Sarcopenia is a clinical syndrome characterized by a progressive and extensive decline in skeletal muscle mass, muscle strength, and function. Sarcopenia and cardiovascular diseases (CVDs) can coexist, which further decreases the quality of life of patients, and increases the mortality rate. MicroRNAs (miRNAs) are unique posttranscriptional regulators of gene expression whose function in aging-related sarcopenia and CVDs has recently begun to unravel. The aim of the present study is to investigate the relationship between sarcopenia and cardiovascular risk factors (CVRF) in the Chinese elderly and describe the circulating miRNAs in sarcopenia patients with the intention of identifying novel diagnostic and therapeutic tools.The well-established CVRF of diabetes, hypertension, and dyslipidemia were assessed. Multiple logistic regression analyses and linear regressions were used to evaluate the components of CVRF and the number of CVRF in elderly patients with sarcopenia. Moreover, we used real-time RT-PCR to measure the abundance of the CVRF-related miRNAs in the plasma of a cohort of 93 control and sarcopenia individuals, including miR-29b, miR-181a, and miR-494.We found that CVRF was associated with a high prevalence of sarcopenia in elderly Chinese populations After adjusting for potential confounders. Furthermore, hypertension and dyslipidemia, but not diabetes, were found to be significantly associated with sarcopenia. A linear increase in the prevalence of sarcopenia was found to be associated with the number of CVRF components in the elderly population. We found that plasma miR-29b levels were significantly down-regulated in response to sarcopenia in the elderly with CVRF. In particular, there was a remarkable correlation between miR-29b and appendicular skeletal muscle mass (ASM)/height2. Collectively, knowledge of CVRF, particularly hypertension and dyslipidemia, may help predict the risk of sarcopenia in the elderly. Our data also show that circulating miR-29b can be considered as possible biomarkers for sarcopenia, which may also be used in the CVD assessment of these patients.We found that the prevalence of sarcopenia was significantly proportional to the number of CVRF components. In particular, hypertension and dyslipidemia were significantly associated with a higher risk of sarcopenia in the adjusted models. Moreover, our study has been proven that c-miRNAs may be considered as possible biomarkers for sarcopenia as a new diagnostic tool to monitor response to treatment. There is also a pressing need for further research on sarcopenia and CVRF to understand their relationship and mechanism. These can provide more evidence to develop potential interventions to improve clinical outcomes. Sarcopenia is a disease characterized by decreased skeletal muscle mass, muscle strength, and physical performance. It is related to the aging process, which can lead to significant morbidity and disability in the elderly population, including reduced poor physical function, loss of independence, poor quality of life, falls, and mortality . A numbeThe pathogenesis of sarcopenia is very complex and there are multiple interactions. The mechanisms responsible for sarcopenia have been extensively studied, including decreased physical activity levels, hormone deficiencies, decreased protein intake, dyslipidemia, insulin resistance, and chronic inflammation that results in the release of catabolic cytokines. Reasonable physical exercise and a balanced diet are the most effective ways for older adults to prevent muscle function decline –11. At pCardiovascular disease is one of the leading causes of death throughout the world, and its prevalence is on the rise in China . Recent MicroRNAs (miRNAs) have increasingly become potential markers of disease with the advancement of precision medicine and next-generation sequencing. It is an endogenous, conserved, single-stranded molecule composed of about 22 small non-coding RNAs, which can regulate the expression of target genes after transcription and has been shown to be involved in various biological processes , 21. ChaFinally, considering the association between sarcopenia and CVD in older people and the absence of appropriate and consistent evidence regarding the association between sarcopenia and CVRF, we conclude that further research is needed to investigate the relationship between sarcopenia and CVRF to improve public health in China. In this study, we examined the effects of the prevalence of different numbers of CVRF components on sarcopenia using the AWGS definition in suburb-dwelling populations of elderly persons aged 65 and older in China. We found that the prevalence of sarcopenia was significantly proportional to the number of CVRF components. In particular, hypertension and dyslipidemia were significantly associated with a higher risk of sarcopenia in the adjusted models. Moreover, we determined the change of the well-functioning specific circulating miRNAs respond to sarcopenia in the elderly. Our data showed that plasma miR-29b levels were significantly downregulated in response to sarcopenia in elderly, while miR-181a and miR-494 were not changed significantly. We also correlated the circulating miRNA changes with diagnostic indicators of sarcopenia , showing the potential of circulating miRNA as biomarkers of sarcopenia in elderly.This research was approved by the Ethics Committee at Ningbo No. 2 Hospital (PJ-NBEY-KY-2016-020-01), and it was conducted according to the principles of the Declaration of Helsinki. All records have been anonymized, and no individual information can be identified. All participants were informed in advance of the procedures, benefits, and probable adverse events associated with the protocol. Study subjects provided written informed consent, including permission to use the collected data for research purposes only.n = 28), or measurement of baPWV (n = 13), or the filled questionnaire (n = 4) were excluded. Thus, a total of 1,002 participants were analyzed. A total of 93 subjects with sarcopenia were diagnosed as having low muscle mass , low muscle strength , and/or low physical performance  by the Asian Working Group for Sarcopenia (AWGS) criteria. Accordingly, 93 non-sarcopenic subjects were screened in a paired design with 93 sarcopenic subjects of the same gender and similar age. The participants were further divided into sarcopenia group (n = 93) and non-sarcopenia group (n = 93)  and drinking habits . Former smokers and current smokers were asked how many cigarettes they smoked per day and how long they had smoked. We next obtained and assessed physical activity levels. The physical activity level was assessed using the short form of the International Physical Activity Questionnaire (IPAQ). A history of physical illness was established using standardized criteria that combined information from a questionnaire regarding the history of a physical illness, a physician’s diagnosis, and the corresponding medication or current or past medical treatment.Data regarding sociodemographic and behavioral characteristics was obtained in a similar manner to our previous studies 2 for males and 5.7 kg/m2 for females, respectively. For low muscle strength, male handgrip strength was <28 kg, and female handgrip strength was <18 kg, respectively. Physical performance could be low with a 4-m walking velocity of 0.8 m/s.Sarcopenia was diagnosed as low muscle mass, low muscle strength, and/or low physical performance by the Asian Working Group for Sarcopenia (AWGS) criteria. For low muscle mass, ASM/Ht2 was <7.0 kg/mThe direct segmental multifrequency bioelectrical impedance analysis was used to analyze body composition features. Appendicular skeletal muscle mass (ASM) was summed up as the total skeletal muscle in the arms and legs. The relative skeletal muscle mass index (ASM/Ht2) was defined as ASM divided by height squared in meters. Muscle strength was collected to the nearest 0.1 kg with an accurate handgrip dynamometer. 4-m walking speed was tested on a straight corridor with a 6-m mark on the ground.Based on previous research, the following are the three major risk factors for CVD: diabetes is defined as the use of hypoglycemic agents, a self-reported history of diabetes, or a FPG ≥ 7.0 mmol/L and/or OGTT 2hPG ≥ 11.1 mmol/L and/or HbA1c ≥ 6.5%; hypertension is defined as resting SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg and/or the self-reported current treatment for hypertension with antihypertensive medication; dyslipidemia is defined as using lipid-lowering drugs or having one or more of the following: TG ≥ 1.7 mmol/L, TC ≥ 5.18 mmol/L, HDL-C < 1.04 mmol/L, and LDL-C ≥ 3.37 mmol/L.Fasting blood was collected in silicone-coated serum tubes with increased silica act clot activator within 1 h of collection in order to obtain plasma. Plasma and erythrocytes were separated by centrifuging blood samples at 845 g for 15 min at 4°C. Plasma was collected in aliquots into RNase/DNase-free tubes and stored at −80°C for further analysis. Total RNA was isolated from the plasma with a mirVana PARIS isolation kit  according to the manufacturer’s instructions. To avoid discrepancies in results, all samples were extracted and analyzed in a single batch to minimize repeated freeze–thaw cycles of plasma samples. Briefly, total RNA was extracted from 400 μl of plasma. After adding the same volume of denaturing solution, the plasma miRNA level was normalized by adding 50 pmol/L of Caenorhabditis elegans miR-39 (cel-miR-39) as the peak control. All the samples were eluted with 100 μl of RNAse-free water.For quantitative miRNA analysis, Bulge-LoopTM miRNA qPCR Primer Sets  were used to detect selected miRNAs