Cypripedium macranthos is one of the few wild orchids with high ornamental value in northern China. However, over the past decade, excessive collection, trading, tourism development, habitat fragmentation, deceptive pollination, and seed germination difficulties have all caused a sharp decline in the number of C. macranthos individuals and its population. In order to propose a scientific and effective conservation strategy, the genetic diversity, genetic structure and gene flow of the current CM population are urgent scientific issues to be clarified.Genetic diversity, genetic structure, and gene flow in plant populations and their influencing factors are important in conservation biology. C. macranthos from north and northeast China were analyzed to evaluate the genetic diversity, gene flow among populations, and genetic structure by genotyping-by-sequencing. More than 68.44 Gb high-quality clean reads and 41,154 SNPs were obtained. Our data based on bioinformatics methods revealed that C. macranthos has lower genetic diversity, high levels of historical gene flow, and moderate-to-high genetic differentiation between populations. The gene migration model revealed that the direction of gene flow was mainly from northeast populations to north populations in China. The results of genetic structure analysis showed that 11 C. macranthos populations can be considered as two groups, and further divided into four subgroups. Moreover, the Mantel test detected no significant “Isolation by Distance” between populations.Here, 99 individuals of C. macranthos populations were mainly caused by biological characteristics, human interference, habitat fragmentation, and restricted gene flow. Finally, constructive measures, which can provide a basis for the proposal of conservation strategies, have been suggested.Our study demonstrates that the present genetic diversity and genetic structure of  The genetic diversity of a species or population is the product of long-term evolution and the premise of its survival and adaptation. The higher the level of genetic diversity of a species, the richer the genetic variation, and the stronger the ability of adapting to different environments. On the one hand, many species may have different levels of genetic diversity and variation to adapt to different environments. On the other hand, habitat fragmentation caused by environmental change or human interference may lead to geographical isolation of natural populations, population degradation, decrease in gene flow, and eventually the loss of genetic diversity and the increase in inbreeding . The difex situ conservation [To formulate scientific and effective conservation strategies and measures for endangered species, it is necessary to understand its genetic diversity, spatial distribution, and relationship with environmental factors, and establish conservation units or select populations with high genetic diversity for in situ or ervation –15.Previous studies of genetic diversity, population genetics, and gene flow mainly used conventional molecular markers . However, on the one hand, few loci can be detected by conventional molecular markers, thus, there are some limitations in explaining geographical differentiation and genetic variation in populations, particularly of rare species. On the other hand, developing molecular markers have many steps and is tedious, time-consuming, and laborious. Excitingly, the rapid development of second and third generation sequencing technology, which comes at a lower cost with higher efficiency, provides researchers with more genetic and genomic datasets compared with traditional methods. In addition, a large number of loci that are evenly distributed throughout the genome can be screened. Therefore, using these datasets to analyze population genetic diversity, genetic structure, and gene flow may improve accuracy and resolution . As one Cypripedium macranthos (CM) belongs to the genus Cypripedium (Orchidaceae). The global distribution is only in Russia [Cypripedium has evolved into a pouch shaped like a slipper; thus, these orchids are often called slipper orchids or lady’s slipper orchids [n Russia , China [n Russia , Japan [n Russia , and then Russia . CM has  orchids . CM is o orchids . Therefo orchids , 28, mos orchids , morphol orchids , reprodu orchids , symbiot orchids , and see orchids .To understand the genetic variation, population structure, and gene flow in CM, and to identify the core population of genetic diversity and propose more accurate conservation strategies, we obtained SNPs of six populations from north China and five populations from northeast China by the GBS method, which can detect a large number of whole genome SNPs. The analysis of SNP characteristics in these different populations provided an insight into the genetic diversity, genetic structure, and gene flow in CM populations under biological barriers (pollinator feeding range and seed germination difficulties) and geographical barriers (Yanshan Mountains and Bohai Sea). Furthermore, we discuss factors that possibly contribute to the genetic diversity and biogeographical pattern of CM populations. Moreover, we assessed the correlation between genetic and geographic distances of CM populations using isolation by distance (IBD) models. Finally, we put forward some suggestions for CM conservation management.Illumina Hiseq Xten PE150 platform was used to sequenced the remaining 99 samples, and 68.44 Gb of data were obtained, with 468,849,522 reads, average reads per accession was 4,735,853.7, average sequencing depth of all samples was 23.2×, and Q20 value of each sample was above 95.5%. By SNP calling and rigorous screening  ≥ 0.01, read depth (DP) ≥ 4), 41,154 SNPs were obtained from data of all samples. Several main indices of genetic diversity were calculated, and 99 individuals were analyzed, as can be seen from the following indices, the overall level of genetic diversity of CM was low, and the effective number of alleles (Ae) varied from 1.0208 to 2.0000 and average was 1.2342, expected heterozygosity (He) ranged from 0.0204 to 0.5000 with an average of 0.1534, and the extent of observed heterozygosity (Ho) ranged from 0.0000 to 1.0000 and average was 0.1335, the polymorphism information content (PIC) values varied from 0.0202 to 0.3750 with an average of 0.1296, and the nucleotide diversity (Pi) varied from 0.0205 to 0.5031 with an average of 0.1543  of all the other populations were positive, and that of BHS population was the highest (Fis = 0.0774). In northeast China, two populations were positive , and three populations were negative , indicating that inbreeding occurred in most populations in North China. In the Northeast China, both inbreeding and outbreeding occurred.To understand the relationship between CM populations and visualize their genetic distance, a phylogenetic tree was constructed based on 41,154 SNPs  was performed based on SNPs obtained from all 99 CM individuals Fig. . PCA shoTo complement the PCA and phylogenetic tree analysis and better understand the population structure, an admixture analyses was performed to evaluate the population structure of 99 CM samples Fig. . UsuallyCorresponding to the results of the phylogenetic tree and genetic structure analyses, strong gene flow (Nm) and moderate-to-high levels of genetic differentiation were detected between population pairwise comparisons Table . The genTreemix software was used to estimate historical gene flow and determine its direction. The main direction of gene flow was from northeast China populations to north China populations, and between north China populations Fig. . Such ge2 = 0.1506, P (rxy-rand ≥ rxy-data) = 0.010) , the population of North China , this indicated that IBD was detected in the North China population to a certain extent, which corresponded to the distribution pattern of the North China population.A Mantel test was run on all samples to evaluate the effect of geographic distance on population genetic distance. No significant correlation was observed between genetic and geographic distances for the 11 CM populations  [Cypripedium flavum  [Cypripedium tibeticum  [Cypripedium kentuckiense  [Based on our experimental data, we found some evidence of genetic diversity in CM, several major indices of genetic diversity  indicated that the genetic diversity of 99 CM was lower than that of Korea and Japan, Ho and He were 0.140 and 0.185 in Korea and 0.163 and 0.187 in Japan, respectively , 28. Com= 0.572) , Cypripe= 0.288) , Cypripe± 0.119) , Cypripe= 0.522) . Several= 0.522) . MoreoveOrchis purpurea, another plant in the orchid family [Each population was analyzed separately, and the BHS population of CM had the highest level of genetic diversity among all populations. This population is located in the Baihuashan National Nature Reserve, which was established in 1985. The number of conserved CM individuals was higher than the other five north China populations. In addition, based on the natural global distribution of CM and its preference for cold climate, the BHS population may be the population that CM spread from north to south and settled down in North China in history, and developed a local CM diversity center. In contrast, the XAS population is located at the Xing’an Temple scenic spot in the center of Yichun city, which is surrounded by the Yichun River and several national roads, forming a geographical barrier. Therefore, the low level of genetic diversity of this population was mainly caused by human interference and the gene flow barrier. Unexpectedly, although SLS population was the smallest population with only three individuals, it was not the lowest in genetic diversity. Considering that this population was located only 21.3 km away from the BHS population, both SLS and BHS populations may have belonged to the same large population historically, SLS populations were split out due to interference from human activities, historical events, and the reproductive characteristics of CM. Thus, it still retains some genetic information of the original large population. Similar results were found not only in the CM population in South Korea , but alsd family . In addiFrom the perspective of large-scale geographical scope, the genetic structure analysis, PCA, and phylogenetic tree analysis showed that CM was divided into two groups. The first group consisted of six populations from north China and the second group included five populations from northeast China. These results were consistent with the geographical distribution of CM populations; these populations of north and northeast China were more than 1,000 km apart, separated by the Yanshan Mountains, the Qilaotu Mountains, and the Bohai Sea. On a finer scale, the north China populations were divided into three subgroups. Based on the geographical distribution pattern, these populations were isolated from each other and were scattered in several high mountains. Therefore, substructures were detected in all samples from north China. The distribution pattern of northeast China populations was different. Except for the PDS population, the distribution of most northeast China populations was in plain and hilly areas, and the gene flow barrier was small, especially the individuals of the XAS, HLHZ_HLHC, and JSTZB_JSTZ populations showed obvious genetic admixtures. Thus, the northeast China populations showed up as a whole. Interestingly, 16 samples of the YWS population were divided into different subgroups, suggesting that this population was formed as a result of the intermixing of several ancestors. On the whole, these results of the population structure were similar to those of the PCA and phylogenetic tree analysis, in which although there was some degree of admixture, all the samples still showed a distinct genetic structure.Cypripedium [We calculated genetic differentiation and gene flow among populations, and the levels of genetic differentiation were significantly different among populations, with high genetic differentiation among populations across regions. Based on the classification of genetic differentiation levels by Wright , moderatripedium . Althougripedium , the intripedium , 55. Genripedium , for exaripedium . In addiripedium , 58. TheWe evaluated the direction of gene flow using Treemix software. Our data indicated that