1.Single-cell transcriptomics identifies PDGFRA+ progenitors orchestrating angiogenesis and periodontal tissue regeneration.
Jianing LIU ; Junxi HE ; Ziqi ZHANG ; Lu LIU ; Yuan CAO ; Xiaohui ZHANG ; Xinyue CAI ; Xinyan LUO ; Xiao LEI ; Nan ZHANG ; Hao WANG ; Ji CHEN ; Peisheng LIU ; Jiongyi TIAN ; Jiexi LIU ; Yuru GAO ; Haokun XU ; Chao MA ; Shengfeng BAI ; Yubohan ZHANG ; Yan JIN ; Chenxi ZHENG ; Bingdong SUI ; Fang JIN
International Journal of Oral Science 2025;17(1):56-56
Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA+ dental follicle stem cells (DFSCs) and CD31+ Endomucin+ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA+ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism*
;
Humans
;
Neovascularization, Physiologic/physiology*
;
Dental Sac/cytology*
;
Single-Cell Analysis
;
Transcriptome
;
Mesenchymal Stem Cells/metabolism*
;
Bone Regeneration
;
Animals
;
Dental Papilla/cytology*
;
Periodontium/physiology*
;
Stem Cells/metabolism*
;
Regeneration
;
Angiogenesis
2.Study of the evaluation methods for evidence and recommendation in Chinese expert consensus on off-label use of drugs
Mingyue ZHANG ; Nan CHEN ; Ling XU ; Zhenggang BAI ; Likai LIN
China Pharmacy 2025;36(6):641-647
OBJECTIVE To provide reference for optimizing or formulating unified evaluation methods for evidence and recommendation in expert consensus on off-label use of drugs. METHODS Retrieved from CNKI, Wanfang data, VIP, CBM, PubMed and Web of Science, Chinese expert consensuses on off-label use of drugs involving evaluation methods for evidence and recommendations were collected from the inception to August 1, 2024. After screening the literature and extracting relevant data, descriptive statistical analysis was conducted. RESULTS & CONCLUSIONS Among the 32 articles included, 14 articles (43.8%) used Micromedex’s Thomson grading system, only 7 articles (21.9%) considered economic factors when forming recommendations, 10 articles (31.3%) reported the conflicts of interest; only 2 articles (6.3%) involved experts in the field of evidence-based medicine methodology. There were differences in the sources of evidence, factors considered in forming recommendations, and the grading standards for evidence and recommendations among different expert consensus evidence evaluation methods. There were also differences in evidence levels and recommendation strength of the same drug off-label use in different expert consensus. It is recommended that in future consensus-building processes, greater attention should be paid to potential conflicts of interest among participants, collaboration with methodological experts should be enhanced, and efforts should be expedited to establish unified standards for evaluating evidence and recommendation methodologies.
3.Expert consensus on intraoperative repositioning for patients with spine fracture and dislocation (version 2025)
Dongmei BIAN ; Ke SUN ; Ningbo CHEN ; Caixia BAI ; Miao WANG ; Yafeng QIAO ; Fei WANG ; Hong WANG ; Feng TIAN ; Mei YAN ; Meng BAI ; Linjuan ZHANG ; Liyan ZHAO ; Yaqing CUI ; Xue JIANG ; Leling FENG ; Ning NING ; Junqin DING ; Lan WEI ; Yonghua ZHAI ; Yu ZENG ; Zengmei ZHANG ; Jiqun HE ; Fenggui BIE ; Hong CHEN ; Zengyan WANG ; Li LI ; Li ZHANG ; Yaying ZHOU ; Bing SHAO ; Ying WANG ; Caixia XIE ; Yanfeng YAO ; Jingjing AN ; Wen SHI ; Xiongtao LIU ; Xiaoyan AN ; Ning NAN ; Lan LI ; Xiaohui GOU ; Qiaomei LI ; Xiuting WU ; Yuqin ZHANG ; Jing LIU ; Fusen XIANG ; Xu XU ; Na MEI ; Jiao ZHOU ; Shan FAN ; Qian WANG ; Shuixia LI
Chinese Journal of Trauma 2025;41(2):138-147
Spine fracture and dislocation are common traumatic spinal conditions that often require surgical intervention due to compromised spinal stability. Surgical approaches include anterior, posterior, and combined anterior-posterior spinal procedures. According to the specific surgical requirements, patients may be placed in the prone position or repositioned between prone and supine positions during surgery. Intraoperative repositioning has become an essential step in patient positioning. However, during repositioning, patients with spinal fracture and dislocation are at increased risk for complications such as hemodynamic instability, nerve injury, and pressure injuries to the skin and soft tissue. Notably, due to the instability of the spinal cord, even minor manipulations can further exacerbate the damage, potentially leading to severe outcomes like paraplegia. Although the current clinical guidelines provide instructive recommendations for standard position, there remains no specific protocols for intraoperative