expressions by quantitative reverse transcription polymerase chain reactions (qRT-PCRs) with iTaqTM Universal SYBR Green Supermix  in the 7900HT Fast Real-Time PCR System as previously reported. All qRT-PCR reactions were performed in triplicate, and the signal was collected at the end of every cycle. As there is no consensus on endogenous stable miRNAs in the circulation to act as house-keepers, the expression level of miRNAs in serum was normalized using spike-in cel-miR-39, which lacks sequence homology to human miRNAs.t-tests, Pearson’s chi-square test, and Kruskal–Wallis rank tests. The associations between sarcopenia and CVRF were determined by analyzing each individual CVRF component or the total number of CVRF components. The simple logistic regression analysis was used to examine the independent influence of CVD risk factors on sarcopenia; the odds ratio (OR) and 95%  were computed. In addition, adjustments for potential confounders such as age, gender, and BMI (model 1), residence, marital status, educational level, smoking status, drinking status, and income (model 2), and stroke, peptic ulcer, and kidney disease (model 3) were performed using multiple logistic regression analyses . Analyses were repeated to determine the effect of individual CVRF components on sarcopenia components. The analysis generated regression coefficients, confidence interval, and Nagelkerke R2. Besides, the area under the receiver operating characteristic (ROC) curve and the Hosmer–Lemeshow goodness of fit statistic were calculated to assess the performance and calibration of the model, respectively. Through the analysis of qRT-PCR data, the 2–ΔΔCt method was used to calculate the relative expression level for each miRNA, and the data was expressed as mean ± SD. An appropriate t-test was performed on the unpaired samples to analyze the miRNA changes. The Pearson’s method was used to conduct the correlation analysis between changes in circulating miRNAs and diagnostic indexes of sarcopenia  as appropriate for data distribution. All the statistical analyses were performed using SPSS version 19.0, and P-values less than 0.05 were considered statistically significant.All other continuous variables were presented as means ± SD; classification variables were reported as percent-ages. Differences in baseline characteristics according to sarcopenia status were analyzed using P < 0.05). There were no statistically significant differences between the overall sarcopenic and non-sarcopenic groups in terms of marital status, residence status, educational status, income level, smoking status, drinking status, TC, LDL-C, HDL-C, and incidence of osteoporosis. Additionally, participants with sarcopenia had a statistically significant lower ASM, ASM/Height2, handgrip strength, 4-m velocity, and knee extension compared with participants without sarcopenia (P < 0.05). Hypertension and diabetes were more prevalent in the sarcopenia participants relative to the non-sarcopenia participants (P < 0.05).The cohort used in this study is the same as previously reported . A totalP < 0.05). The OR and 95% CI for hypertension, which was significantly associated with sarcopenia, was 0.397 (0.200–0.789). After further adjusting for pertinent variables in Models 2–3, the CVRF components, including hypertension and dyslipidemia, were found to be significantly associated with sarcopenia (P < 0.05). For CVRF components, individuals with both hypertension [0.406 (0.182–0.906)] and dyslipidemia [0.415 (0.186–0.922)] were significantly associated with sarcopenia (P < 0.05), but not diabetes in the adjusted Model 3.The associations between the sarcopenia and the different CVRF components are present in P-values for the trends <0.001), respectively. It was showed that he prevalence of sarcopenia increased steeply with numbers of CVRF. Lastly, all models were evaluated for performance and calibration. All models performed well in terms of performance and calibration .As shown in The expression of CVRF-associated miRNAs [miR-29b , 25, miRr = 0.1862, P < 0.05)   . In furt < 0.05) . Finally < 0.05) .This study was conducted to analyze the effects of varying CVRF component numbers on sarcopenia in China’s suburban-dwelling elderly population aged 65 and older, using the AWGS definition. We observed that sarcopenia prevalence correlated significantly with the number of CVRF components. As a result of the adjusted models, hypertension and dyslipidemia were significantly associated with an increased risk of sarcopenia. Then, we also found that plasma miR-29b levels were significantly downregulated in response to sarcopenia in elderly with CVRF. In particular, there was a remarkable correlation between miR-29b and ASM/height2.Researchers are currently focusing on two aspects of sarcopenia and CVD. On the one hand, sarcopenia is directly associated with CVD, while on the other, sarcopenia is indirectly related to CVD by affecting CVRF. It has previously been suggested that the prevalence of sarcopenia is closely associated with increased risk factors and may itself be an individual risk factor for CVD , 33. In First, hypertension, one of the main chronic diseases of CVD, poses a serious threat to the health of humans . ObesitySecondly, sarcopenia and dyslipidemia have been associated with only a few studies in Asia. In this study, although univariate analysis showed no correlation between sarcopenia and dyslipidemia, multivariate statistical analysis indicated that dyslipidemia was the second-most significant feature that was associated with sarcopenia after adjusting for confounding factors such as age, gender, BMI, marital status, educational level, and smoking, which is consistent with previous findings. According to a study from South Korea, the elderly with sarcopenia were at higher risk for dyslipidemia . In addiFinally, our study showed that there was no correlation between diabetes and sarcopenia. However, Srikanthan et al. reported that sarcopenia was associated with an increased risk of diabetes, and skeletal muscle is involved in insulin-mediated glucose absorption and is the main target of insulin action . LeenderAs markers of cellular biological processes, changes in circulating miRNA levels can provide information about cells. In this study, selected miRNA-29b, miRNA-181a, and miR-484 are involved in diabetes and hypertension and/or clinical relevance, as they are closely related to CVD. Indeed, our study showed that plasma miR-29b levels were significantly downregulated in response to sarcopenia in elderly with CVRF. In this study, our results were similar to those found in previous studies. It was previously reported that exercise attenuates Ang II-induced muscle atrophy by suppression of miR-29b , 51. In According to AWGS criteria definition, sarcopenia is characterized by low muscle mass, low muscle strength, and/or low physical performance. ASM/height2, handgrip strength, and 4-m velocity are the current diagnostic criteria for sarcopenia . In the There are still some limitations in our research. First, the study is a single-center clinical trial with a small sample size, and the results may need to be confirmed in a multicenter study with a larger sample size and area of coverage. The results would be more reliable if more patients of different races were included. Second, only three targeted miRNAs that were associated with CVRF in the literature were examined due to cost; thus, there may be other unstudied miRNAs that may be better indicators of CVD and sarcopenia status. Moreover, even though the study participants were relatively healthy, some of them may have certain diseases. The expression levels of miRNAs may be altered by disease conditions, such as degenerative diseases, malignancies, and autoimmune diseases.In conclusion, we found that the prevalence of sarcopenia was significantly proportional to the number of CVRF components. In particular, hypertension and dyslipidemia were significantly associated with a higher risk of sarcopenia in the adjusted models. Therefore, the prevention and treatment of CVRF may be useful in preventing and delaying the onset of sarcopenia. A further prospective study is needed to establish the causality of CVRF components and sarcopenia. Moreover, our study has been proven that c-miRNAs may be considered as possible biomarkers for sarcopenia as a new diagnostic tool to monitor response to treatment. There is also a pressing need for further research on sarcopenia and CVRF to understand their relationship and mechanism. These can provide more evidence to develop potential interventions to improve clinical outcomes.The 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 Ningbo No. 2 Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.HY conceived and designed this study and revised the manuscript. NH and YLZ performed the experiments and collected and analyzed the data. NH, BF, ZZ, and YZ contributed the reagents, materials, and analysis tools that used in this study. NH wrote the manuscript. All authors contributed to the article and approved the submitted version.


Due to a production error, the citation for the book being reviewed was missing from the article. These details have now been inserted at the beginning of the article. The text that has been inserted is:“A Book Review onPandemics, politics, and society: Critical perspectives on the Covid-19 crisisby Gerard Delanty (Berlin: De Gruyter), 2021, 215 pages, ISBN: 978-3110713237.”Due to a production error, the running title was incorrect. The running title has been updated to “Book Review: Pandemics, Politics and Society”.The publisher apologizes for these mistakes. The original version of this article has been updated.


