the Kruskal–Wallis rank sum test was performed.The display of angiogenesis, CD8 T effectors, EMT1, EMT2, EMT3, and panfibroblast TGFb enrichment scores between different Fe.cluster groups was also performed for ssGSEA following the method described above; the enrichment score of each sample was obtained for these six biological functions, the R package limma was used for differential gene analysis, with a differential gene screening threshold of abs[log2(fold change)] > log2(1.25) and BH correction p-value < 0.05. Multiple sets of differential genes were obtained, and the intersection was taken as the final differential gene. The R package clusterProfiler was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the screening threshold was BH correction p-value < 0.05 and Q-value < 0.05. The top 20 enrichment items of biological processes (BP), cell components (CC), molecular function (MF), and KEGG were selected, and a bubble chart was drawn to display the results.The Fe.clusters were grouped in pairs, the expression matrix was extracted, and the R package ConsensusClusterPlus was used to perform unsupervised clustering. The parameters were set as follows: m = 6, reps = 1,000, pItem = 0.8, pFeature = 1, clusterAlg = “pam,” and distance = “spearman.” The output results were synthesized, the K values were filtered, and the classification of each sample was obtained. Sample clinical data were integrated, survival analysis was performed on Fe.gene.cluster, and Kaplan–Meier curves were drawn. The expression matrix of 60 ferroptosis genes was extracted, and the R package ggpubr was used to draw a box plot to show the expression in different Fe.gene.clusters and perform the Kruskal–Wallis rank sum test.The differential gene expression matrix of 544 tumor samples was extracted as the input file, and the R package survival was used to perform single-factor Cox risk regression analysis, and genes were screened according to a p-value < 0.05. For the retained genes, the R package randomForestSRC was used to construct a random forest model, and then important feature variables were screened as ferroptosis gene signatures.For differentially expressed genes, the R package The expression matrix of ferroptosis gene signatures was selected, PCA was performed, the two principal components were selected as PC1 and PC2, and the ferroptosis score (Fe.score) was calculated according to the following formula:survival was used to analyze the survival of the Fe.score, and the R package survivalROC was used to draw a 5-year ROC curve to evaluate the Fe.score survival model.Sample clinical data were integrated and divided into high Fe.score and low Fe.score according to the median Fe.score. The R package p-value. The R package corrplot was used to draw the correlation diagram, and a p-value < 0.01 was considered to be extremely significant. Dots of the corresponding colors were drawn in the figure according to the correlation coefficient.The ferroptosis gene and the top 10 differential gene sets of the three groups of GSVA were integrated to perform ssGSEA, and then the enrichment score was combined with the Fe.score to calculate the Pearson correlation coefficient matrix and calculate the pRRophetic was used to perform GDSC drug IC50 prediction, and a box plot was drawn to show the IC50 difference between Fe.score groups. The bladder cancer data set (IMvigor210)   was usedigor210) , and theggalluvial was used to draw the Fe.cluster, Fe.gene.cluster, and Fe.score grouping of 544 samples and survival status mulberry charts. The R package maftools was used to draw the somatic mutation map and CNV peak map, and the Gistic2 analysis result file of the sample was required when drawing CNV. However, there was no complete Gistic2 result in the TCGA database, so DNA copy was used to perform Gistic2 analysis first. For analysis methods and parameter settings, refer to http://docs.gdc.cancer.gov/Data/Bioinformatics_Pipelines/CNV_Pipeline/. The R package ComplexHeatmap was used to draw heat maps. The Spearman correlation coefficient between ferroptosis genes was calculated, and screening was performed according to a p-value < 0.001 and an absolute value of the correlation coefficient greater than 0.2. Using consensus clustering to cluster genes, single-factor Cox risk regression was used to determine the prognostic effects of genes, and the results were sorted into tables and imported into Cytoscape (3.7.2) to draw gene interaction network diagrams.The comparison of the two groups in the box plot in this paper uses the nonparametric Wilcox rank sum test; the comparison of multiple groups uses the Kruskal–Wallis rank sum test. The R package We first screened 60 ferroptosis genes, and the positions of 60 ferroptosis genes in the reference genome hg38 are shown in p-value < 0.001 and the absolute value of the correlation coefficient was greater than 0.2, the genes were considered to have an interaction relationship. As shown in We first performed cluster analysis of ferroptosis genes and divided them into four clusters: regulator cluster A, regulator cluster B, regulator cluster C, and regulator cluster D   . Figure In this article, we first explored the expression and mutation of ferroptosis-related genes in normal and EC tissues. According to the different expression levels of related genes, 544 EC samples were divided into four clusters, and most of the infiltrating immune cells were