the direction of historical gene flow was mainly from northeast China populations to north China populations. It implied that the north China populations were formed by the gradual migration and settlement of northeast populations by seed-mediated gene flow, which is consistent with the dominant distribution of CM and its preference for cold climates. In the resource survey, northeast China populations were widely distributed, ranging from the plain at 200 m above sea level to the Greater Khingan Mountains at more than 1,200 m above sea level, whereas the north China populations were only distributed in the subalpine meadows of several mountains. In addition, the petals of CM individuals in northeast China were purplish red, pure white, and light pink, and individuals with rich color variations in their petals have also been found in the Russian Far East and in Rebun Island, Japan , 25. How2 = 0.3117, P = 0.010), this result corresponds to the pattern of North China populations distributed independently in several high mountains, and inbreeding occurred in most populations. Therefore, more attention should be paid to the population in North China. On the whole, external factors  and internal factors (deceptive pollination and low seed germination rate) have accelerated the rapid decline in CM population size and distribution area in the past, weakened or even hindered recent gene flow, and finally led to the genetic differentiation of the population. The present distribution pattern and genetic diversity of CM have been formed due to these factors.The Mantel test is often used to detect IBD in populations in order to understand the relationship between genetic and geographic distances between populations of different geographical origins . AlthougCypripedium, a highly evolved group of plants in the Orchidaceae.The results of the bioinformatics analyses revealed that CM had a low level of genetic diversity and that genetic differentiation occurred between populations of north and northeast China, showing a distinct genetic structure; in particular, substructures were found among north China populations. These results were mainly due to the comprehensive effects of over-collection, habitat fragmentation, limited recent gene flow, and biological characteristics of CM. Our results provide information on the level of genetic diversity, genetic differentiation, population genetic structure, gene flow, and IBD of CM distributed in mainland China, and provide scientific reference for conservation and rational management measures. To protect the existing population and to re-establish population, we propose the following recommendations: (1) Popularize CM as a national key protected plant and improve awareness of CM protection, especially at forest parks or scenic spots where it is distributed. (2) Strengthen resource surveys and monitor the population size of CM to ensure the accuracy and the integrity of conservation. (3) Collect germplasm resources to establish a germplasm bank for rare and endangered species. Although CM tissue culture was a breakthrough in the laboratory, large-scale tissue culture technology and the survival rate of tissue culture seedlings require to be improved. (4) Gradually reintroduce allogeneic individuals in regions suitable for the growth of CM, such as the middle region of north and northeast China, to build a bridge of gene flow and reduce genetic differentiation between populations. (5) Prioritize protection of north China populations from the perspective of ecological edge effect and island effect. (6) Perform more research on the pollinators of CM and understand the pollination biology of the genus In this study, one healthy leaf was collected from each individual as experimental material before June 2021, as CM is mainly propagated by rhizomes, in order to avoid cloning plants, the individuals we sampled were more than 10 m apart, and 106 individuals were randomly selected. The collection was approved by the local forestry departments in Heilongjiang, Hebei and Beijing. The samples were carefully identified by Engineer Shang Dong of Yichun Branch of Heilongjiang Academy of Forestry, a voucher specimen was deposited in the Yichun Forest Museum with an accession number ycl20210607005.The extraction of DNA from each sample was followed the kit manufacturer’s procedure (TIANGEN BIOTECH (BEIJING) CO., LTD), the quality and concentration of DNA were detected until the requirements for library sequencing were met.The libraries were prepared by following the protocol developed by Qi et al. . BrieflyIn order to ensure the quality of subsequent analysis, Raw Reads were filtered according to the following conditions , and fasBased on the comparison results between samples and reference, the SNP sites in samples were predicted by GATK software (V3.8-1) Unified program . And usep value was calculated VCFtools software (V0.1.16) [Ho, He, A, Ae, PIC, indexes of CM populations that primarily reflect levels of genetic diversity were analyzed by R package genepop (V1.1.4) as described , Pi and V0.1.16) .To understand the relationship between populations and visualization of genetic distance, Neighbor-joining tree was constructed with Treebest (V1.9.2)  under thhttps://speciationgenomics.github.io/Treemix/) [The StAMPP program package (V1.6.1)  and Weirreemix/)  was usedThe Mantel test program in GenAlEx (V6.5)  was perf


Objective: The objective of this systematic review and meta-analysis is to assess the effectiveness and security of Chinese herbal medicine (CHM) in the therapy of painful diabetic neuropathy (PDN).Methods: We searched databases for randomized controlled trials (RCTs) of CHM in the treatment of PDN. Outcome indicators included nerve conduction velocity, clinical efficiency, pain score, TCM syndrome score, and adverse events. Stata 16.0 was used to carry out the Meta-analysis.Results: A total of 21 RCTs with 1,737 participants were included. This meta-analysis found that using CHM as adjuvant treatment or as monotherapy for PDN can improve SCV of median nerve , MCV of median nerve , SCV of common peroneal nerve , MCV of common peroneal nerve , SCV of gastrocnemius nerve , SCV of tibial nerve , MCV of tibial nerve  and clinical effective rate  and reduce pain score , TCM syndrome score . In addition, compared to the control group, adverse events of Chinese medicine intervention occurred less.Conclusion: CHM as adjuvant therapy or single treatment has a good curative effect and is safe for patients with PDN, which is worthy of clinical promotion and use, however; higher quality clinical studies are still needed to prove.Systematic Review Registration:https://www.crd.york.ac.uk/, identifier CRD42022327967 Painful diabetic neuropathy (PDN) is a common complication of type 2 diabetes, and about 16%–26% of diabetic patients will progress to PDN . The disChinese herbal medicine which is an essential part of traditional Chinese medicine, has been utilized successfully in China as a supplement and alternative form of therapy for thousands of years. Due to its “comprehensive, multi-channel, multi-target” therapy qualities, CHM has garnered increasing attention in the management of disease and comorbidities . In factIn past decades, the number of RCTs assessing the safety and effectiveness of CHM as a single or adjuvant therapy for PDN has significantly expanded. However, there is still no systematic evaluation and meta-analysis of this issue to date. The purpose of this study is to systematically evaluate the efficacy and safety of CHM in the treatment of PDN, so as to provide high-quality evidence-based basis and treatment strategies for CHN in the treatment of PDN.We completed this study using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines  Supplem. In addiPubMed, Embase, The Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and CBM were the eight databases we scanned through. All databases are available from their inception to 21 April 2022. The main search terms are: “Chinese herbal medicine”, “painful diabetic neuropathy”, “Chinese medicine”, and “diabetic neuropathic pain”.Two researchers (ZP-S and WY-L) independently imported all the retrieved literature into the software EndnoteX9.0 for management and screening. For controversial literature, two researchers negotiate with a third researcher (YT-X).The inclusion criteria were:1) participants: PDN patients ; 2) study format: RCTs; 3) Interventions: the intervention group received CHM treatment (whether CHM as a single therapy or adjuvant therapy) and the control group used western medicine (WM) or placebo; and 4) outcomes: the main outcome indicators include SCV, MCV, pain score, and clinical efficiency The Secondary outcome indicators include TCM syndrome score and adverse events. The exclusion criteria were:1) treatment using acupuncture, massage, or other Chinese medicine; 2) Intervention time is not appropriate; and 3) patients without clear diagnostic criteria or accompanied by other diseases.Herein, the definition of clinical efficiency in each trial is not the same, and the clinical efficiency of the included trials is based on the following criteria. a: Effectiveness: peripheral nerve function or clinical symptoms improved. b: Ineffectiveness: peripheral nerve function or clinical symptoms were not significantly improved or not improved .Data was separately extracted and cross-checked by the two researchers (ZG-L and JH-Z). The extracted data primarily include: 1) the fundamental information of the selected research; 2) key elements of bias risk assessment; 3) outcome data: if the data type were measurement data, the mean and standard deviation were extracted, if the data were count data, the number of events and the total number were extracted.Using the Risk of Bias instrument developed by the Cochrane Collaboration , two resχ2 test (test level = 0.10) was utilized to examine the heterogeneity of the outcomes of these studies, and the I2 test was used to quantify the heterogeneity. If p≥0.10 and I2<50%, the fixed effect model was used for analysis. If p<0.10 and I2 ≥ 50%, it indicates that a huge heterogeneity appeared among the studies, and then subgroup analyses have been conducted so as to make out the origin of heterogeneity. The analysis was carried out using a random effect model when methodological heterogeneity and clinical heterogeneity are absent. α = 0.05 was used as the meta-analysis test level. Through sensitivity analysis, the stability and reliability of the analysis’s results are examined. Publication bias was evaluated using the funnel plot, Begg’s test, and Egger’s test.The meta-analysis of the research data was carried out using Stata16.0 software. The effect analysis statistic for categorical data was OR, while the effect analysis statistic for continuous data was either MD or SMD. For each effect, the 95% CI was calculated. The A sum of 492 papers was found during the preliminary screening, however, 184 papers were eliminated due to repetition, 247 papers were eliminated by reading their titles and abstracts, and 40 papers were eliminated by reading the complete text. Finally, the quantitative analysis covered 21 articles . Figure There are 1737 patients altogether in the sample size of the 21 studies, which include 871 patients in the intervention group and 866 patients in the control group. The intervention group and the control group had equivalent pre-treatment data . All 21 studies were from China , Table 2Among the 21 studies included, 7 studies  were grop < 0.10, I2 = 97.1%). Thus, to combine the effect sizes, we employ a random effects model. The outcomes demonstrated that, in comparison to the control group, the intervention group was able to significantly reduce pain and increase pain scores and the change was statistically meaningful , Angelica sinensis (Oliv.) Diels , and Cnidium monnieri (L.) Cusson  frequency rank among the top three, whose frequency is more than 10 times. This conclusion agrees with the findings of Zhang Fuzhi et al. . Studies have found that ligustrazine can delay the development of DR by inhibiting oxidative stress and retinal ganglion cell apoptosis, down-regulating AGEs content and other ways . Astragal-2 axis . Astragal-2 axis .Although there are more and more clinical studies on the treatment of PDN with CHM, there is no