Cerebral palsy (CP) is one of the most common causes of disability in children. It is characterized by impairment in motor function and coordination and difficulties in performing daily life activities. Previous research supports that neurologic music therapy (NMT) was effective in improving motor function, cognition, and emotional wellbeing in patients with various neurologic disorders. However, the benefit of NMT in patients with CP have not yet been thoroughly investigated. The aim of this review was to investigate the potential effect of NMT motor rehabilitation techniques for patients.We searched articles published up to May 24, 2022 in PubMed, Embase, Scopus, Cochrane library, Web of science, and Ovid MEDLINEdatabases. We included studies that investigated the effect of NMT in patients with CP.After search, 4,117 articles were identified using the search terms. After reading the titles and abstracts, 4,089 articles that did not meet our inclusion criteria were excluded. The remaining 28 articles which were assessed for eligibility. Finally, 15 studies were included in this systematic review. Among 15 studies that investigated the effect of NMT on patients with CP, 7 studies were on rhythmic auditory stimulation (RAS), 6 studies were on therapeutic instrumental music performance (TIMP), and 2 studies were on patterned sensory enhancement (PSE).Various techniques of NMT brings beneficial effects for gross and fine motor improvements in patients with CP. NMT techniques, such as RAS, TIMP, and PSE, may be a potential alternative rehabilitation strategy to enhance gross and fine motor skills for patients with CP. Cerebral palsy (CP) is a non-progressive motor disorder caused by injury to brain structures or abnormal development of the brain . It is oNeurologic music therapy (NMT) is defined as the therapeutic approach for motor, sensory, cognitive, and language dysfunctions due to disease or injury to the human nervous system based on neuroscientific models of music perception and music production . It usesPrevious research supports that NMT was effective in improving motor function, cognition, and emotional wellbeing in patients with stroke, dementia, Parkinson's disease, epilepsy, or multiple sclerosis –19. HoweA systematic review of studies which investigated the effect of NMT in patients with CP was conducted.*,” “music therapy,” “neurologic music therapy,” “cerebral palsy,” “cerebral pals*,” and “CP.”This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines . We systThe eligibility criteria for this review was informed by the Population Intervention Comparator Outcome (PICO) framework . StudiesAll data were extracted independently by two reviewers (SYY and MCC) using a standard data collection form. The following data were recorded using a table from each eligible article: (1) the name of the first author, (2) year of publication, (3) number of patients, (4) type of NMT intervention, (5) results.Two reviewers (SYY and MCC) independently assessed the risk of bias according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions for the included randomized controlled trials  and the After search, 4,117 articles were identified. After reading the titles and abstracts, we excluded 4,089 out of 4,117 articles that did not meet our inclusion criteria . The remWe categorized 15 studies according to the type of NMT interventions: RAS, TIMP, and PSE. RAS is a training method that uses external auditory cues to guide movement through anticipated temporal sequence to enhance motor skills by providing rhythmic stimulation to the motor center of the brain . TIMP usversus complex chords . This study also suggested that other factors, such as physical ability, cognitive functioning, and support of parents, may have influenced on the effectiveness of RAS and outcomes of the training.The potential use of RAS as a therapeutic strategy for gait training in patients with CP was suggested by the 2007 study of Kwak, which showed that RAS improved gait performance in 18 patients with CP . PatientIn 2011, Kim et al. enrolled 14 adult patients with CP and compared the effect of RAS on gait patterns with 30 healthy controls . RAS indIn 2012, Kim et al. enrolled 28 patients with CP and compared the effect of RAS with neurodevelopmental treatment  . PatientA study on the effect of RAS was also conducted by Efraimidou and Proios in 2016 . In thisA 2018 study of Ben-Pazi et al., compared 9 children with CP who received auditory stimulation embedded in music with 9 children with CP listened to music alone . ChildreMost recently, in 2020, Kim et al. investigated the effect of RAS by comparing the use of simple vs. complex chords . ThirteeSeven studies used musical instruments in patients with CP to improve their motor and functional skills. Most studies used piano or keyboard as an instrument for TIMP.In 2010, Nasuruddin enrolled 9 children with CP and applied therapeutic intervention including Gamelan music and theater games . This tyThe improvement in hand function was observed in 5 adults with CP in the 2013 study of Chong et al. . KeyboarIn 2015, Lampe et al. included 10 children with CP who had impaired hand motor function to investigate whether learning to play the piano helped to improve their hand motor skills . PatientA 2017 study of Alves-Pinto et al. investigated the effect of piano training for 16 adolescents and adults with CP (P < 0.05) after handling musical instruments through TIMP, showing the development of manual function. The optimized intervention of TIMP can improve upper limb function in children with severe bilateral CP and this effect lasted 4 months after the treatment.In 2018, Marrades-Caballero et al. enrolled 18 patients with severe CP and demonstrated that they could benefit from TIMP program in addition to usual physiotherapy . SignifiMost recently, in 2021, Dogruoz Karatekin and Icagasioglu investigated the effect of TIMP in 9 adolescents with piano training sessions, consisting 40 min of training twice a week for 3 months . After pP = 0.009), total extensor power (P = 0.015), and center-of-mass smoothness (P = 0.01) were observed, which showed that individualized PSE music helped to improve the performance of STS.Two studies used PSE as a therapeutic technique in patients with CP and reported the positive effect of PSE. In 2011, Peng et al. conducted a study involving 23 patients with CP . This stThe effect of PSE music was also investigated by Wang et al. in 2013 . Thirty-Patients with CP have impairment in the development of movements and postures, difficulties in performing activities . ImpaireNMT induces positive effects during rehabilitation through repetition, organization, participation, reward, and motivation. It improves motor control through neurophysiological processes such as priming and entrainment , 13, 42.RAS uses regularly timed external auditory stimulation during gait training . ExternaGait training with RAS involves musical properties, and uses metronomes or original recorded music. RAS is associated with improvement in spatiotemporal gait parameters such as walking speed and length of stride, and kinematic parameters such as joint movements during a gait cycle . ExternaTIMP addresses motor rehabilitation by using musical instruments to train motor functions and facilitate functional movement patterns , 12. TIMPlaying an instrument involves repetition of fine finger movements, finger and hand coordination, and auditory feedback. After receiving an immediate auditory feedback, the player tries to process his performance and tries to correct it. By doing so, he trains fine motor skills and integrates audio-visual information with motor control and coordinates finger and hand movements . TIMP aiTwo studies on the effect of PSE in patients with CP were included in this review. The goal of PSE is to translate movement patterns into sound patterns in order to give the spatial, temporal, and force cueing. PSE uses rhythm, pitch, dynamics to regulate movement patterns to facilitate movement execution . Pitch vThe current review investigated the effect of NMT in patients with CP, and this review has some limitations. Some studies compared the effect of NMT with controls (no-CP controls or no-NMT controls) , 32, 38.Various techniques of NMT brings beneficial effects for gross and fine motor improvements in patients with CP. NMT techniques, such as RAS, TIMP, and PSE, may be a potential alternative rehabilitation strategy to enhance gross and fine motor skills for patients with CP.The original contributions presented in the study are included in the article/SY and MC: conceptualization and methodology. JS and SK: writing-original draft. SY: writing-review. MC: editing and supervision. All authors contributed to the article and approved the submitted version.This work was supported by the Ewha Womans University Research Grant of 1-2021-1794-001-1 and the National Research Foundation of Korea Grant funded by the Korean Government (Grant No: NRF-2019M3E5D1A02069399).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.


Glaucoma is a leading cause of blindness worldwide. It is suggested that primary open angle glaucoma (POAG), the most common form of glaucoma, may be associated with significant metabolic alternations, but the systemic literature review and meta-analysis in the area have been missing. Altered metabolomic profiles in the aqueous humor and plasma may serve as possible biomarkers for early detection or treatment targets. In this article, we performed a systematic meta-analysis of the current literature surrounding the metabolomics of patients with POAG and metabolites associated with the disease. Results suggest several metabolites found to be specifically altered in patients with POAG, suggesting broad generalizability and pathways for future research. Glaucoma is the leading cause of irreversible blindness characterized by progressive damage of retinal ganglion cells (RGCs) and the optic nerve. It affects nearly 80 million people worldwide, and this number is expected to reach 111.8 million by 2040 . As the + regulatory T cells and microglia  was used for quality assessment. The NOS contains eight items , which fit into three categories: selection (four scores), comparability (two scores), and exposure of a case–control study or outcome of a cohort study (three scores). A score of ≥6 indicates good quality.All metabolites and differentially expressed metabolites (DEMs) were summarized as pooled DEMs for aqueous humor and plasma, respectively. Pathways enrichment analysis of pooled DEMs was conducted using MetaboAnalyst v4.0 and Kyoto Encyclopedia of Genes and Genomes (KEGG) database .via a standard form: first author, year of publication, country, age of the patient, sex of the patient, sample size, sample material, quality control, and metabolomic analyzing platform. The second reviewer double-checked all data. The included studies reported the outcomes with various forms. To get the same form of the outcomes, the fold change (FC) and standard error (SE) were calculated as follows:The patient data were extracted from the selected studies (1) If the median and interquartile range (IQR) are available in the included studies, we estimated mean = median and estimated standard deviation (SD) = IQR/1.35, and then the SE of the log FC was calculated as follows :FC = m1/m2, m1 and m2 are the mean values, s1 and s2 are the SDs, and n1 and n2 are the sample sizes.Where (2) If mean and SD are available in the included studies, then the SE of the log FC was directly calculated as the above formula.p-value or adjust p-value are available in the included studies, then the adjust p-value  was transferred to p as:(3) If FC and i is the rank and N is the total detected metabolites.Where Then the SE of the log FC was calculated as follows:z-score was calculated from p/2 value (one side).Where FC), SE, n1, and n2 were used to perform the meta-analysis.Finally, the log and 95% confidence interval (CI) were calculated from selected outcomes. A value of We performed a systemic search of databases and literature in PubMed, Embase, and Web of Science using the words “glaucoma” and “metabolomics” or “metabolomic” . Among tData from the 18 case–control studies identified 133 metabolites in aqueous humor and 101 in plasma that were uniquely changed in patients with POAG compared to control subjects. The metabolites that were shown to be significantly altered/differentially expressed (DEMs) in either the aqueous humor or plasma of patients with POAG are summarized in p < 0.01). The analysis identified four significantly enriched pathways in the plasma of patients with POAG vs. control subjects, including arginine and proline metabolism, glyoxylate and dicarboxylate metabolism, and beta-alanine metabolism (p < 0.05). Thus, arginine metabolism, which is both enriched in aqueous humor and plasma, is the most striking pathway altered in patients with POAG based on previous studies.We next performed pathway enrichment analysis based on the metabolites pooled from all 18 studies that were found in the aqueous humor and plasma . The topp = 0.04, I2 = 79%), glycine , lysine , and alanine , were shown to be significantly higher in the aqueous humors of patients with POAG than that in the control subjects  were noted in 6 studies that analyzed the aqueous humors of control and patients with POAG . Since Msubjects .p < 0.001, I2 = 0%) and hydroxyproline  were significantly higher in the plasma of patients with POAG ]. Among these studies, some changes were found to be common in several reports and share similar or overlapping metabolic pathways. For instance, significant upregulation of the metabolites in responding to oxidative stress was reported in both studies by Lysine is found to be increased in the aqueous humor of patients with POAG. It is an essential amino acid that helps the body produce infection-fighting antibodies, enzymes, hormones, and body tissues. If not used for protein synthesis, lysine is catabolized in mitochondria. Thus, lysine and its degradation product are the reflections of mitochondrial homeostasis. It is reported that lysine supplement boosts the immune responses . The stuin vitro (via T-cell receptor (TCR) signaling  and arginine and proline metabolisms are the most striking and common alterations in patients with POAG. ARSs are involved in a broad range of physiological processes , and then > 200), no differences in plasma arginine were noted between POAG and control subjects (This study underwent thorough vetting of the current literature to create a meta-analysis as holistic as possible. For the included studies, gender, platforms, and patient populations are among the top three intrinsic biases. For instance, no female subject was included in the control group of the report by subjects . In addisubjects . A broadThe datasets presented in the study are included in the article, further inquiries can be directed to the corresponding author/s.DC and XS contributed to the conception and design of the study. YT and SS searched for the databases. YT analyzed the data. YT, SS, K-SC, and DC wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.DC is a consultant for Boston Pharmaceuticals, FireCyte Therapeutics, i-Lumen Scientific, and PriMed. K-SC is a consultant for SunRegen. XS is a consultant for Rimonci, BELKIN Vision, AffaMed, NovaSight, Ocumension, and KBI. DC, K-SC, and XS are inventors on patents and patents application related to glaucoma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The intake of ultra-processed foods (UPFs) has increased rapidly in recent years. Evidence has suggested that UPFs has adverse effects on several health outcomes. This study aimed to first evaluate the association between the intake of UPFs and asthenozoospermia odds.A hospital-based case-control study including 549 cases and 581 controls was performed in the infertility clinics of Shengjing Hospital of China Medical University from June 2020 to December 2020. Dietary intake was assessed using a validated food frequency questionnaire. Food items were categorized by the NOVA classification system based on the degree of processing. Semen parameters were analyzed according to the World Health Organization guidelines.P for trend < 0.05), compared with the lowest tertile. Similar patterns were also found in subgroup analyses among participants with age ≥32 years , BMI ≥ 24 kg/m2 , ever cigarette smoking , and ever alcohol drinking , and in sensitivity analyses by using absolute amount (g/day) to calculate the intake of UPFs.The highest tertile of UPFs intake  was positively associated with the odds of asthenozoospermia (odds ratio [OR] = 1.53; 95% confidence interval [CI]: 1.12, 2.10; Higher consumption of UPFs was positively associated with the odds of asthenozoospermia. More studies are needed to confirm our findings. Infertility is a major issue of human reproductive health, affecting approximately 15% of couples worldwide . AsthenoAs one of the most important environmental factors, the diet factor has also been proposed to play crucial roles in the etiology of asthenozoospermiais , 11. UltTo the best of our knowledge, there has been no efforts to explore the relationship between the intake of UPF and the odds of asthenozoospermia. Therefore, the purpose of this study was to investigate the potential association of aforementioned topic.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist . The detn = 597) were diagnosed according to the fifth edition of World Health Organization laboratory manual for the examination and processing of human semen, and defined as total motility (progressive + non-progressive) <40%, including both rapidly and slowly progressive motility, sluggish motility, and non-progressive motility (n = 612) were normozoospermic men from infertile couples, with ≥15 × 106 of sperms/mL, ≥40% total motility, ≥32% progressive motility, and ≥4% normal forms (N = 28), missing covariates and semen parameters data (N = 22), and a history of varicocele (N = 29). Finally, 549 cases and 581 controls were included in our study and met the requirement of sample size. In addition, the participation rates of cases and controls were 91.96 and 94.93%, respectively  , educational level , dietary intake, dietary change status (yes or no), ever cigarette smoking (yes or no), ever alcohol drinking (yes or no), and physical activity. For dietary change status, participants were asked whether they had changed their diets since this year and before. Cigarette smoking and alcohol drinking were defined as at least one per day and once a week, respectively, for more than six consecutive months. In addition, physical activity was evaluated according to the previous study . Briefly2) . Accordiectively .A validated semi-quantitative food frequency questionnaire (FFQ) which included 110 food items with specified serving sizes was used to assess dietary intake for participants over the past year. The FFQ used in the present study was based on FFQ used in a large cohort study in the northeast of China , 30. TheP < 0.001), suggesting that data was suitable for factor analysis. Varimax rotation was used to increase data interpretability , and total energy intake . Model 2 was further adjusted for annual family income , educational level , ever cigarette smoking (yes or no), ever alcohol drinking (yes or no), abstinence time , physical activity , and dietary change status (yes or no) based on Model 1. To consider the potential effect of nutritional quality, we further adjusted these five dietary patterns (continuous) in Model 3 based on Model 2. There was no collinearity among all variables in our analysis. Linear trends across tertiles were tested by modeling the median value of each tertile as a continuous variable.The Kolmogorov-Smirnov test was used to assess the normality of continuous variables. To assess the characteristics of participants, continuous variables were all presented as median and interquartile range as they were not normally distributed, and categorical variables were presented as number and percentage. To compare differences between groups, the Kruskal-Wallis was used for continuous variables, and the Chi-square test was used for categorical variables. The proportion of UPFs weighted by total energy intake  was categorized into three groups according to control distribution with the lowest tertile as the reference group. In the main analysis, Unconditional logistic regression analyses were used to assess associations between UPFs and the odds of asthenozoospermia. ORs and 95% CIs were calculated. The covariates included in the model were determined by univariate logistic regression and published literature for asthenozoospermia , 24, 38.2), ever cigarette smoking (Yes or No), and ever alcohol drinking (Yes or No). And the likelihood test was used to evaluate potential interactions between UPFs intake and stratification variables.Subgroup analyses were performed to examine potential effect modifications according to age (<32 or ≥32 years), BMI  and the odds of asthenozoospermia in sensitivity analyses to examine the robustness of the results. In the secondary analysis, we also assessed the effects of unprocessed or minimally processed foods and processed foods on asthenozoospermia. All statistical analyses were performed with SAS software version 9.4 . All statistical tests were two sided and statistical significance was set at P < 0.05) higher age and abstinence time, but lower proportion of ever alcohol drinking and semen parameters . In terms of diet and related nutrients intake, cases had significantly (P < 0.05) higher consumption of sodium than controls.The distribution of general characteristics among cases and controls is shown in P for trend < 0.05) and model 2 , compared with the lowest tertile. And this positive association remained significant in the fully adjusted model 3 .2 , ever cigarette smoking , and ever alcohol drinking . However, no multiplicative interactions were found between UPFs intake and these stratifying variables .In the fully adjusted model (model 3), the positive association was also observed when evaluating the association between absolute amount of UPFs intake (g/day) and the odds of asthenozoospermia . In addi2, ever cigarette smoking, and ever alcohol drinking in the subgroup analyses, and in sensitivity analyses by using absolute amount to calculate UPFs intake.In this hospital-based case-control study, to our knowledge, we first found that the highest tertile of UPFs intake was positively associated with the odds of asthenozoospermia, compared with the lowest tertile. Similar patterns were also observed among participants with age ≥ 32 yeas, BMI ≥ 24 kg/mAlthough no epidemiological study assessed the association between UPFs intake and the odds of asthenozoospermia, some previous observational studies regarding diet factors and the odds of asthenozoospermia have been in line with our findings , 24, 39.Although the underlying mechanism is not yet clear, there have been some possible explanations for the positive association between UPFs intake and the odds of asthenozoospermia. First, UPFs strongly affect the nutritional quality of diets , and areSecond, UPFs usually contain food additives, and recent studies had indicated that food additives could cause microbiota-mediated adverse effects in the host . In factThird, some contaminants can be formed during the industrial process. Indeed phthalates can migrate from plastic packaging to foods, and act as endocrine disruptors . An epidOur study had some strengths. First, we provided a new sight for exploring the relationship between dietary factors and asthenozoospermia by considering the degree of food processing. Our findings supported the need for public health policies to limit the intake of ultra-processed foods and increase the intake of unprocessed or minimally processed foods instead. Second, our study had a relatively large sample size and high participation rates, which were conducive to reducing random errors. Third, our study adjusted for a variety of confounding factors to increase the credibility of our conclusions. However, our study also had some limitations. First, our FFQ was not designed by considering the NOVA classification, therefore the degree of processing of several food items was ambiguous. However, it is essential to reasonably recognize food items according to the NOVA classification. In order to reduce the bias caused by misclassification, the food items included in our FFQ were classified by two investigators independently, and any discrepancy was judged by the third investigator. Second, although FFQ was commonly used for dietary assessment, dietary intake of participants could not be calculated accurately based on the standard food portions and relatively limited food items number. Therefore, the measurement bias was unavoidable, and this might have led to the misestimation of the association between UPFs and asthenozoospermia. To reduce the bias, we excluded the participants who reported total energy intake values outside of predefined limits. Third, as a case-control study, selection biases and recall biases could not be avoided, and causation could not be confirmed either. To improve the comparability of case and control, the same clinic controls were applied, and highly trained and skilled researchers were selected to collect information for reducing the recall bias , 56. FouIn conclusion, our study indicated that there was a positive association between the intake of UPFs and the odds of asthenozoospermia. Large prospective studies in different populations and settings are needed in the future to confirm our findings.The raw data supporting the conclusions of this article will be made available by the authors, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committee of Shengjing Hospital of China Medical University. The patients/participants provided their written informed consent to participate in this study.J-LL, Q-JW, X-BW, B-CP, and Y-HZ conceived the study. Q-JW, B-CP, and Y-HZ contributed to the design. X-BW, QD, R-HG, XL, and B-CP collected the data. JL-L and F-HL cleaned the data, checked the discrepancy, and analyzed the data. JL-L, Q-JW, X-BW, and B-CP interpreted the data. All authors interpreted the data, read the manuscript, and approved the final vision.This work was supported by the National Key R&D Program of China (No. 2017YFC0907403 to Y-HZ), Shengjing Hospital Clinical Research Project (No. M0071 to B-CP), 345 Talent Project of Shengjing Hospital of China Medical University (Q-JW), the Liaoning Revitalization Talents Program (No. XLYC1802095 to Y-HZ), and the unveiling and leading project of Liaoning province (No. 2021JH1/10400050 to Y-HZ).