significantly different among the four groups. The tumor stages and grades of Fe.cluster A and Fe.cluster B were lower, and the enrichment scores of angiogenesis, CD8 T effector, EMT2, and panfibroblast TGFb were significantly different among Fe.clusters. A gene expression difference analysis between Fe.cluster groups was performed, and 438 overlap difference genes were obtained by taking the intersection. According to the difference genes, the samples were again divided into three Fe.gene.clusters. Fe.gene.cluster A and Fe.gene.cluster B have survival advantages. Finally, 13 characteristic genes were selected as ferroptosis gene signatures, and the Fe.score was obtained by calculation. A low Fe.score has a significant survival advantage, and GDSC predicts that the IC50 of multiple chemotherapeutic drugs is also significantly different between the two groups. The low-Fe.score group in the bladder cancer data set also had a very significant survival advantage, and CR/PR patients accounted for a relatively high proportion. Compared with previous prognostic models of EC, our prognostic model based on ferroptosis genes is more accurate and simpler .– inhibitors in vitro and provides a selective pharmacodynamic marker for ferroptosis induced by system xc– inhibitors  as ferroptosis gene signatures. The current research shows that most of these 13 genes are closely related to the occurrence and development of tumors, like the TMPRSS2 gene, which is abnormally expressed in approximately 50% of cases of prostate cancer and is a key driver of prostate oncogenesis ; COL23A1There are still some flaws in this study. When Fe.cluster was divided into four categories, the overlapping difference genes have only single digits, so the Fe.cluster D group has to be removed before the difference analysis is performed. Fe.cluster D had only a few samples, the expression of some genes  was particularly high, and some clinical indicators, such as BMI, were very different from the other three clusters. However, whether Fe.cluster D truly represents a special subtype with the same clinical or molecular characteristics still needs to be verified by more samples. When we perform ferroptosis score calculation, we did not consider the negative eigen values. We hope that we can re-establish the model and reanalyze the negative eigen values in the future. In addition, since there are no immunotherapy results for EC, we used bladder cancer immunotherapy data (large sample size) to evaluate whether the Fe.score can predict the effect of immunotherapy. Although our results were validated in the bladder cancer data set and the previous literature has also verified that using other cancer data sets is feasible , we hopeFe.score can not only reflect the immunological and carcinogenic status but also predict the prognosis of patients. In addition, Fe.score provides additional prognostic value for existing FIGO and molecular subtypes. In conclusion, our research has explored the relationship between EC and ferroptosis in detail, provides comprehensive insights for ferroptosis-mediated EC mechanism research, and emphasizes the clinical application potential of Fe.score-based immunotherapy strategies.The original contributions presented in the study are included in the article/HW and MX contributed to the conceptualization. YW participated in data curation. HW and YW participated in formal analysis. MH contributed to the methodology. HW took charge of the software. HW, YW, MH, SC, and YY participated in writing – original draft. MX participated in writing – review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Background and Objectives: The aim of this study was to assess if there are structural and functional changes of hands and legs already in early rheumatoid arthritis (ERA), compared with the population-based control group. Additionally, we aimed to identify if the changes are symmetrical in hands and legs and if there are factors that are associated with these changes. The study was conducted, and, thus far, the results have been controversial. Materials and Methods: The study group consisted of 83 consecutive patients with ERA and 321 control subjects. Dual-Energy X-Ray Absorptiometry (DXA) machine was used to measure bone, lean and fat mass. Inflammation and bone markers, smoking and nutritional habits were assessed, to evaluate the effects of different factors. The 30-Second Chair Stand Test (30-CST) and the Handgrip Strength Test (HST) were used to estimate muscle strength. Results: The presence of ERA was associated with lower arm, leg lean mass and higher fat mass of arm, compared with control subjects. ERA was also associated with lower mean handgrip in HST and worse muscle strength of legs in the 30-CST. Bone mass changes were not so evident both in arms and legs. Smoking habits did not seem to have relevant effect on bone mass, muscle structural and functional changes, both on hands and legs. In ERA, lean mass of arm and leg was negatively associated with C-reactive protein (CRP). The intake of proteins in ERA was not associated with lean mass changes both in hands and legs. Conclusions: Structural and functional changes of hands and legs are different in ERA. ERA patients had higher fat mass of arm, lower lean mass of arm and leg and, accordingly, decreased muscle function. The lowering of lean mass of arm and leg in ERA was associated with the elevation of CRP. Rheumatoid