repositioning in patients with spine fracture and dislocation. With a concern for the lack of clinical studies on positioning techniques, risk prevention, and operational norms for special patients, no applicable guidelines or standards are available. A consensus was required to provide clinical reference, meet the requirements of surgical treatment, and minimize the safety risks of patients caused by improper placement of positions. Professional Committee of Operating Room Nursing of Shaanxi Nursing Association organized experts in nursing management and operating room nursing from major hospitals across China to formulate Expert consensus on intraoperative repositioning for patients with spinal fracture and dislocation ( version 2025). The consensus provides 11 recommendations covering pre-repositioning preparation, intraoperative maneuvers, and post-repositioning observation, aiming to provide references for clinical standardization of the intraoperative repositioning process and protection of patients′ safety.
4.Association of Body Mass Index with All-Cause Mortality and Cause-Specific Mortality in Rural China: 10-Year Follow-up of a Population-Based Multicenter Prospective Study.
Juan Juan HUANG ; Yuan Zhi DI ; Ling Yu SHEN ; Jian Guo LIANG ; Jiang DU ; Xue Fang CAO ; Wei Tao DUAN ; Ai Wei HE ; Jun LIANG ; Li Mei ZHU ; Zi Sen LIU ; Fang LIU ; Shu Min YANG ; Zu Hui XU ; Cheng CHEN ; Bin ZHANG ; Jiao Xia YAN ; Yan Chun LIANG ; Rong LIU ; Tao ZHU ; Hong Zhi LI ; Fei SHEN ; Bo Xuan FENG ; Yi Jun HE ; Zi Han LI ; Ya Qi ZHAO ; Tong Lei GUO ; Li Qiong BAI ; Wei LU ; Qi JIN ; Lei GAO ; He Nan XIN
Biomedical and Environmental Sciences 2025;38(10):1179-1193
OBJECTIVE:
This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study.
METHODS:
A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants.
RESULTS:
Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m 2) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m 2) and obesity (≥ 28.0 kg/m 2) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m 2 ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses.
CONCLUSION
This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans
;
Body Mass Index
;
China/epidemiology*
;
Male
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Female
;
Middle Aged
;
Prospective Studies
;
Rural Population/statistics & numerical data*
;
Aged
;
Follow-Up Studies
;
Adult
;
Mortality
;
Cause of Death
;
Obesity/mortality*
;
Overweight/mortality*
5.Effect of Guanxinning injection on myocardial infarction by regulating cardiac immunity through CCL21
Yu-xin BAI ; Ying-xue ZHANG ; Ting-ting SHI ; Si-nan ZHU ; Zhen-kun XU ; Hong WANG ; Lu CHEN
Chinese Pharmacological Bulletin 2025;41(5):960-969
Aim To investigate the mechanism of Guanxinning injection regulating cardiac immune mi-croenvironment to improve myocardial infarction in mice.Methods In this study,MI model was estab-lished by permanent ligation of left anterior descending coronary artery in mice.The mice were divided into five groups:sham operation group,model group,Guanxinning injection low dose group,Guanxinning in-jection high dose group and positive drug captopril group.Hearts were weighed,heart tissues were collect-ed,and Masson staining was used for pathological anal-ysis of heart tissues;immunofluorescence staining was used to detect apoptosis and CCL21 expression in the infarct border zone;flow cytometry was used to detect the proportion of immune cells in myocardial ischemia tissues and lymph nodes;PCR was used to detect CCL21 expression in heart and in vitro human lymphat-ic endothelial cells(HLEC).Results Compared with the model group,the low and high dose groups of Guanxinning injection significantly improved cardiac hypertrophy.Apoptosis in the border zone of myocardi-al infarction was reduced in the low and high dose groups of Guanxinning injection and captopril group.Compared with the model group,the proportion of leu-kocytes in the infarct border zone was dreduced and the proportion of CD4+T cells,Treg cells,and CD8+T cells in the mediastinal lymph nodes and infarct border zone of the heart was regulated in the low and high dose groups of Guanxinning injection;CCL21 secretion by the heart and lymphatic vessels increased.Conclu-sions Guanxinning injection can significantly improve cardiac hypertrophy and fibrosis in MI mice,reduce ap-optosis in the infarct border zone,and play a role in an-ti-myocardial ischemia injury by promoting CCL21 ex-pression in lymphatic vessels to regulate the proportion of mediastinal lymph nodes and cardiac T cells after myocardial infarction.