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background and Objectives: This study investigated the usefulness of deep neural network (DNN) models based on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and blood inflammatory markers to assess the therapeutic response in pyogenic vertebral osteomyelitis (PVO). Materials and Methods: This was a retrospective study with prospectively collected data. Seventy-four patients diagnosed with PVO underwent clinical assessment for therapeutic responses based on clinical features during antibiotic therapy. The decisions of the clinical assessment were confirmed as ‘Cured’ or ‘Non-cured’. FDG-PETs were conducted concomitantly regardless of the decision at each clinical assessment. We developed DNN models depending on the use of attributes, including C-reactive protein (CRP), erythrocyte sedimentation ratio (ESR), and maximum standardized FDG uptake values of PVO lesions (SUVmax), and we compared their performances to predict PVO remission. Results: The 126 decisions (80 ‘Cured’ and 46 ‘Non-cured’ patients) were randomly assigned with training and test sets (7:3). We trained DNN models using a training set and evaluated their performances for a test set. DNN model 1 had an accuracy of 76.3% and an area under the receiver operating characteristic curve (AUC) of 0.768  using CRP and ESR, and these values were 79% and 0.804 [0.674–0.933] for DNN model 2 using ESR and SUVmax, 86.8% and 0.851 [0.726–0.976] for DNN model 3 using CRP and SUVmax, and 89.5% and 0.902 [0.804–0.999] for DNN model 4 using ESR, CRP, and SUVmax, respectively. Conclusions: The DNN models using SUVmax showed better performances when predicting the remission of PVO compared to CRP and ESR. The best performance was obtained in the DNN model using all attributes, including CRP, ESR, and SUVmax, which may be helpful for predicting the accurate remission of PVO. Pyogenic vertebral osteomyelitis (PVO) invades the spine and adjacent structures, shows non-specific symptoms, and is usually progresses to destructive spondylodiscitis with abscess formation at the time of diagnosis ,2,3,4. L18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the assessment of the therapeutic response in PVO  in DNN model 1; 75%, 85.7%, 90%, 66.7%, 79%, and 0.804 [0.674–0.933] in DNN model 2; 91.7%, 78.6%, 88%, 84.6%, 86.8%, and 0.851 [0.726–0.976] in DNN model 3; and 87.5%, 92.9%, 95.5%, 81.3%, 89.5%, and 0.902 [0.804–0.999] in DNN model 4. The performances of the DNN models are summarized in DNN model 4 using ESR, CRP, and SUVmax showed the best performance with approximately 90% accuracy to predict the remission of PVO. There were 4 incorrect predictions among the 38 cases in the test set. DNN model 4 showed opposite predictions for three cases in group C and one case in group NC. The detailed data are presented in S. aureus was the main causative bacteria, and approximately 40% had methicillin resistance. For the treatment of PVO, an average of 6 weeks of parenteral antibiotics is usually recommended, although there some studies that considered 2–4 weeks sufficient [To date, the assessment of therapeutic responses in PVO has been performed mainly based on changes in clinical symptoms and blood inflammatory markers. However, no clear standards have yet been established. Generally, compared with ESR and white blood cell (WBC) count, CRP was highly correlated with clinical symptoms and rapidly decreased as the clinical condition improved . In partfficient ,26,27. HThe application of FDG-PET to assess therapeutic responses in PVO has been attempted for the last 10 years ,13,14. Tmax also showed some variability, although it was less than that observed for CRP. Here, we discuss the reasons for the abnormally increased FDG uptake on the FDG-PET imaging of cured PVO, which was obtained at the time of antibiotic therapy discontinuation and showed no recurrence during the follow-up [max were located in the bone marrow within the vertebral body or presented as a form of intramuscular abscess, the SUVmax was higher than that observed on the intervertebral structures. However, the value of SUVmax was not related to the clinical symptoms, and the destruction of the intervertebral structure as the main PVO lesion was the main cause of the sustained back pain, even after successful treatment. Second, when the damaged intervertebral structure of the PVO was healed by autofusion with a loss of joint function during the follow-up period, a higher SUVmax was observed in the intervertebral structure, including the endplate and disc on FDG-PET imaging, of those with cured PVO. We hypothesize that these various features of FDG uptake on the FDG-PET imaging of cured PVO patients might be an important reference for interpreting the value of SUVmax to assess therapeutic responses. However, considering the variability in FDG uptake as described above, FDG-PET is still limited for use as an absolute standard method to assess therapeutic responses in PVO. It will be effective to supplement FDG-PET with hematological inflammatory makers, which are still used as a popular treatment method. As a result, we analyzed the performance of ESR, CRP, and SUVmax applied together based on a DNN in this study.However, FDG uptake presented as SUVollow-up ,16. Firsmax to increase the reliability of the results. All DNN models developed in this study were started to overfit with the presenting estrangement of loss between the training and test sets at approximately 100 epochs, and there was a decrease in accuracy with training at over 100 epochs. Therefore, a comparison of the performances between the DNN models depending on the use of attributes was possible and appropriate at 100 epochs. The best performance was obtained with DNN model 4, which had an accuracy of 89.5% and an AUC of 0.902. DNN model 1 had the lowest performance, with an accuracy of 76.3% and an AUC of 0.768 when using ESR and CRP. Of note, ESR and CRP, currently used as important measurement methods at clinical assessment, were confirmed to have the lowest performance even after using deep learning. These results might be explained by the fundamental limitations of ESR and CRP themselves, which are susceptible to other general conditions. Overall, the DNN models that included SUVmax as an attribute showed better performances than models without it. It is thought that the FDG uptake of FDG-PET also indicated the status of PVO lesions more objectively than ESR and CRP under a predictive DNN model, as confirmed in previous studies using conventional statistics.Back pain is one of the main clinical symptoms of PVO and can be considered an indicator for assessing therapeutic responses in PVO. However, back pain can easily be influenced by individual subjective factors or psychological status. It is difficult to measure back pain objectively and the reliability of the measurement result may be low. In this study, we developed DNN models using only automatically and objectively measured ESR, CRP, and SUVmax. These are likely to be judged as ‘Non-cured’ using blood inflammatory markers in the currently applied clinical assessment. In one other case in group C (case number 45), a markedly elevated SUVmax value led to a ‘Non-cured’ decision under DNN model 4, although it was highly likely to be judged as ‘Cured’ based on the ESR and CRP levels by clinical assessment. An elevated SUVmax value was identified in three out of four incorrect predictions. Based on the aforementioned theory, we may consider the reasons for elevated SUVmax values in terms of the location of the main PVO lesion and autofusion. However, although these analyses of the characteristics of PVO lesions can help to understand elevated SUVmax values in cases with cured PVO, additional studies with more cases are required to apply these theories to the DNN model for predicting the remission of PVO. Considering the possibility of false-positives of SUVmax as seen for the above incorrect predictions, blood inflammatory markers can partially contribute to achieving improved performance in a DNN model by compensating for the shortcomings of the SUVmax. The last incorrect prediction of group NC (case number 126) with normalized values of ESR and CRP and a markedly decreased SUVmax was suitable to be determined as ‘Cured’ in the clinical assessment and with DNN model 4, although residual PVO persisted. This was an unpredictable case and this shortcoming should be overcome to improve the performance of DNN models in future studies.DNN model 4 based on the ESR, CRP, and SUVmax as attributes showed approximately 90% accuracy for predicting the remission of PVO, and there were incorrect predictions in 4 out of 38 cases in the test set. DNN model 4 showed opposite predictions for three cases in group C and one case in group NC. In two cases in group C (case numbers 33 and 107), there were sustained increases in ESR and CRP levels, with a moderate elevation of the SUVmax based on the exact anatomical structure of the PVO lesion under MRI, and the availability of FDG-PET/MRI is still poor compared that of FDG-PET/CT. To overcome these limitations and clearly confirm the usefulness of FDG-PET in PVO, additional multi-center studies with a larger number of participants are required.Our study had several limitations. First, decision making for therapeutic responses in this study was conducted based on the existing method currently used in the medical field. There is still no definite method to confirm the presence of residual PVO in group NC, although patients in group C can finally be determined as ‘Cured’ with a sufficient follow-up period. This problem remains a major limitation in many studies of PVO. In this study, we limited cases to group NC only when there was a definite aggravation of the PVO lesion on MRI and/or persistent causative bacteria on the PVO lesion under the additional bacterial culture. The decision of ‘Non-cured’, which did not meet these conditions , was excluded to increase the reliability of the study. Second, this study was conducted based on a relatively small number of FDG-PET images compared with recent studies using deep learning. The application of FDG-PET for diagnosis and assessing therapeutic responses in PVO has not yet been generalized, and it is not easy to conduct a large-scale study considering the cost of FDG-PET. However, based on the high accuracy of using FDG-PET to assess therapeutic responses in PVO, as demonstrated in previous studies, we think that the AUC observed in this small-scale study will be reproduced in large-scale studies. Lastly, this study was conducted in a single center and our results were not confirmed under the same conditions as those in other institutions. Multicenter research is an important factor to obtain high reliability of research results. Unfortunately, this study was conducted with FDG-PET/MRI for various reasons, including the measurement of SUVmax had a better performance for predicting the remission of PVO compared to those using CRP and ESR. However, the best performance was obtained in a DNN model using all attributes, including CRP, ESR, and SUVmax, which may be achieved by compensating for the limitations of each attribute. We expect that the use of a DNN model based on a combination of FDG-PET and blood inflammatory markers may help accurately predict remission in PVO.DNN models using SUV