arthritis (RA) is a chronic autoimmune disease mainly affecting the small joints of the hands and feet. It is characterized by persistent synovitis, accompanied with systemic inflammation , the desAn early characteristic sign of appendicular bone damage is peri-articular osteoporosis or osteopenia that precedes the development of erosions . Dual EnLocal and generalized bone loss have the same pathway: the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) route ,16, whicA recent study showed that ERA patients had lower appendicular lean mass compared to healthy subjects, an effect related to catabolism-inducing factors (inflammation) and lower protein intake . In addiIn RA, usually only the small joints of hands are evaluated when assessing disease activity, as most widely used scales do not assess the small joints of legs. Still, half of RA patients already experience foot problems by the time of diagnosis ,27, and The study was conducted, as, thus far, the results have been controversial. The aim of this study was to assess if there are structural and functional changes of hands and legs already in early RA, compared with the population-based control group. Additionally, we aimed to identify if the changes are symmetrical in hands and legs and if there are factors that associate with these changes.n = 83).The study group consisted of 83 patients with ERA (age: 19–79 years) and 321 subjects in a control group (age: 20–79 years). One hundred consecutive patients referred to Tartu University Hospital with newly diagnosed RA were recruited between 2012 and 2014, in order to form the ERA group. Their diagnosis was established according to American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2012 criteria for RA, and patients with symptom duration up to one year (early arthritis) were invited to participate in the study. Nine patients with missing outcome data were excluded, as were another 8 patients who did not fulfil ACR/EULAR 2012 criteria for RA on a follow-up visit one year after their first visit (n = 321). The same control group was used in another population-based cross-sectional study conducted in the same geographic location [In order to form the control group, 350 subjects adjusted for the age and gender composition of the Estonian population in 2013 were randomly selected from a primary healthcare center practice list . Cross-sectional data were gathered from September 2014 to March 2015. Invitations with introductory materials were mailed to 350 people. The primary healthcare center was contacted by a total number of 332 subjects for further instructions, and finally 330 people were recruited during the study period. Three subjects missed their study appointment, and six patients with missing outcome data were excluded (location . Study p2), overweight (BMI: 25–29.9 kg/m2) and obese (BMI: ≥30 kg/m2) [Body mass index (BMI) was calculated according to the standard formula: weight in kilograms divided by height in meters squared. Based on the World Health Organization (WHO) criteria, the following groups of BMI were formed: normal weight  machine was used to separately measure arm, leg and whole body bone, lean and fat mass. A qualified and experienced technician performed all DXA measurements on all participating subjects.The 30-Second Chair Stand Test (30-CST) and the Handgrip Strength Test (HST) were used to estimate and compare muscle strength. The 30-CST was used for assessing leg muscle function. While conducting the 30-CST, patients were asked to sit on a chair, with their spine straight and hands placed crossed across their chest, on opposite shoulders. On a signal, subjects rose at their own pace, to a full standing position, and then returned to seated position as many times as they were able. A 30 s trial was preceded by a practice attempt of 1–3 repetitions. The total number of unassisted full-stands during the 30 s time was considered the final chair-stand score .The HST was used for assessing hand muscle function. Grip strength was measured with a calibrated Riester Dynatest dynamometer, in bars. One practice attempt was followed by three additional consecutive attempts, with pauses in between, of up to 60 s. The average value of three test trials of both hands was used for statistical analysis.Blood samples included measuring vitamin D3, calcium, OPG and C-reactive protein (CRP). IL-6, TNFa, and IL-1b were evaluated, using Luminex’s xMAP technology. Anti-CCP, RF and erythrocyte sedimentation rate (ESR) were measured only in the arthritis group. An electrochemiluminescence assay was used with the cutoff value of 17 kU/L for anti-CCP positivity. RF was measured, using the immunoturbidimetric method, and it was assessed positive if RF value was >14 IU/mL. The ESR was evaluated by using a modified Westergren method.To assess disease activity, the number of tender and swollen joints in the ERA group was evaluated (28 joint scores), and according to the standard formula, DAS28 scores were calculated, using CRP. According to the DAS28 score, patients were grouped as having low disease activity (DAS28 score <3.2), moderate disease activity (≥3.2 to ≤5.1) or high disease activity (>5.1) .A 24 h dietary recall method was used for nutritional assessment, and data were analyzed with NutriData software developed by the Estonian National Institute for Health Development .t-test (for mean) and Mann–Whitney U test (for median) were used