systematic evaluation and meta-analysis in this direction. This study is the first study to systematically evaluate CHM for PDN, filling the evidence-based gap in CHM for PDN. The advantages of this meta-analysis mainly include a clear research topic, its selects high-quality RCTs that meet the inclusion criteria and conducted a statistical analysis of this study in strict accordance with the systematic review method. At the same time, we are more cautious about the explanation of the results. We conducted a subgroup analysis to find out the cause of heterogeneity, and we also conducted a sensitivity analysis and publication bias test. This study found that CHM can be recommended for the treatment of PDN, which offers fresh perspectives and ideas for researching PDN.However, there are a few shortcomings in this work that deserve discussion. First of all, the majority of the included researchers did not use the allocation concealment and blind method, which could cause bias in both selection and implementation. Second, there was significant clinical heterogeneity in the 21 studies with differences in composition, dose, and dosage form of CHM, as well as differences in interventions (type of WM) and duration of intervention in the control group. This would result in a high level of heterogeneity within subgroups when subgroup analyses are performed. However, because of the limited number of studies, we cannot perform relevant subgroup analysis, which in turn affects the accuracy of the results. Third, the duration of the study’s intervention ranged from 4 to 12 weeks, and we could not assess the long-term safety of CHM treatment. Finally, since the randomized controlled trials included in this study are all from China, our study may not be extended to the world. Therefore, a large sample of multi-center studies is needed in the future.In short, CHM, whether a single treatment or adjuvant therapy, can improve nerve conduction velocity in patients with PDN, reduce pain score and TCM syndrome score, and improve clinical efficiency. These results can guide clinical practice. In addition, CHM is well tolerated and safe in patients with PDN, with a low incidence of adverse events. However, given the study’s heterogeneity and small sample size, bigger multi-center, high-quality RCTs will be required in the future to evaluate the advantages and safety of CHM in the treatment of PDN.


Impaired trunk control is common in neurological disorders; however, trunk control has not been examined in patients with cervical dystonia (CD). Therefore, the primary aim was to compare trunk control between patients with CD and healthy people. The secondary aim was to investigate the relationship between trunk control and balance, functional mobility, and disease severity in patients with CD.This cross-sectional study included 32 patients with CD and 32 healthy people. Trunk control was compared using the trunk impairment scale (TIS) that consists of three subscales: static sitting balance, dynamic sitting balance, and trunk coordination between two groups. Balance was assessed using Berg Balance Scale, four square step test, and one-leg stance test. The Timed Up and Go Test was measured to determine functional mobility. Toronto Western Spasmodic Torticollis Rating Scale was used to evaluate disease severity.Patients with CD demonstrated worse performance on the TIS-total with TIS-dynamic sitting subscale and TIS-trunk coordination subscale , except for TIS-static sitting subscale (p = 0.078) compared to healthy people. TIS-total scores had moderate to strong correlations with balance, functional mobility, and disease severity . There was no correlation between TIS-total scores and disease severity (p = 0.102).Patients with CD had impaired trunk control, especially in dynamic sitting balance and trunk coordination. Impaired trunk control was also associated with balance and functional mobility but not disease severity. These findings suggest that trunk control deficits should receive attention in the assessment and treatment of patients with CD. Cervical dystonia (CD) is a chronic neurologic disease characterized by sustained and involuntary contractions of the neck muscles that cause nonfunctional neck and head postures ,2. The pDystonia can adversely affect movement control and balance even when it does not have a direct impact on the limbs or trunk such as CD . CompareThis cross-sectional study was performed at the Department of Neurology of Gazi University, between May and July 2022. This study was confirmed by Gazi University Clinical Research Ethics Committee , and was in accordance with the Declaration of Helsinki. All participants signed informed consent prior to participation in the study.No study has examined the trunk impairment scale in patients with CD up to now; therefore, the sample size was provided with a power calculation based on the differences in trunk impairment scale (TIS) score between multiple sclerosis as a neurological disease and healthy people. A previous study reported that patients with multiple sclerosis had 20.29 ± 4.88 points while healthy people had 23.00 ± 0.0 points on the TIS . To detePatients, who were diagnosed with CD, were invited by a neurologist in the present study. Inclusion criteria were at least 18 years of age, able to walk independently with or without a walking aid, and at least 3 months since the last injection or immediately prior to a new injection of botulinum toxin to minimize the clinical effect of the injection. Exclusion criteria were other neurologic disorders, antalgic/pathologic gait pattern, secondary or hereditary forms of dystonia, dystonia in other body parts than the neck, and any other conditions that affect trunk, balance, and gait. Age- and sex-matched healthy participants with the same exclusion criteria were included as the control group in the study.Demographic and clinical characteristics of all participants were recorded. Patients with CD were assessed with the TIS, Berg Balance Scale (BBS), four square step test (FSST), one-leg stance test (OLST), timed up and go test (TUG), and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), respectively. Three different assessments, which were the BBS, FSST, and OLST, were used to measure the functional, dynamic and static components of balance, respectively. To compare patients with CD, healthy people only performed the TIS.The TIS is used to assess trunk control, and has three subscales including static sitting balance, dynamic sitting balance, and trunk coordination. The maximal score of the static and dynamic sitting balance and trunk coordination is 7, 10, and 6, respectively. The total score of TIS ranges between 0 and 23. Higher score indicates better trunk control . The tesThe BBS evaluates functional balance, and has 14 items related to daily living activities. Each item is scored from 0 to 4. The total score is between 0 and 56, with higher scores representing better functional balance . The BBSThe FSST is a clinical test assessing dynamic balance performance. Participants are asked to step forward, backward, and sideways over canes on the floor as rapidly as possible. The completion time is recorded, with lower time demonstrating better dynamic balance . For patThe OLST assesses static balance performance. Participants are instructed to stand barefoot on one leg, eyes open, with the arms folded their chest, for a maximum of 30 s. The time is started when participants raised their leg and is stopped when participants’ foot either contacts with the floor or touches with the other leg or participant moves the standing foot or participant’s arms leaved the trunk. Higher time reflects better static balance . The OLSThe TUG is commonly used to measure functional mobility. In this test, participants are required to stand up from a chair, walk 3 m, turn around, return to the chair, and sit down again. The time taken to complete the test is recorded. Lower time demonstrates better functional mobility performance . The TUGThe TWSTRS is originally developed to measure the severity of CD. Its scores range from 0 to 85 points, with higher score showing higher disease severity , 28. TheAll statistical analyses were performed using the Statistical Package for the Social Sciences version 17.0 . Descriptive statistics were used to describe the demographic and clinical characteristics of the participants. The normality of the distribution for all variables was evaluated by the Shapiro-Wilk test. Differences in the mean values between patients with CD and healthy people were analyzed using independent t-tests. Correlations between the TIS-total and the BBS, FSST, OLST, TUG, and TWSTRS were analyzed with Pearson’s correlation coefficients (r). The degree of correlation coefficients were classified as poor (0.0–0.25), fair (0.25–0.50), moderate (0.50–0.75), or strong (0.75–1.0) . The staIn total, 32 patients with CD  and 32 healthy people  were recruited for this study. There were no significant differences in age, sex, weight, and height between patients with CD and healthy people . Demographic and clinical characteristics of the study participants are presented in Compared to the healthy people, patients with CD had significantly lower scores on the TIS-total (p < 0.001) with the TIS-dynamic sitting balance subscale (p < 0.001), and TIS-trunk coordination subscale (p < 0.001) except for TIS-static sitting balance subscale (p = 0.078) .For the patients with CD, the values of the BBS, FSST, OLST, TUG, and TWSTRS, and their correlations with the TIS-total are presented in The main result of the study is that impaired trunk control, particularly the loss of performance in dynamic sitting balance and trunk coordination, was found for patients with CD. In addition, trunk control was associated with balance and functional mobility but no association with disease severity in CD.Patients with CD demonstrated decreased trunk control compared to healthy people. Especially, dynamic sitting balance and trunk coordination worsened, except for static sitting balance for CD. The pathological head deviation could result from an offset of a nonsensory set point input that is required for head-on-trunk control . AbnormaThe strength of the neck reflexes, specifically the cervico-collic and vestibulo-collic reflexes, reflect the link between the head and trunk . DeterioTrunk control showed moderate to high correlations with static, dynamic, and functional balance. These results were in line with previous studies conducted on stroke , 43, mulThere was a moderate correlation between trunk control and functional mobility. It was documented that poor mobility level was closely associated with poor trunk control in different neurological populations ,49. AccoThere was no significant correlation between trunk control and disease severity. After botulinum toxin treatment, reduced disease severity with improved head posture and movements did not enhance balance performance ,56. In aThe present study has several limitations. First, this study was a cross-sectional design; thus, the interpretation of the causal relationship between trunk control and balance, functional mobility, and disease severity was limited. Future studies should use a prospective design with pre and postintervention evaluations on the trunk control and a no-intervention comparison group to investigate the effects of trunk control intervention. All of the patients with CD were community-dwelling and could walk without physical assistance, which may restrict the generalizability of the findings. Generally, botulinum toxin is injected into the affected muscles of most of the patients with CD at 12-week intervals in the standard medical care of the disease, so the trunk control and its association with balance, functional mobility, disease severity should be assessed across the treatment cycle.The results of this study demonstrated that patients with CD had impaired trunk control, especially dynamic sitting balance and trunk control, compared with healthy people. Impaired trunk control was associated with balance and functional mobility but not with disease severity. In clinical practice, the development of effective strategies for assessing and increasing trunk control should be included in the treatment programs to enhance balance and functional mobility.