The multiple regression model showed that only age (p = 0.028), SBP z-score (p = 0.006), and heart rate (p = 0.001) were significantly associated with PWV. The results were superimposable when the DBP z-score replaced the SBP z-score in the model. Mediation models showed that the effect of eGFR on PWV was fully mediated by SUA (p = 0.015) and that the effect of SUA on PWV was totally mediated by HOMA-index (p < 0.001). Both SUA (p < 0.01) and HOMA-index (p < 0.01) had a significant association with higher SBP (DBP) z-scores. The double mediation model including both BP and HOMA-index showed that the SUA effect on PWV was totally mediated by both variables . The results were superimposable when the DBP z-score replaced the SBP z-score in the model. In conclusion, insulin resistance and BP are both important mediators of the association between SUA and vascular stiffness in pediatric age.Several studies describe the association between serum uric acid (SUA) and arterial stiffness in adults. Uric acid contributes through several mechanisms to the increase in blood pressure (BP) and adversely affects the insulin signaling pathway. Moreover, SUA predict the development of hypertension and insulin resistance up to type 2 diabetes. Early arterial stiffening, estimated by carotid-femoral pulse wave velocity (PWV), may already be present in pediatric age. Aim of our study was to investigate the relationship between SUA and PWV in a pediatric population and its interaction with insulin resistance and BP. In 322 children and adolescents , we measured weight, height, waist circumference, BP and PWV. We also assayed SUA and estimated glomerular filtration rate (eGFR) and calculated HOMA-index as a marker of insulin resistance. Simple and multiple regression analyses were performed to assess variables associated with PWV. Mediation models were applied to identify the direct and indirect effects of individual variables on PWV. On univariate analysis, age ( Hyperuricemia and insulin resistance (IR) are well known risk factors for hypertension (HT) , 2, evenLongitudinal studies performed in adults show that SUA and IR influence blood pressure (BP) and the risk of cardiovascular events , 9. ThisSerum uric acid and homeostatic model assessment (HOMA) index, a recognized indicator of IR, are also associated with vascular damage in adulthood . Due to Carotid–femoral pulse wave velocity (PWV) is the non-invasive gold standard measurement of arterial stiffness , and it While a joint effect of increased SUA and IR on the development of subclinical vascular damage has been described in adults , it has The aim of the study was to investigate the complex relationship between SUA levels, IR, BP and subclinical organ damage in children and adolescents at increased cardiovascular risk. In the attempt to optimize our methodological approach, in addition to classical statistical regression models, we used a mediation analysis, an efficient method to clarify the causal paths underlying the association between the explanatory factors and the outcome.We studied a cohort of 322 children and adolescents (3.7–18.4 years), consecutively referred from 06/08/2012 to 10/06/2020 to our Unit for Cardiovascular Risk Assessment in Children  by their primary care pediatricians, because of evidence of elevated BP values and/or excess weight. Exclusion criteria were: diabetes mellitus, any form of secondary HT and treatment with antihypertensive drugs.The study protocol was approved by the local institutional ethics committee and conformed to the ethical guidelines of the 1975 Declaration of Helsinki . An informed consent was obtained from parents or legal representatives before the enrolment in the study.2. Waist-to-height-ratio (WtHr) was calculated dividing WC by height and expressed as percentage. BMI z-scores were calculated using the Centre for Disease and Control prevention charts available at https://www.cdc.gov/growthcharts/clinical_charts.htm. Weight class was defined according to the International Obesity Task Force classification  were measured. Weight was approximated to the nearest 100 grams, and height to the nearest 1 mm. Waist circumference was measured to the nearest 0.5 cm by a flexible tape in standing position. Body mass index (BMI) was calculated as weight (kg)/height (m)fication  distingufication , consideBlood pressure was measured using an oscillometric device validated in children  with the appropriate cuff for the children's upper-arm size.z-scores were calculated according to the nomograms of the National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Children and Adolescents  and the average of the last two measurements was considered. Systolic BP (SBP) and diastolic BP (DBP) percentiles and lescents . The chiBlood samples were taken from all subjects after a 12-h fasting period to measure serum concentrations of glucose, insulin, SUA and creatinine. Commercial kits, normally used for routine examinations of patients, were employed for all analyses. In detail: enzymatic method with hexokinase Glucose HK Gen.3 Cobas Roche, for glucose assay; immuno Assay in ElectroChemiLuminescence Elecsys Insulin Cobas Roche for insulin assay; colorimetric enzymatic test Uric Acid 2 Cobas Roche for uric acid assay; colorimetric kinetic test based on the Jaffé method Creatinine Jaffé Gen.2 Cobas Roche for creatinine assay. HOMA-index was calculated by dividing the product of serum insulin (μU/ml) and serum glucose (mmol/L) by 22.5 .Measurements were obtained in a stable room temperature after 10 min of rest. A validated, easy-to-use and high-fidelity PulsePen tonometer  was used in this study , 25. RepT-test and Chi-square test.Continuous variables were expressed as mean and standard deviation, the categorical variables as percentages on relative frequencies. Comparisons across strata, defined by gender, were obtained by The relationship between the outcome (PWV) and explanatory variables was investigated through univariate and multivariable linear regression models.A mediation analysis through Structural Equation Modeling (SEM) was then performed to more deeply explore the roles of explanatory variables as predictors and possible mediators of PWV. Structural Equation Modeling is a very powerful multivariate technique that allows to examine a set of relationships among a few variables at the same time. It is based on a system of linked regression-style equations. In a classic regression model framework, there is a clear distinction between dependent and independent variables. In a SEM framework, however, a dependent variable in one model equation can become an independent variable in other components of the SEM system . RelatioThe mediation model was applied according to the following strategy. We explored the possible presence of an impact of SUA, mediated by HOMA-index, on PWV. Similarly, we explored the possible presence of an impact of HOMA-index, mediated by SUA, on PWV. The same approach was used to explore a possible mediation between SUA and HOMA-index on SBP and DBP and of SUA and eGFR on PWV. Suggested mediation paths were then included in a comprehensive model of PWV.Three hundred and twenty-two children and adolescents  were enrolled. p < 0.001), onset of pubertal developmental (p = 0.002), WtHr % (p = 0.036), SBP and DBP z-scores (p < 0.001), and heart rate (p = 0.028). There was a significant and positive association between PWV values and SUA (p = 0.002) and HOMA-index (p < 0.001), while the relationship between PWV and eGFR was inverse (p = 0.014).Univariable and multivariable linear regression models on PWV are shown in z-scores, the variables that were shown to be significantly associated to PWV values were: age (p = 0.028), SBP z-scores (p = 0.006), and heart rate (p = 0.001) , DBP z-scores (p = 0.005), and heart rate (p = 0.002)  , Model A= 0.002) , Model Bp < 0.001, p = 0.075).In the mediation analysis with PWV as outcome , the effz-scores and DBP z-scores as outcomes instead of PWV, HOMA-index and SUA showed both significant direct and indirect effects in the causal paths , whereas the effect of SUA on PWV was not mediated by eGFR .In the mediation analysis with PWV as outcome , the impz-score as mediators  ediators . In thisSimilar results were obtained including the direct impact of other confounders on PWV  and on SUA (eGFR) .z-scores), age, and heart rate maintain a significant association with PWV values. However, when the data are analyzed using mediation analysis, IR maintains an effect on vascular stiffness that is independent of SBP and DBP, while the association between SUA and PWV values turn out to be totally mediated by HOMA-index and BP.Our study shows that, in a population of children and adolescents with high BP and/or excess weight, IR (quantified by the HOMA-index) and SUA values are strongly associated with increased aortic stiffness, as assessed by carotid-femoral PWV. This relationship seems to be lost when the statistical model is corrected for possible confounding factors. In fact, at classical multiple regression analysis, only BP . The distribution of risk factors, but especially the time these risk factors had to exert their negative effect, varies with increasing age of children. It is very likely that the metabolic risk factors considered in the study, even if present very early in life, exert their negative effect to an increasing extent as the time since their onset increases. In the present study, age is significantly associated with higher PWV values in the multivariable regression model. To try to mitigate this drawback, we performed an age adjustment of the final mediation model. Age maintains its impact on PWV values, however, the main results of the study remain unchanged. Importantly, eGFR, which is strongly inversely related to SUA values, does not appear to have a direct effect on PWV levels, but only an indirect effect mediated by SUA, which, in turn, exerts its indirect effect on PWV through the HOMA-index. This result is probably because none of the children of the study had chronic kidney disease. Therefore, while the inverse relationship between eGFR and SUA is present even with normal renal function, the impact that a reduction in eGFR might have on the development of organ damage is determined by factors  that begin to act when renal damage is clinically evident.To better understand our results, and to find out whether the effects of any of the variables considered were mediated by those attributable to another variable, in addition to performing a classic uni- and multivariate analyses, we made use of mediation analysis. The mediation analysis is a method that can be applied to explain the causal paths underlying the association between the exposure and the outcome. If the mediators are on the causal path, then the exposure affects the mediator, which in turn affects the outcome. The total effect of exposure can pass both through the mediators (indirect effect) and through a direct pathway (direct effect). The mediation analysis makes it possible to identify the proportion of the direct and indirect effects of the exposure on the outcome. If the mediators fully mediate the effect from the exposure to the outcome, it is a full mediation case. Alternatively, situations where the mediators do not fully mediate the effect of the exposure on the outcome, represent partial mediation cases. In the present study the mediation analysis showed that both SUA and HOMA-index had a direct effect on SBP and DBP Our study has some limitations as well as several strengths. Among the first ones, other factors that we did not consider in this study may alter endothelial function  and may play an important role in determining vascular stiffness in this age group , 52. On In conclusion, the interactions between BP, IR and SUA on one side and vascular stiffness on the other side are extremely complex, and a statistical analysis performed with classical methods  is likely to miss this complexity. Our data suggest that SUA through the effects of IR and BP may cause structural remodeling of the macrovascular wall, which may further trigger arteriolar narrowing and increased large artery stiffness. The subclinical alterations of the vascular phenotype may play a key role in mediating the incidence of deleterious cardiovascular outcomes later in life. For this reason, PWV may be useful as a non-invasive tool to identify the presence of arterial stiffness in young people at increased cardiovascular risk. The presence of insulin resistance and hyperuricemia are not always considered important cardiovascular risk factors in children. Our study shows that these two metabolic factors are not only associated with the presence of HT in children and adolescents, but are also mediators of the onset of early organ damage, such as increased vascular stiffness, both directly (HOMA index) and indirectly (SUA). These findings should suggest the need for interventions aimed at reducing HOMA index and SUA values as early as pediatric age. Nevertheless, the results of our study contribute to the comprehension of the relationship between SUA levels, BP, IR and the occurrence of subclinical organ damage, without the chance to give indications about the threshold levels at which starting treatment strategies might be useful for primary prevention. It is therefore important to study potential preclinical mechanisms that lead to early disease pathogenesis to facilitate the identification of high-risk patients and thereby implement early therapeutic prevention strategies. Being able to analyze these phenomena in a pediatric population prior to the onset of clinical complications represents a very important because it allows to avoid some confounding factors such as vascular aging, drug interference, or smoking. Indeed, investigating changes observed in children offers a fascinating model for understanding the early pathophysiological mechanisms underlying HT.The 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 Ethic Committee Name: Istituto Auxologico Italiano, Approval Code: 2015102002, Approval Date: 20/11/2015. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.SG conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. IP, GL, AO, and MG collected data. LM and LA performed data analysis. GP, PS, and FV reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.Research funded by the Italian Ministry of Health.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.