to make comparisons between ERA patients and controls.All data were tested for normality. The continuous data were presented as mean (±SD) if distributed normally, or else by median with 25% and 75% percentiles. Unpaired two-tailed Student’s Multiple linear regression with binary exposure variables was carried out, to assess bone, lean, fat mass of arms, as well as legs, and also muscle function mean difference between ERA (ERA = 1) and control group (control group = 0). Model was adjusted for age, gender, height and weight, as ERA patients differed from controls by age and gender. Multiple linear regression analysis was done to assess in ERA the association of smoking to arms and legs bone mass; the influence of CRP and the amount of consumed proteins to lean-mass changes. Smoking was chosen for bone analysis, as this can possibly have influence on bone changes ,12. CRP All analyses were performed, using Statistica version 13.3 for Windows.The study was approved by the Research Ethics Committee of the University of Tartu , ERA group study approval: 221/M-9 . All subjects participating in the study signed written informed consent forms.ERA patients had significantly lower weight than controls. Moreover, ERA patients were older than controls. Smoking anamnesis had 33.7% (28) of ERA patients and 20.6% (66) of control subjects.In total, 65.1% (54) of ERA patients were RF positive, and 71.1% (59) were anti-CCP positive . A totalp < 0.0001; see The inflammation markers CRP, IL-6, TNFa and IL1-b were all significantly higher in the ERA group, as expected. OPG was almost two times higher in the ERA patients, as compared to control-group subjects  and function , compared with control subjects. The multiple regression models adjusted for age, gender, height and weight revealed that in ERA subjects arm, leg and trunk bone-mass changes, due to the ERA disease, were not statistically significant .The results of regression analysis showed that the presence of ERA was associated with lower arm (b −304.6) and leg (b −943.4) lean mass compared with control subjects. ERA was also associated with lower mean handgrip in HST (b −0.08) and worse muscle strength of legs in the 30-CST (b −2.3), .The fat mass of arm was higher (b 220.0) in ERA compared with control group subjects, but there was no difference in leg fat mass .Additional regression analysis for only ERA subjects indicated that in ERA arm and leg bone mass changes were not associated with smoking , RF posiThe aim of this study was to assess if there are structural and functional changes of hands and legs already in ERA, compared with the population-based control group. Additionally, we aimed to identify if the changes are symmetrical in hands and legs and if there are factors that associate with these changes. Our study confirmed that there are structural and functional changes of hands and legs already in ERA, compared with the population-based control group. In our ERA subjects , arm and leg bone mass changes due to the ERA disease were not statistically significant. In ERA subjects, arm and leg bone mass changes were not associated with smoking, RF positivity and OPG. Smoking is a risk factor for bone-structure changes , but we RA patients have reported foot problems being a major concern affecting their lives ,29. Chanp < 0.0001) and legs in the 30-S CST (p = 0.004), compared with control subjects. Similarly, it was found previously that muscle volume was lower in ERA compared with controls, indicating muscle atrophy in RA [Interestingly, we saw that the most evident changes were in limbs lean mass, and there was an especially prevalent reduction of leg lean mass in ERA patients. Accordingly, ERA patients had worse muscle function of hands in HST  are produced by adipocytes, obese patients have elevated cytokine circulating plasma levels. Their levels seem to correlate with the amount of body fat and fall in response to weight loss . TNF-a aPrevious data suggest that, in both genders, inflammation can be more severe when sex hormone levels decrease ,41,42. TTestosterone inhibits OPG production in men. In women, we see less of this effect , due to In addition to hormonal changes, it has been previously suggested that, as a part of diet, daily intake of monounsaturated fatty acids may lower disease activity in RA patients , and theWe can consider it a limitation that we did not assess the level of sex hormones, which can possibly alter the course of disease. Our study was also limited by small study groups, but this was due to the small total size of the Estonian population.The results of the conducted study indicated that there are structural and functional changes of hands and legs already in ERA, compared with the population-based control group. The changes of hands and legs are different in ERA. ERA patients had lower lean mass of arm and leg and, accordingly, decreased muscle function. The lowering of lean mass of arm and leg in ERA was associated with the elevation of CRP. ERA patients also had higher fat mass of arm. It seems that lifestyle factors do not affect hands and legs in ERA. Arthritis involvement can vary among people, so it is therefore important in ERA to assess hands and legs in parallel, as the structural changes differ. This knowledge may alter the evaluation of disease activity, affect treatment strategy and perhaps someday help work out a new score for better assessing ERA patients.