Understanding nutritional status among women of childbearing age (WCA) is of increasing concern, as nutrient intakes may affect the health of WCA and well-being of their offspring. This study aimed to investigate secular trends of dietary energy and macronutrients intakes and access longitudinally the urban-rural and geographic disparities among Chinese WCA.A total of 10,219 participants were involved in three rounds of the Chinese Health and Nutrition Survey . Average macronutrients intakes were compared against the Chinese Dietary Reference Intakes Standard (DRIs) to better assess adequacy. Mixed effect models were used to estimate the secular trends of dietary intake.A total of 10,219 participants were involved. Dietary fat, the percentage of energy (%E) from fat, and the proportion with more than 30% of energy from fat and less than 50% from carbohydrates increased notably over time (p < 0.001). In 2015, urban western WCA had the most dietary fat (89.5 g/d), %E from fat (41.4%), with the highest proportion of energy from fat (81.7%) and carbohydrate (72.1%) out the range of DRIs. From 1991 to 2015, the average urban-rural differences in dietary fat decreased from 15.7 g/d to 3.2 g/d among eastern WCA. However, it increased to 16.4 g/d and 6.3 g/d among central and western WCA, respectively.WCA was experiencing a rapid transformation to a high-fat diet. Temporal variation with obvious urban-rural and geographic disparities in dietary. energy and macronutrient composition persistently existed among Chinese WCA.These findings have implications of future public strategies to strengthen the nutrition propaganda and education of balanced diet for WCA to help them to improve their nutritional status, especially for those living in western China. Women of childbearing age (WCA) are at greater risk of adverse health outcomes than other groups due to their higher physiological requirements. In particular, the need for appropriate nutrient intakes increases significantly during pregnancy, lactation, or menstruation. Adequate access to nutritional information not only helps to provide targeted dietary advice for WCA but also indirectly promotes the well-being of their children, who will eventually become the main workforce or leaders of the country –3. In ChIn China, people’s diets and lifestyles have undergone significant changes towards choosing a western-style diet high in fat and animal-based foods with rapid urbanization and socioeconomic transition over the past few decades . In partBeing the largest developing country in the world, WCA accounted for 24.7% of the total population of China. The Chinese government recently adopted a program encouraging couples to have three children, which has increased the number of multi- parent families . AccordiTo date, a growing volume of epidemiological studies has been conducted to evaluate nutrient adequacy and urban-rural disparities in nutrition in China. However, most investigations in this area have been focused on the Chinese elderly and children, but seldom on WCA –20. FurtThis was a population-based, longitudinal study. The related data of WCA were derived from the China Health and Nutrition Survey (CHNS), which was conducted every two or three years from 1989 up to the present . Each roTrained healthcare workers conducted face-to-face interviews with participants and their families at baseline to collect data on demographic characteristics, eating habits, and frequency of dietary, and nutrient intake, as well as behavioral factors of WCA. To observe and compare the degree of transformation and trends at intervals of more than a decade, the present analysis was based on three rounds of the CHNS, conducted in 1991, 2004, and 2015. A total of 10,219 women aged between 15 and 49 years old with complete data on demographic, socioeconomic status, and dietary information in a survey year were included in the present study after excluding participants with (n = 121) implausible energy intakes  from the analysis .The three consecutive 24-hour dietary recall was used to collect food intake information in each wave of CHNS, except for the condiment intake, which was collected by the weighting method . Partici2) [The educational level was classified as primary school or illiterate, middle school, high school, or above. The per-capital annual income in each survey was inflated to values in 2015. The marital status was divided into single or married. Participants’ height (seca 260) and weight (seca 880) were measured by trained health workers, and their Body Mass Index (BMI) was calculated using the standard formula: weight in kilograms/square of height in meters (kg/m2) . Partici2) . Smoking2) .2) test was used to assess the association between the different levels  of DRIs for macronutrients. T-tests were used to estimate the differences in dietary intake within a year. Mixed effect models were used to calculate the adjusted intake of dietary energy, macronutrients, and macronutrient-energy percentages, and to estimate the dietary trend across the survey rounds and the dietary differences between years, stratified by urban-rural and geographic districts. Meanwhile, dietary energy and macronutrient composition were treated as the dependent variables in each model. Statistical significance was considered if p values＜0.05.These analyses were performed with the use of SAS software  version 9.4. Continuous variables were presented as mean and standard error (SE) and categorical variables by percentage and SE of percentage. The chi-square . The smoking status of WCA was relatively stable, but the drinking status increased significantly over time (p < 0.001). The proportion of WCA from eastern China increased notably from 1991 to 2015 (p < 0.001).The general characteristics of participants in three rounds of CHNS  are presented in Table Table As seen in Table As seen in Fig. As seen in Table A Comparison of the change values of urban-rural differences in dietary fat, protein, and carbohydrate intake in every two rounds of surveys is presented in Fig. Based on more than two decades of data from the CHNS, the current study provides useful information on the nutritional status of Chinese WCA. This is the first attempt, to our knowledge, to gain access to the nutrition of Chinese WCA, with a focus on urban-rural and geographic differences, through the interpretation of a longitudinal study on nutritional status. China has achieved significant progress in WCA nutrition. We did notice, however, that Chinese WCA were making a rapid nutritional shift to a high-fat diet over time. Meanwhile, in the distribution of dietary energy consumption and macronutrient composition, there were persisting urban-rural and geographic differences. In comparison to other groups, WCA in urban western China consumes higher dietary fat.Over the last two decades, China has experienced fast economic expansion and significant urbanization. In the meantime, the Chinese people are undergoing a significant nutritional shift. The current study found that the amount of dietary energy consumed by Chinese WCA decreased over time. In 2015, the average daily energy intake was 1,870 kcal, which was higher than the Moroccan study but lower than the Tunisian women’s consumption , 31. ThiA previous study reported that commercial logistics facilities in rural areas remain weak and vulnerable, which hampers rural consumption. The food consumers of urban residents mainly rely on market supply, while the rural population mainly relies on self-produced agricultural products . In the China has a remarkable urban-rural dual economic structure, as well as regional differences in economic structure. To narrow the gaps between regions and promote balanced and coordinated development between urban and rural areas, the Chinese government has promulgated a series of policies and measures . A recenNutritional knowledge and attitudes are important factors in dietary habits. They are essential for good pregnancy outcomes and for improving the nutritional status of their children . FindingAlthough the present research is significant and novel in some respects, certain limitations should be considered when interpreting the results. First, our findings were based on three consecutive 24-hour dietary recall methods, and the associated over or underestimation of dietary energy and macronutrient intakes is a common situation with such dietary assessment tools. Second, dietary energy and macronutrients existed in a variety of foods, but this study did not estimate the specific types of food consumption by food groups, which makes it impossible for us to consider which food causes the above unreasonable diet, to further provide suggestions on food frequency for Chinese WCA.The Chinese WCA was undergoing a dramatic nutritional transformation to an unhealthy, high-fat diet. In the distribution of dietary energy intake and macronutrient composition in the Chinese WCA, obvious urban-rural and geographic disparities persisted. Policymakers should adopt more targeted policies and dietary improvement approaches in urban and rural areas and between different regions of China, as well as strengthen nutrition promotion and education on a balanced diet, especially for those living in western China.