Pseudomonas aeruginosa is a ubiquitous opportunistic bacterial pathogen, which is a leading cause of nosocomial pneumonia. Early identification of the risk factors is urgently needed for severe infection patients with P. aeruginosa. However, no detailed relevant investigation based on machine learning has been reported, and little research has focused on exploring relationships between key risk clinical variables and clinical outcome of patients. In this study, we collected 571 severe infections with P. aeruginosa patients admitted to the Xijing Hospital of the Fourth Military Medical University from January 2010 to July 2021. Basic clinical information, clinical signs and symptoms, laboratory indicators, bacterial culture, and drug related were recorded. Machine learning algorithm of XGBoost was applied to build a model for predicting mortality risk of P. aeruginosa infection in severe patients. The performance of XGBoost model  was greater than the performance of support vector machine  and random forest . This study also aimed to interpret the model and to explore the impact of clinical variables. The interpretation analysis highlighted the effects of age, high-alert drugs, and the number of drug varieties. Further stratification clarified the necessity of different treatment for severe infection for different populations. Pseudomonas aeruginosa (P. aeruginosa), a ubiquitous Gram-negative pathogen, can colonize almost any part of the human body . More thPseudomonas aeruginosa infection with diverse pathological background exerts a heavy health burden for modern society. Thus, there is an urgent need to identify the mortality risk factors of infection for severe infection patients with P. aeruginosa early. A retrospective study has shown that APACHE II score and septic shock are critical factors for mortality in P. aeruginosa bacteremia, and combination therapy does not significantly reduce overall 14-day mortality . SeveralMachine learning is a data-driven computing method, which does a lot of work based on big data. While machine learning has been demonstrated in a few different fields, it has only recently been gaining popularity in the field of medicine. Compared to logistic regression, machine learning methods are often more comprehensive, accurate, and rapid in clinical risk prediction . VariousIn this study, we proposed a mortality risk prediction framework for severe infection patients with P. aeruginosa infection based on machine learning. Our framework focused on decision support and model interpretation. Based on XGBoost algorithm and electronic medical records (EMR) data, we built a machine learning model with good predictive performance using grid searching and cross-validation . FurtherThe study was conducted at the Xijing Hospital of the Fourth Military Medical University, and a total of 571 patients with severe infections were included in the study between January 2010 and July 2021. There were 338 patients in the death group and 233 patients in the control group. Our study was approved by the domestic ethics committee with the approval number KY20212130-C-1. This study is a retrospective, observational study design that does not require informed consent. The collected research data were de-identified and analyzed anonymously.https://www.cpa.org.cn/index.php?do=info&cid=75676) and the management of high-alert medication in Xijing Hospital of the Fourth Military Medical University. The details of high-alert medication can be found in the Supplementary Section ; Some comorbidities such as autoimmune diseases , malignant tumors  were excluded; Suspected contaminated specimens (the same sample culture of 3 or more pathogenic bacteria); Non-infected or colonized patient, such as the patient's clinical symptoms, signs, laboratory indicators, imageology were not abnormal; Hospitalization for less than 3 days.All the clinical variables we collected could be divided into numerical and categorical variables according to clinical significance, and longitudinal and non-longitudinal variables according to whether repeated monitoring occurred during admission. Then, the categorical variables were converted into one-hot vectors. For clinical longitudinal variables, we extracted the maximum increase and maximum decrease during hospitalization for each variable. For laboratory longitudinal variables, we extracted the slope of all laboratory variables over time, the maximum increase and decrease during hospitalization. Finally, we got 91 variables in total (including derived variables). A detailed description and classification of all variables can be found in the Supplementary Section .Outliers were detected using the interquartile range (IQR). As a threshold, the 2 times of IQR were used, and points exceeding this threshold  were defined as outliers. Data points out of the valid value threshold were identified as outliers. The excluded outliers were modified as the nearest threshold.Variables which had more than 50% missing values were deleted, while variables which had less than 20% missing values were replaced by the median values. Multivariate imputation by chained equations (MICE) was used to impute missing values while loss rates of variables were between 20 and 50%.z-score normalization was only performed for the all continuous values used by Support Vector Machine (SVM)  . Since tLightGBM , CatBoosLightGBM , and RanLightGBM .The XGBoost is a scalable end-to-end tree boosting system, which implements machine learning algorithms in a gradient enhancement framework that is efficient, flexible, and portable. It could be used for handling sparse data, and solving many data science problems quickly and accurately. The XGBoost has been widely used by data scientists to obtain state-of-the-art results in many machine learning challenges. The equations were as follow:l is a loss function that measures the differences between the prediction ŷiand the target yi. The Ω penalizes the complexity of the model.Here, In order to minimize the Here, all XGBoost models were implemented by using XGBoost (version 1.5.1). All codes were implemented using Python 3.7.9.In order to evaluate the performance of our model, we compared the XGBoost with LightGBM, CatBoost, SVM, and RF methods. All models have been optimized by grid searching to adjust hyperparameters. The detailed hyperparameters of XGBoost were described in Section 3.2. We selected the best model for predicting mortality risk for patients with severe P. aeruginosa infection.The different parameters of LightGBM, CatBoost, SVM, and RF are summarized in Supplementary Section . LightGBThe performance of the machine learning classifier was assessed using accuracy (ACC), receiver operator characteristics (ROC) curve, precision recall (PR) curve, area under the receiver operator characteristics curve (AUROC), and area under the precision recall curve (AUPRC), as defined by the following metrics:where TP, TN, FP, and FN refer to true positives, true negatives, false positives, and false negatives, respectively. Here, a “positive” label means that the outcome indicator of sample is death.In order to interpret the prediction results of XGBoost, Shapley additive explanations values were introduced, which unify Shapley regression values , Shapleyz′∈{0, 1}M, M is the number of simplified input feature, and ∅i∈ℝ. ∅0 is the constant of the interpretation model, ∅i is the predicted mean value of all training samples, and is the attribution value of each feature.Where t-tests were used for the statistical analysis. A p-value of less than 0.05 was considered significant. All statistical analyses were performed using Scipy 1.7.2.In this paper, two independent-sample A total of 571 hospitalized patients infected with P. aeruginosa were included in this study. The flow chart of this study is shown in To optimize the XGBoost model, the dataset was divided into five sets. One of the five sets was selected as test set, the rest four sets were selected as training set. We explored different hyperparameters through a grid search, such as the maximum depth, the number of estimators, and learning rate. We considered the maximum depth with 2, 4, 8, 16, and 32, the number of estimators with 5, 10, 15, 20, 25, and 30, and the learning rate with 0.01, 0.05, 0.1, 0.2, 0.3, and 0.5. The best models with different hyperparameters were selected according to the mean performance based on cross validation.The ROC curve and PR curve of three machine learning models are shown in Although the XGBoost model can achieve good predictions performance, the lacking of interpretation limits the application in clinical practice. To facilitate interpretation of the prediction model, an artificial intelligence SHAP values for global model interpretation were introduced . CompareAccording to the importance and impacts of variables on model prediction, a bee swarm plot was formed for each feature. As shown in We found that older (red) patients had a higher risk of mortality than younger (blue) patients . Similarly, patients who used more types of high-alert medications and more types of intravenous drugs had higher risk of mortality than those who used fewer types. The lower the maximum decrease in respiratory rate , the higher the risk of mortality. In addition, patients who underwent drainage (red) had a lower risk of mortality than patients who did not undergo drainage (blue). It is important to emphasize that all effects only describe the behavior of the model and are not causality in the real world.To further elucidate the detailed relationship between mortality risk and clinical variables, SHAP interaction values were used to reveal the dependencies relationships based on the key feature of importance the bee swarm plots. Here, each point corresponds to a sample of infected patients, and each scatter plot shows the effect of features on SHAP interaction values. The results were shown in SHAP dependence plots . By analIn addition to P. aeruginosa, Klebsiella pneumoniae (K. pneumoniae) is major hospital-acquired pathogen, causing pneumonia, urinary tract infection, intra-abdominal infection, and bacteremia in immunocompromised patients .Here, we build a clinical dataset of K. pneumoniae infections as an external validation for testing and discussing the generalization performance of our model. The hyperparameters of model were obtained from the best performance in Section 3.2. Five sub-models trained on the 5-fold cross validation were used in the external validation set. The average performance of each sub-model on these external test sets is shown in p < 0.01), and the death group was often accompanied by 0–3 co-infections, when infection site was blood. The association between the infection site and the number of high warning drugs used was also analyzed. p < 0.01).p < 0.01). p < 0.01). p < 0.05 or p < 0.01). While the patients were older than 75, the number of B-alert drugs used in the death group was significantly different from that of the control group (p < 0.01).These results in p < 0.01 or p < 0.05). p < 0.01). p < 0.01), and close attention should be paid to patients whose maximum decreases in diastolic blood pressure were small and the number of intravenous drug varieties was more than 10.P. aeruginosa infection constitutes a major clinical challenge . TherefoThe most obvious finding to emerge from the analysis above was that advanced age was one of the mortality risk factors for P. aeruginosa infection in severe patients, which was consistent with the results of a previous study . Then, tIn addition, we further stratified to explore the relationships between the site of infection, age stratification, and the number of medication species with important variables, laying the foundation for future variable interaction studies. The conclusion also verified that the risk of death from blood culture with P. aeruginosa was higher than other sites, and it was consistent with our common knowledge. Simultaneously, with patients' ages increasing and the higher the number of intravenous drug varieties used, the number of deaths showed an increasing trend. It suggested that risk factors such as advanced age and the number of drug varieties used need to be actively paid attention to for patients infected with P. aeruginosa, especially when the age was greater than 75 and the number of drug species was > 10. These conclusions were preliminary and needed to be further validated.This retrospective study still had several limitations. Firstly, this was a single-center study and, therefore, has all the limitations inherent in such a study design. The distribution and characteristics of the clinical data used in this study could vary among different regions. In future works, integrating more data and having more precise estimates are possible. The clinical data from the multi-centric will help researchers to build more generalization and prospective prediction models. Future works should be used in elucidate the diversity of AMP resistance mechanisms in more realistic clinical settings. In future works, our model should be used in the multi-centric study or other clinical datasets such as MIMIC III  or a criThe original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Institutional Medical Ethical Committee of the First affiliated Hospital of Air Force Medical University, China  on August 30, 2021. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.MW and XZ contributed to data collecting and processing. CC contributed to modeling and calculations. FM and MT performed the results analysis. CC, FM, and MT drafted the manuscript. RL contributed to manuscript revision. JW and YG provided overall supervision and undertook the responsibility of submitting the manuscript for publication. All authors discussed and commented on the manuscript.This research was financially supported by the National Natural Science Foundation of China .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.


Arthritis and Rheumatism are the most productive research institutions and journals. Tak PP’s  paper has the highest publication and citation scores. The keywords “bone loss” and “polarization” have the highest frequency. Additionally, the study of macrophage polarization in RA has been research focus in recent years. This study demonstrates that research on macrophages in RA will continue. China is a significant producer, whereas the United States is an influential nation in this regard. In the last decade, most studies have concentrated on fundamental research. Recent studies have shown how macrophages play a role in controlling and weakening inflammation, and drug delivery and mechanism have come to the fore.Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by macrophage activation. The current characteristics, hotspots, and research frontiers of macrophage-related RA were analyzed using bibliometric analysis. Relatedpapers published from 2000 to 2021 in the Web of Science database were retrieved. The diagrams were generated and analyzed using the bibliometric software package. VOSviewer and CiteSpace were used to evaluate and visualize the research trends and hotspots in macrophage-related RA. A total of 7253 original articles were obtained. Global research on macrophage-related RA is in an advanced stage of development, with core authors, teams and research institutions emerging. United States has published the most papers, received the most citations, and had the highest H-index over the last 22 years. The University of Amsterdam and the journal of  Rheumatoid arthritis (RA) is an autoimmune disease associated with macrophages that manifests as a chronic inflammatory condition marked by severe joint damage and synovial joint destruction , 2. RA hvia statistical analysis of published data (Bibliometrics is a method for assessing and monitoring the progress of specific disciplines hed data . Bibliomhed data . Using bThe Science Citation Index (SCI) Expanded Database of the Web of Science (WoS) was used to obtain bibliographic data. To avoid bias caused by daily database updates. All documents published between 2000 and 2021 were retrieved and downloaded from the WoS Core Collection (WoSCC) database on January 19, 2022. The search strategy applied was Title = (rheumatoid arthritis OR RA) AND Title = (macrophage OR macrophages). Only English-language research papers and review articles were retrieved. Two investigators (YLX and JLH) independently conducted the primary data search and discussed any discrepancies. The final agreement reached a value of 0.90, indicating a substantial agreement .The data was saved and stored in download_txt format. For further analysis, only research articles and review articles chosen, as data acquisition flowchart presented in For visual analysis, all valid data collected from the WoSCC database was imported into CiteSpace (version 5.7) and OVSviewer (version 1.6.16) . CiteSpa2 = 0.9423). Overall, these findings indicate that the research on macrophage-related RA has gradually stabilized.The total number of publications (NP) over a given period can objectively and quantitatively reflect a field’s overall development trend. A total of 7253 publications were chosen based on the defined search terms. Among these publications, 6076 (83.77%) were original articles, and 6076 (16.23%) were reviews. The annual NP is depicted in The publications originated from 103 countries/regions, and 64 countries/regions had more than four publications. The top 10 most influential countries/regions are listed in More than 5409 institutions have made contributions to this field, with 161 producing more than 18 papers. The visual cluster analysis (threshold > 18 papers) result is depicted in Funding support plays a vital role in scientific advancement. via co-citations. Among the 120146 cited authors, 140 (classified into seven clusters) had at least 106 citations. Based on the cluster summary, the authors devoted their minds to summarizing the evolving concepts, pathogenesis, related outcomes, and interventions of RA. Firestein GS ranked the highest in NC (798), followed by McInnes IB (770), Feldmann M (758), Tak PP (576), and Smolen JS (559). Over 36894 authors have authored in this field. Among them, 207 authors contributed at least eight papers to this collection. Arthritis and Rheumatism was the most prolific journal (NP=347) with the highest NC (27563), and AC (80.76). Annals of the Rheumatic Diseases had the highest IF (27.973), followed by Arthritis and Rheumatology (15.483), respectively.A total of 1382 journals published specific articles on macrophage-related RA. Among them, 160 journals contributed at least eight papers. Journal of Immunology, Arthritis and Rheumatism, the Journal of Biological Chemistry, Journal of Experimental Medicine, and Annals of the Rheumatic Diseases were the five most frequently and centrally cited journals. Co-cited journals are those in which two or more journals are cited concurrently by researchers. The threshold was met by 141 of met the 12023 cited references (minimum citations > 400). The Of the 7253 documents, 384 met the threshold of minimum citations >145. The top 10 articles with the highest NC are presented in Arthritis and Rheumatism was ranked first in the terms of publications and citations , follow by Arthritis Research and Therapy  and Annals of the Rheumatic Diseases . Of the 1382 documents sources, 103 met the criterion (minimum number of documents of a source > 12). Burst detection, an algorithm developed by Kleinberg , is an eKeyword analysis can also determine the time when keyword with a frequency change rate first appeared in a node, thereby defining the the research field’s boundaries. Between 2000 and 2021,19174 keywords were used, with 140 of them appearing more than 69 times. These studies look at RA’s clinicopathological diagnosis, RA related-inflammatory markers, the pathogenic mechanisms of RA, the therapeutic interventions, and how drugs work to treat RA. As illustrated in “Burst words” are words that are frequently cited in connection with a particular subject at a specific time. They enable the observation of emerging theories and the prediction of the research frontier base on the distribution of keywords with the highest citation burst. A bibliometric analysis was performed to investigate the developmental trends and hotspots of research on macrophage-related RA from the SCI-Expanded database using VOSviewer and CiteSpace. A total of 7253 original articles and reviews published from 2000 to 2021 were obtained. According to the polynomial fitting curve, the annual NP was generally upward, but the growth stalled in the second half of the curve, particularly after 2015. The lack of high-impact, ground breaking publications was the main reason why the annual NP didn’t move forward for recent three years . This finding indicates that publishing research on macrophage-related RA in high-quality journals is not a challenging. The 50 articles with high NC were published in journals with a high-IF, indicating that these journals have published a greater number of potential breakthroughs in this field. As a result, researchers interested in this field should pay more attention to the news in these journals.There are many different immune cells affect in RA development. In addition to macrophages, immune cells such as T cell, B cell, dendritic cell, mast cell, natural killer cell are also involved in immune responses , 25. Of via TNF, IL-1 and other pro-inflammatory cytokines, as well as cell-to-cell contact, aggravating RA’s disease 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.