Australian and New Zealand Journal of Public Health is the most prominent journal publishing in the field. The most commonly co-occurring keyword was “health,” and the keyword “risk” had the longest citation burst. Five keyword clusters were identified; “cultural safety” was the largest. This study articulates the knowledge structure of the research, revealing a shift from population-level and data-driven studies to more applied research that informs Indigenous peoples health and wellbeing. Based on this review, we anticipate emergent research areas to (1) reflect a more comprehensive understanding of the multidimensional factors that shape Indigenous health and wellbeing; (2) move beyond a deficit-based perspective; (3) respect cultural protocols and protect the rights and privacy of Indigenous participants; (4) address racism and discrimination within the healthcare system; (5) foster respectful, equitable, and collaborative research practices with Indigenous peoples; (6) provide culturally appropriate and effective interventions for prevention, early intervention, and treatment; and (7) ensure equitable change in systems to enhance access, quality, and outcomes in health and wellbeing.The health and wellbeing of Australian Indigenous peoples is a nationally sanctioned priority, but despite this, few studies have comprehensively analyzed the features and characteristics of the research in the field. In this regard, a comprehensive scientometric analysis and knowledge mapping to systematically summarize and discuss the current state of research, research trends, and emerging areas of research were conducted. Original articles and reviews published between 2003 and 2022 were obtained from the Web of Science Core Collection. CiteSpace and VOSviewer software were used to perform scientometric analysis and knowledge mapping. An examination of document and citation trends, authors, institutions, countries/regions, journals, and keywords was untaken, while co-citation, co-occurrence, and burst analysis provide insights and future development in this area. A total of 2,468 documents in this field were retrieved. A gradual increase in the number of documents over the past two decades is observed, with the number of documents doubling every ~7.5 years. Author Thompson SC and Charles Darwin University published the most documents, and 85.6% were affiliated with only Australian-based researchers. The  In 2018One direction is to investigate the evolution of a research topic. In our attempt to detect trends in Indigenous health and wellbeing research, we combine modelling and visualization to establish a knowledge base that will have important value for academics, practitioners, and government departments to formulate public health strategies and provide support and guidance for future research.In this study, we combine bibliometric and scientometric techniques to analyze the knowledge structure regarding research productivity, and collaboration across authors, institutions, and countries/regions, and to reveal trends and forecast emerging areas of research. Despite similar approaches in other fields , this stRQ1. What are the trends and forecasted growth in documents?RQ2. Who are the most influential authors, institutions, countries/regions, and journals?RQ3. Which documents and keywords are the most impactful?RQ4. What are the dominant topics, trends, and emerging research areas?Addressing these research questions will fill important gaps in the current body of knowledge, and advance our understanding of research related to the health and wellbeing of Australian Indigenous peoples.22.1This study examines the published scientific literature related to Indigenous health and wellbeing using scientometric analysis and knowledge mapping. The detailed procedure is discussed in the following sections.2.2Scientometric analysis is a quantitative research method that focuses on the analysis and mapping of scientific literature, to explore research themes and collaboration clusters, and to identify gaps and trends . It invo2.3The selected source for the literature search and collection is the Web of Science Core Collection (WoSCC) database . A retriOriginal articles and reviews (including early access articles) were included. A total of 2,800 documents were identified, of which, 332 records were excluded: meeting abstracts, editorial material, letters, and proceeding/data papers. Ethical approval was not applicable. For the present study, 2,468 documents  were obtained as the final dataset for analysis. Data were obtained from WoSCC in .csv format for analysis, and in plain text format (full records and cited references) to visualize the data.2.4Number of documents: To quantify the amount of research conducted over time, as distributed by authors, institutions, countries/regions, journals, and research categories.Number of citations: To examine trends in research over time, and to identify the most influential authors, institutions, countries/regions, and journals.Co-authorship: To evaluate collaboration networks of authors, institutions, and countries/regions, providing insight into the social connections across the domain.Co-citation: To analyze the frequency with which documents are cited together by other researchers, and to reveal clusters of interdisciplinary research trends.Co-occurrence: To identify related keywords and measure the strength of their links to visualize trending and emerging research themes.h-index: To quantify both productivity and impact.Journal Impact factor (JIF) and quartile in category (Q1-Q4) were obtained from the 2021 Journal Citation Report .2.5Based on the analysis approach, Microsoft Excel 2022  was used to analyze and graph document and citation metrics. The most influential documents were identified based on their citation count, and the top 10 authors, institutions, countries/regions, and journals were identified based on the number of documents. Journal research categories are presented as document counts and proportions.VOSviewer (version 1.6.16)  was used to visualize the networks of authors and institutions . Full-coCiteSpace (version 6.1.R6)  was usedTo achieve this, the following scientometric techniques were employed:Co-citation analysis of documents quantifies how often documents are cited together, revealing influential publications with high citations (bursts) and related clusters.Keyword co-occurrence analysis identifies the most important keywords  that represent the conceptual building blocks of the scientific literature.Burst detection of highly co-cited documents and keyword co-occurrences highlight significant literature and keywords . The burCluster analysis divides the networks into clusters by extricating terms from the title, abstract, author keywords, and keyword plus using the default algorithm log-likelihood ratio test. The top 50 keywords that appear in each time slice are presented and clusters are identified using distinct colors and labelled using CiteSpace.Timeline visualizations are generated from cluster analysis on a discrete horizontal axis. The term source includes title, abstract, author, keywords, and keyword plus of cited documents using the log-likelihood ratio algorithm. Clusters are arranged in a vertical manner descending in size, with the largest cluster at the top (#0). Each node represents a document, links between two nodes represent the co-citation/co-occurrence, and color corresponds to the year they most recently appeared. Documents with a citation burst and/or highly cited are denoted with a bright purple ring.33.1R2 = 0.9792) over time. A forecast estimate of future trends in Indigenous health and wellbeing research based on the equation of model fit indicates an additional 1,488 documents  published in the next five years (2023–2027); representing an average annual performance of 6.20% (95% CI 4.7 to 10.9%).Overall, publications have steadily increased from 21 documents in 2003, to 236 documents in 2022 (an average of 123 documents published/year). The average annual performance is 15.1% (95% CI 8.1 to 23.1%) and on average, the number of documents doubled every 7.5 years . In the 3.2n = 2,344) of documents are co-authored, and the median number of authors per paper is five (range: 1 to 65). The top 10 authors with the greatest number of documents are listed in n = 608; 24.6%) of all documents included in this study. These authors are affiliated with eight institutions, four of which are members of Australia’s leading research-intensive universities, known as the Group of Eight (Go8) (n = 87), total citations , and h-index  . Thompso h-index  related n = 57 and 79 links), Thompson, SC  has the most citations (n = 931), and Ward, J  has the highest TLS of 209. Other authors with notably high TLS include Brown, A (196), Garvey, G  (179), and Thompson SC (157).3.3n = 476), and the Menzies School of Health Research (n = 417). A visualization of the institution network highlights four clusters. As can be seen in A network of 1,616 institutions has contributed to the research; 3.4n = 2,113) are authored by Australian institutions only, and the remaining 355 publications are affiliated with authors predominantly from the United States (25.07%), Canada (24.22%), England (22.53%), and New Zealand (20.28%)  . While t3.5Australian and New Zealand Journal of Public Health has published the most documents (n = 113), followed by the International Journal of Environmental Research and Public Health (n = 96). The Medical Journal of Australia is the only Q1-ranked journal and has the highest impact factor at 12.766. Six of the 10 journals are classified as Public, Environmental, and Occupational Health based on the journal’s research area (as categorized by WoSCC).Over the past two decades, a total of 632 journals have been the 2,468 documents. The top 10 most active journals are presented in 3.6n = 241, links = 2,987). To ensure a clearer picture, only nodes with ≥60 co-citations are labelled. The top three highly co-cited documents are the publications by Key steps to building a knowledge structure include identification of highly cited articles and key research areas. Based on the co-citation analysis network , cluster3.7The keywords of a document reflect the research focus of publications. Here, we analyze the co-occurrence of keyword trends to explore research topics and frontiers in the field of Indigenous health and wellbeing. A network of 145 nodes (related keywords), and 862 links (connections), with a density of 0.0826 is shown in The keyword network was divided into five clusters which represent the main keyword categories of Indigenous health and wellbeing research see . The evo4This study provides an extended view of Indigenous health and wellbeing research published over the past two decades – offering insights into the achievements, knowledge structure, research trends and emerging areas. It is the first to apply scientometric techniques to represent the dynamic and structural features of the research visually.Our analysis of 2,468 documents reveals prominent authors, institutions, countries/regions, and journals who have contributed to Indigenous health and wellbeing research over the past two decades - with an estimated 60% increase in the volume of documents by 2027. This growth likely reflects the growing national priorities for the health and wellbeing outcomes for Indigenous peoples and communities in Australia , the avaEach of the top 10 authors published at least 36 documents. Thompson SC had the greatest number of documents, number of total citations, and highest h-index. The focus of Professor Thompson’s research is the prevention and management of chronic disease in remote communities and Aboriginal health. In a 2010 review of Australia’s National bowel cancer screening program, barriers that exclude vulnerable minorities, including Indigenous groups, from participating in bowel cancer screening initiatives and the greater incidence of late-stage cancer and mortality among Indigenous peoples are highlighted . Since tn = 508; 20.6%), and despite the University of Melbourne ranking fourth, it had the highest average citation rate of 17.7. The University of Sydney co-authored the greatest number of publications with international institutions (n = 84). It is worth noting that these lead institutions are renowned research and higher education organizations with prominent positions in Indigenous health research portfolios. Collectively, authors with affiliations to institutions based in the USA co-authored the most documents with Australia, albeit authors affiliated with the University of Toronto had the greatest single number of documents (n = 31).According to our analysis, authors affiliated with Charles Darwin University had published the most documents , and the Medical Journal of Australia had the highest impact factor (12.776) and citation count . It is worth noting that most JCR partitions are categorized as Q2 and only one is a Q1 journal. These data will help researchers when they submit articles about Indigenous health and wellbeing in the future.The 4.1Medical Journal of Australia (IF = 7.738) and two in the Lancet (IF = 79.321). The document that received the most citations (n = 481) accounts for 1.37% of the total citation count , of which 42 belonged to cluster #1 “First Nations” and two belonged to cluster #2 “child health” . The “Fi4.2Next, we reflect on trends in the research based on the timeline view of keyword co-occurrence clusters . In the During the mid-2000s, Indigenous health and wellbeing research shifted to understanding and improving the experiences and participation of Indigenous peoples in health services. It explored the role of communication and cultural knowledge in enhancing healthcare interactions and outcomes and it sought to identify the unique challenges faced by Indigenous women in accessing and receiving appropriate healthcare services. The impact of cultural factors on health-seeking behaviors, and the role of education and knowledge exchange in improving health literacy within Indigenous communities is also a focus. This research would inform strategies to improve healthcare delivery, promote culturally sensitive practices, and develop targeted interventions that address the specific needs and experiences of Indigenous peoples. Ultimately, the research sought to contribute by ensuring active participation and improved experiences in healthcare settings for Indigenous communities.By the late 2000s, a surge in research to understand and mitigate the burden experienced by Indigenous peoples in Australia, particularly associated with the impact of racism, historical colonization, and socio-cultural determinants, can be observed. Although instances of racism in Aboriginal and Torres Strait Islander health have been documented since the introduction of Closing the Gap in 2020, it was the Black Lives Matter movement that garnered worldwide recognition . Studies4.3Despite the high level of investment, the gap in health and wellbeing outcomes between Indigenous and non-indigenous Australians remains alarmingly wide. Based on this study and through extensive reading of the literature, we consider the following areas to be emergent research approaches and practices .Emergent approaches will contribute to a more holistic understanding of health and wellbeing, foster respect for Indigenous ways of knowing, and promote more equitable and inclusive research practices. An example is the concept of Two-Eyed Seeing introduced by Mi’kmaq Elders Albert and Murdena Marshall . This apIntersectionality and holistic advances: Taking a more comprehensive understanding of the complex and multidimensional factors that shape Indigenous health, but in particular, wellbeing. This includes exploring the intersectionality of various factors, such as gender, age, socioeconomic status, highest educational attainment, and geographic location, to gain a more comprehensive and nuanced understanding of disparities, and lead to more effective interventions and policies that address the diverse needs and experiences of Indigenous peoples, recognizing their cultural strengths and promoting holistic health outcomes.Strengths-based and resilience-focused: Exploring the strengths and resilience within Indigenous communities, highlighting protective factors and successful health promotion strategies. This includes Indigenous leadership and governance in decision-making processes, policy development, and program implementation, or approaches that recognize the wisdom and guidance of Elders and traditional knowledge holders within communities. This approach aims to move beyond a deficit-based perspective, promote culturally appropriate and sustainable strategies, and empower Indigenous peoples to take an active role in their health and wellbeing.Indigenous data sovereignty and ethical research: A growing emphasis on Indigenous data sovereignty, which involves Indigenous control and ownership of data collected from the community. Researchers need to uphold ethical research practices that respect cultural protocols and protect the rights and privacy of Indigenous participants.Emergent practices signify a shift toward more respectful, equitable, and effective research practices that honor Indigenous self-determination and prioritize the wellbeing of Indigenous peoples. An example is community-based participatory research that engages Indigenous communities as active partners in the research process, from defining research questions to interpreting results and implementing findings. This approach aims to address the historical power imbalances that have often characterized research involving Indigenous peoples and ensure that research is conducted in a way that aligns with the values, needs, and priorities of the community. Practices may include:Culturally responsive healthcare: Delving deeper into the concept of cultural safety in healthcare settings, examining strategies and interventions that promote culturally competent care delivery and addressing racism and discrimination within the healthcare system are warranted. This includes cultural awareness and competence training, communication collaborative decision-making, respect for cultural protocols and practices, workforce development, and addressing systemic issues and power imbalance.Indigenous-led research and community partnerships: There is increasing recognition of the importance of Indigenous-led research and community partnerships that foster respectful, equitable, and collaborative research practices and value Indigenous knowledge, perspectives, and self-determination. Research that involves close collaborations with Indigenous communities, ensuring their active participation in research design, implementation, and decision-making processes.Mental health and social and emotional wellbeing: While already a focus in earlier research, a deeper understanding of the specific mental health challenges faced by Indigenous peoples is culturally appropriate and culturally safe for prevention, early intervention, and treatment.Health policy and system reform: Continuing to inform health policies, and organizational and administrative procedures that advocate for system changes to reduce health disparities, improve access to quality healthcare services, and address the social determinants of health that contribute to Indigenous health inequities.5To the best of our knowledge, this study is the first to systematically examine Indigenous health and wellbeing research using scientometric analysis and knowledge mapping - filling a significant gap in the existing literature. We review a substantial body of literature in a precise and objective manner, to provide insights for researchers engaged in the field. An exploration of the interrelationships among authors, institutions, countries/regions, journals, keywords, citations/co-citations, and references strengthens the robustness of our findings. Nonetheless, it is crucial to acknowledge the existence of limitations.Firstly, we selected the WoSCC database as a comprehensive and respected platform for bibliometric analysis. Despite the standardization and consistency of publication records, there remains the potential that this approach is a non-exhaustive exploration of the literature . Second,on Indigenous peoples and research with Indigenous peoples is critical. The latter necessitates a sense of relational accountability and research solely on Indigenous peoples often produces findings with diminished validity and reliability, and in the worst cases, it exacerbates the persistent overrepresentation of Indigenous populations facing significant challenges to their wellbeing.Despite not being within the scope of this study, we still acknowledge that distinguishing between research 6with Indigenous communities. This shift away from conventional deficit mindsets, coupled with a heightened focus on recognizing cultural protocols and privacy considerations, will increasingly underpin the exploration of Indigenous individuals’ experiences as they navigate their health and wellbeing. In an era of heightened awareness and significant investment in Indigenous health and wellbeing research in Australia, the imperative to articulate and prioritize outcomes for Indigenous peoples is more compelling than ever. By presenting this updated perspective based on two decades of published literature, this study not only provides an enhanced understanding of the knowledge in this field but also guides future research efforts.This study represents a comprehensive scientometric analysis and knowledge mapping of Indigenous health and wellbeing research in Australia spanning 2003 to 2022. Our findings not only highlight a substantial and escalating focus of research within this field but also a change from population-level and data-driven studies towards community-based practices and applied research methodologies. Looking ahead in Indigenous health and wellbeing research, we can anticipate a growing emphasis on practices and methodologies that give precedence to forging robust partnerships The original contributions presented in the study are included in the article/MK: Conceptualization, data Curation, Formal Analysis, Investigation, Methodology. Visualisation, Writing – original draft, Writing – review & editing. KH: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. PA: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. CS: Investigation, Methodology, Resources, Writing – review & editing, Writing – original draft.


Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database  was searched on 17 October 2022, using the search terms “marker *” OR biomarker * AND “renal disease” OR “kidney disease” AND “proteome *” OR “peptid *” AND “urin *”. English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers. Chronic kidney disease (CKD) is one of the most challenging global health burdens in present time and has a severe impact on the morbidity and mortality of western societies . The guiA review of the recent literature regarding the urinary biomarkers of CKD was performed, strictly following the PRISMA guidelines and using the Web of Science database . Manuscripts published from October 2017 until October 2022 were considered eligible for this review. Titles and topics were screened for the search terms “marker *” OR biomarker * AND “renal disease” OR “kidney disease” AND “proteome *” OR “peptid *” AND “urin *”. The search strategy is presented in The numerously cited research articles from the last 5 years revealed a collection of single protein-based biomarkers for kidney diseases and disease progression. Most of them were established in prior years and are still the focus of current investigations, highlighting their importance for the monitoring of CKD.Nephrotic syndrome is the second most common cause of CKD in the first three decades of life. Its underlying pathologies move on a spectrum of diseases and a correct diagnosis is pivotal for an estimation of its prognosis and therapy, as some are steroid-sensitive and others are not. There has been ongoing discussion about the differentiation of minimal change disease (MCD) and focal segmental glomerular sclerosis (FSGS), which may be manifestations of the same pathomechanism at different stages . DiscrimDickkopf-related protein 3 (DKK3) is a secreted glycoprotein derived from tubular epithelia cells. Its involvement in the canonical WNT-β-Catenin signalling pathway has been shown to be a potential driver of kidney fibrosis, a hallmark of progressing CKD ,18. DKK3p < 0.001). In the longitudinal observation of the advanced DKD cases, the uEGF/Cr was associated with a percentage change in the eGFR slope, a composite endpoint of ESKD, and a 30% reduction in eGFR [p < 0.001), and the predictive value of uEGF/Cr was superior to eGFR or proteinuria, with an AUC of 0.88 vs 0.77 and 0.81, respectively. These findings show promise for uEGF as a progression marker for CKD and especially DKD [Epidermal growth factor (EGF) is a tubule-specific kidney polypeptide which confers biological functions such as cellular metabolism and glomerular hemodynamics, cell growth, and injury repair . While E in eGFR . Menez e in eGFR . In a No in eGFR . In a smally DKD .Kidney injury molecule 1 (KIM-1) is a membrane protein expressed in the liver, spleen, and kidney. It has been shown to play a role in kidney disease and kidney injury through a number of different molecular targets and serve as a biomarker for AKI and CKD . In a stn = 48). The prediction of kidney involvement, as well as the treatment response to Rituximab, were tested. The uMCP-1 levels were higher in the SLE patients compared to those in the healthy controls, and MCP-1, among four other markers, was higher in patients with active LN compared to non-active LN. An ROC analysis using a combined biomarker, including MCP-1, showed an AUC of 0.898 for predicting LN. A different biomarker combination encompassing MCP-1 was predictive of the treatment response to Rituximab [Monocyte chemoattractant protein-1 (MCP-1) or CC-chemokine ligand 2 (CCL2) is a chemotactic cytokine that confers innate immunity and tissue inflammation through its role in monocyte/macrophage recruitment and migration. Several kidney cells, including mesangial cells and podocytes, have been shown to release MCP-1 after a variety of inflammatory stimuli and induce numerous inflammatory cascades . In a laituximab . In a seituximab . In a thituximab . In the ituximab . In concMatrix Metalloproteinase 7 is a zinc-dependent endopeptidase upregulated in the kidney in acute or chronic kidney damage, transcriptionally activated by the WNT/β-Catenin pathway. Two independent studies showed the potential role of MMP-7 in AKI and CKD. In a cohort of 102 CKD patients, the urinary levels of MMP-7 were elevated in the CKD group compared to the healthy controls. MMP-7 was correlated with the degree of kidney fibrosis and inversely correlated with kidney function in patients with moderate CKD . In a prp =0008) to be independently correlated with eGFR [NGAL is a protein that was initially discovered in activated neutrophils, which then was shown to be produced in a variety of other cells, including kidney tubule cells, as a response to injury. NGAL has been shown to have predictive properties in AKI and, subsequently, evidence has been found for its importance in CKD, specifically in polycystic kidney disease and glomerulonephritis . Four ofith eGFR . In a reith eGFR . A prospith eGFR . In the ith eGFR . Uromodulin  is produced in the kidney and physiologically excreted into the urine. It has been associated with immunological mechanisms and electrolyte balance and shown to have protective functions against urinary tract infections and kidney stone formation in animal knockout models. Several studies have investigated uromodulin as a serum marker for AKI and CKD ,48,49,50p < 0.001) [p < 0.0001) and outperformed proteinuria [84 patients who underwent kidney biopsies were assessed for serum and urinary growth differentiation factor–15 (GDF15), a member of the TGF-β superfamily, and followed-up for 29 ± 17 months. The urinary GDF15 levels were higher in patients with DKD. Urinary GDF15 was predictive of patient survival and a composite outcome of mortality and kidney replacement therapy with an ROC-AUC of 0.95  . A study< 0.001) . A popul< 0.001) . Serum G< 0.001) . Endotro< 0.001) . Other u< 0.001) . In two < 0.001) . In a seteinuria .As evident from the studies presented above, the accuracy and consequent reproducibility of findings based on single biomarkers are moderate, sometimes even with conflicting results. These issues, which also hold true for the classical biomarkers eGFR and albuminuria, have resulted in the concept of using multiple biomarkers to reduce variability and thereby increase precision. In the majority of peptide-based biomarker research studies on CKD, authors choose a panel of individual peptide biomarkers and combine them to a biomarker model. Such a combination of multiple peptide biomarkers increases stability and accuracy ,63.This emphasizes a potential benefit of choosing a large-scale, hypothesis-free approach when trying to discover the relevant biomarkers in certain populations or disease entities. Proteomic research offers high-resolution and high-throughput methods for identifying thousands of peptides within a specimen. The quantification and differential occurrence of peptide fragments can then be used to generate multidimensional classifiers containing up to hundreds of peptides differentially abundant between patient groups. Following this, we want to discuss the novel proteomic biomarkers and studies with impacts on CKD diagnosis, evaluation of progression, and the guidance of its treatment.CKD273 is a urinary proteomic classifier containing 273 peptides that was originally discovered in 2010 . It was Recent studies on CKD273 have almost exclusively been focused on its predictive performance in patients with early-stage CKD, where the shortcomings of classical biomarkers such as eGFR and albuminuria limit their potential.2) was raised. A total of 2087 individuals with an eGFR of >60 mL/min/1.73 m2 and minimal to normal albuminuria were included. Over a median follow-up of 4.6 years, CKD273 was superior to UACR in predicting a first and sustained renal endpoint [2 and urinary albumin excretions of <20 μg/min, showing the ability of CKD273 to identify the progression to eGFRs of <60 mL/min/1.73 m2 [In a study by Pontillo et al., the question if CKD273 is superior to UACR in predicting CKD progression up to stage three . The recruited patients had type 2 diabetes, a normal urinary albumin excretion, and preserved kidney function. The cohort was divided into a high- and a low-risk group according to their CKD273 scoring. The high-risk patients underwent placebo-controlled treatment, with 25 mg daily of spironolactone. The primary endpoint was the development of microalbuminuria. CKD273 proved to be predictive for the development of albuminuria; however, treatment with spironolactone did not significantly alter the progression course . SimilarIn addition to CKD273, other proteomic-based biomarkers have been suggested for the assessment of DKD within the last 5 years. In a Taiwanese cohort of early-stage DKD patients, a proteomic approach was used to identify the candidate biomarkers, which were subsequently verified by an enzyme-linked immunosorbent assay. An analysis of a total of 114 patients led to the identification of candidate biomarkers, eight of which could be validated. This ultimately led to the identification of haptoglobin as a urine biomarker for early DKD detection and the prediction of early decline in kidney function . In anotp < 0.0001), and was significantly correlated with the degree of IFTA [Kidney fibrosis is a hallmark of progressive disease in virtually all entities of CKD . As of n of IFTA . A large of IFTA .p < 0.0001, 95%-CI 0.65–0.90) [IgA nephropathy (IgAN) is the most common primary glomerulonephritis and is characterized by a wide range of progression rates . Therefo65–0.90) . Autosom65–0.90) . In Fabr65–0.90) . In anot65–0.90) . In a pr65–0.90) . Diagnoses of CKD etiologies currently need a combination of clinical data, biomarkers, and foremost, kidney biopsies. In a recent study, the discrimination of seven different CKD etiologies from healthy controls and from each other was achieved through proteomic classifier development. In a cohort of 1180 patients, seven proteomic classifiers were developed to specifically differentiate MNGN, FSGS, LN, Vasculitis, IgAN, MCD, and DKD. The generated classifiers led to ROC-AUCs for discriminating these disease entities from others that ranged from 0.82 in IgAN to 0.95 in vasculitis-associated kidney diseases . FurtherIn this review, we systematically searched the literature for frequently cited original articles published within the last 5 years that presented evidence for urinary peptide biomarkers in the context of CKD. In the first section, single peptide biomarkers are presented, followed by a section on proteomic biomarkers.Recent studies on CD80 as a urinary biomarker have provided new evidence for its potential use as biomarker in the context of nephrotic syndrome. Its ability to differentiate MCD from other causes of nephrotic syndrome has been especially underlined. Another study from 2018, which did not reach the needed number of citations for this review, focused on its ability to differentiate MCD in relapse from FSGS and did not reach the conclusion that it has sufficient biomarker properties in this regard . This isDKK3, as a marker of tubular damage, is described in this review and has been shown to have implications as a biomarker for CKD and kidney damage in the context of diabetes, after cardiac surgery, and in contrast-media-associated kidney injury ,22,23,24As EGF is virtually absent in the plasma, there is no question about it being a urine-exclusive biomarker. The studies included in this review mainly provided evidence for its implications in reflecting kidney damage and predicting kidney function decline in DKD, after cardiac surgery and in Alport syndrome ,29,30,31The transmembrane protein KIM-1 was shown to predict kidney function decline and reflect albuminuria in different cohorts of DKD in this review ,34,36. FThe chemotactic cytokine MCP-1 was extensively reviewed here, with evidence for its properties as a biomarker in DKD, after cardiac surgery, and in LN ,37,38,39MMP-7 is a secreted, zinc-dependent endopeptidase that is implicated in the regulation of kidney homeostasis and disease. Reviews about the regulation, role, and mechanisms of MMP-7 in the pathogenesis of kidney diseases have recently been provided . In thisPerhaps one of the most promising biomarkers regarding this review, but also historically, is NGAL, which was identified as a urinary biomarker for ischemic kidney damage roughly 20 years ago . A multiUromodulin has been described as a promising serum biomarker for AKI and CKD ,48,49,50Most of the reviewed single peptide biomarkers had been described in the past and recent studies have only delivered mostly confirmatory evidence of known biomarker properties and limitations. The new discovery of single peptide biomarkers in the context of CKD has slowed down and biomarker discovery has shifted to high-throughput methods, which are able to analyze a multitude of peptide fragments in specimens, namely proteomics. Evidence for proteomic-based biomarkers is reviewed in this publication. CKD273 and IgAN237 have been extensively evaluated in prospective studies over the last 5 years ,79,80,91This article and the biomarkers discussed within have limitations. First, the time frame selected for biomarker revision is rather short and thus the degree of evidence for every biomarker must be read with caution, as important preceding studies that did not fall in the search time frame might not be acknowledged. Secondly, we focused on urinary biomarkers specifically, and some of the mentioned biomarkers might have a higher importance and benefit as serum biomarkers. The heterogeneity of the biomarker studies selected in this article was high. Even if only human, clinical studies were included, and the patient numbers, biomarker assays, and definition of outcomes varied immensely across the studies. That was the main reason that we specifically decided not to perform a meta-analysis. Even though urine is a stable, easy-access, and reliable biomarker specimen, longer storage times, times of collection, bacterial contamination, and the need for time correction (creatinine correction) are factors that can limit the quality of urine specimens and thus influence the biomarker quality.Urine is an easily and readily available specimen that allows unlimited and longitudinal sampling and testing. The advantage of urinary proteins and peptides is their stability . MoreoveSingle-peptide-based biomarker research has been the state of art in biomedical research for decades. It requires a predefined pathophysiological hypothesis and has led to the discovery of many important biomarkers in the past. In the last 5 years, known urinary biomarkers have been addressed in single-peptide-based trials, but the discovery of new biomarkers has fallen behind. Proteomic biomarker studies offer a new hypothesis-free tool for biomarker discovery in biomedical research. Through an analysis of a multitude of potentially relevant peptides and a combination into multidimensional classifiers, they better reflect the complex nature of diseases such as CKD. These studies can offer new insights into the disease mechanism, diagnosis, prediction of disease progression, and treatment response. As discussed, the first important steps, such as the differentiation of different forms of kidney disease, prediction of the degree of kidney fibrosis, and prediction of progressive kidney disease, have been undertaken successfully.Urinary peptidomic and proteomic biomarkers hold the promise to significantly improve CKD management in the future. The next essential step is to move from discovery to application and demonstrate the value of urinary proteins and peptides in guiding interventions in the context of CKD, in order to make an impact on patient management. Since CKD is a risk factor for cardiovascular disease (CVD), the ultimate goal of biomarker development is to ensure a reduction in the progression of early towards established CKD and CVD and in preventing target organ damage. The analysis of the entirety of urinary peptides/proteins provides the possibility of distinguishing and studying multiple kidney pathologies via an analysis of only one urine sample . A schem


VS), this study explored the aberrant dynamics of electroencephalogram (EEG) microstates and their correlations with tinnitus features in VS patients. Clinical and EEG data were collected from 98 VS patients, including 76 with tinnitus and 22 without tinnitus. Microstates were clustered into four categories. Our EEG microstate analysis revealed that VS patients with tinnitus exhibited an increased frequency of microstate C compared to those without tinnitus. Furthermore, correlation analysis demonstrated that the Tinnitus Handicap Inventory (THI) score was negatively associated with the duration of microstate A and positively associated with the frequency of microstate C. These findings suggest that the time series and syntax characteristics of EEG microstates differ significantly between VS patients with and without tinnitus, potentially reflecting abnormal allocation of neural resources and transition of functional brain activity. Our results provide a foundation for developing diverse treatments for tinnitus in VS patients.Tinnitus is closely associated with cognition functioning. In order to clarify the central reorganization of tinnitus in patients with vestibular schwannoma ( Tinnitus is defined as the perception of sound without external stimulation, and its high incidence results in a significant social and economic burden . TinnituVS patients is influenced by auditory system interference factors and has fewer confounding factors. Additionally, it has been demonstrated that vestibular schwannoma-induced tinnitus is not significantly correlated with gender, age, tumor size, or hearing status  and then rapidly switch to another relatively stable state . Indeed,VS patients with tinnitus have been reported. Higher incidence of tinnitus in VS patients indicates that the mechanism of tinnitus may be different from that in healthy people , commonly used hand, education background, tinnitus period, loudness, and SAS, SDS VAS, and THI scores. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Chinese PLA General Hospital (No. S2021-179-02).Exclusion criteria included: (1) patients with severe anxiety or depression diagnosed by SAS and SDS scales, (2) patients with neurofibromatosis type II, (3) non-right-handed patients, (4) accompanied with severe other intracranial organic diseases, and (5) and having a history of psychotropic drug use or head injury in the last 3 months. Accordingly, a total of 106 patients were enrolled .Entire process of EEG data collection was conducted in a soundproof room under electric shielding. The temperature was maintained at 28°C, and outdoor personnel was prevented from walking to ensure that subjects were in a good mental state. Before collecting EEG data, we also considered removing skin cutin, using Quik-Gel conductive gel to fill the space between the electrode and scalp, and controlling all scalp resistance below 10 kΩ. During the data collection process, we told the subjects to close their eyes, relax, and keep still and awake. The whole quiescent EEG data sampling time were about 10–15 min. The EEG data were collected using a 64-guide EEG recorder (Neuroscan). The EEG recording system is a Curry 8 system with a data sampling rate of 1,000 Hz.EEG data were pre-processed using EEGLAB (v13.0.0) in MATLAB (R2013b) following some steps that were conducted according to international practices . (1) EEGi is the transient potential of the ith electrode at moment t, and Vmean (t) is the average transient potential of all electrodes at moment t. GFP is usually used to reflect the rapid changes in brain activity. Many peaks and troughs were expected in the whole EEG recording process. The peak topological map had a better signal-to-noise ratio and was more similar to the topological map at the nearby time point. The valley topological map was quite different from the one at the nearby time point, which was considered a switching process for different microstates. We extracted the topological maps of EEG at the local maximum of the GFP curve as the representative topological map. Based on the Atomize and Agglomerate Hierarchical Clustering (AAHC) algorithm, we performed clustering analysis and divided the usual topological maps of EEG into microstates A, B, C, and D . The independent sample t-test was employed for group comparisons of count data that conform to a normal distribution, while the Mann–Whitney VS) who did not have tinnitus, with an average age of 46.8 years, including 13 males and 9 females. Among them, 14 had left-sided tumors and 8 had right-sided tumors, with an average tumor size of 19.9 mm. The average hearing level on the side with the tumor was 60.5 dB HL, while the average hearing level on the contralateral side was 15.0 dB HL. Of these patients, 11 reported experiencing vestibular symptoms, while the other 11 did not. Additionally, we enrolled 76 patients with VS and tinnitus, with an average age of 47.0 years, including 35 males and 41 females. Among them, 36 had left-sided tumors and 40 had right-sided tumors, with an average tumor size of 17.9 mm. The average hearing level on the side with the tumor was 58.5 dB HL, while the average hearing level on the contralateral side was 16.3 dB HL. Of these patients, 33 reported experiencing vestibular symptoms, while the other 43 did not. There were no significant differences between the two groups in terms of age, gender, tumor side, tumor size, hearing level on the tumor side, hearing level on the contralateral side, vestibular symptoms, or education background  (We enrolled 22 patients with vestibular schwannoma (ctively) . FurtherAfter hierarchical clustering of non-tinnitus group and tinnitus group, two groups of microstates were constructed, including A, B, C, and D, respectively. The clustering topological map phenotype was consistent with previous literature findings . We idenp-value = 0.010) , although not pass the multiple comparison correction. No significant difference was found in other indicators. We also investigated the differences in microstate indicators between VS patients with left and right tumors, but no statistically significant differences were found.The microstates results showed that the frequency of microstates C of the non-tinnitus group was significantly lower than that in the tinnitus group  . The staVS patients, including tinnitus loudness and duration, THI and VAS scores, and microstates parameters . It was found that the THI score was negatively related to the duration of microstates A , positively correlated with the frequency of microstate C   . No signVS patients with tinnitus. There is evidence that the tinnitus perception is related to cognition and cortical plastic changes. Meanwhile, EEG research has been widely used in the field of cognition  can modulate the excitability of the brain cortex   . As a reThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Chinese PLA General Hospital. The patients/participants provided their written informed consent to participate in this study.CZ, XW, and FW: study design. CZ, ZD, HZ, PL, and XX: data collection. CZ, XW, and ZD: data analysis and manuscript drafting. FW, SY, WS, JC, and FW: recruitment of patients. All authors contributed to the article and approved the submitted version.This work was supported by grants from the National Key Research and Development Project (2019YFC0121302); the National Key Research and Development Project (2019YFC0840707); the Beijing Nova Program (Z201100006820133); the National Key Research and Development Project (2020YFC2005203); and the National Natural Science Foundation of China (81820108009).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.