6.Study on the development and reliability and validity of Transsexualism Screening Questionnaire
Na LIU ; Jingyi BAI ; Junjuan ZHU ; Nan HUANG ; Yi XU ; Jing CHEN ; Jie ZHANG ; Zheng LU
Chinese Journal of Psychiatry 2025;58(5):365-372
Objective:This study aims to develop a questionnaire for transsexualism screening and validate its reliability and validity, to provide a culturally adapted screening tool for Chinese clinicians.Methods:Referencing internationally validated instruments related to transsexualism, items closely aligned with the diagnostic criteria of the International Classification of Diseases, 10th Revision (ICD-10) for transsexualism were extracted. Items reflecting Chinese family cultural characteristics were integrated. The overall structure of the questionnaire was refined through expert consultations. A total of 111 patients diagnosed with transsexualism according to ICD-10 diagnostic criteria (78 male-to-female (MtF), 33 female-to-male (FtM)) were recruited from the outpatient clinic of Shanghai Mental Health Center between June 2021 and April 2024. Additionally, 232 cisgender participants, whose self-reported gender identity aligned with their birth sex, were recruited via the Wenjuanxing platform from June 14 to 22, 2022, comprising 64 heterosexual males, 16 non-heterosexual males, 120 heterosexual females, and 32 non-heterosexual females. Both the transsexual and cisgender groups completed the screening questionnaire. The internal consistency reliability was assessed using Cronbach′s α coefficient, and the corrected item-total correlation (CITC) was employed to measure the relationship between individual items and the total score. Structural validity was verified through structural equation modeling (SEM) using AMOS software. The receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal screening cutoff value, with the area under the curve (AUC) used to evaluate diagnostic accuracy. Effect sizes (Cohen's d) were calculated to compare the average scores of the questionnaire across groups. Results:The Transsexualism Screening Questionnaire consists of 15 items including 4 reverse-scored questions, rated on a 5-point Likert scale. The Cronbach′s α coefficient was 0.953 and the CITC for all items exceeded the recommended threshold of 0.3. After rotation based on eigenvalues>1, one principal component explained 61.67% of the total variance. Confirmatory factor analysis indicated acceptable model fit (χ2/ df = 3.887, standardized root mean square residual (SRMR) = 0.064, root mean square error of approximation (RMSEA)=0.092, comparative fit index (CFI)=0.952, normed fit index (NFI)=0.936, Tucker-Lewis index (TLI)=0.943, incremental fit index (IFI)=0.952). Factor loadings for each item ranged from 0.435 to 0.914. ROC curve analysis revealed that the optimal cutoff values were a mean score of 2.83 and a total score of 42.5, achieving 100% sensitivity and 98.7% specificity, with a Youden index of 0.987. Effect size comparisons showed a Cohen′s d of 6.112 between MtF individuals and cisgender heterosexual males, and a Cohen′s d of 9.287 between FtM individuals and cisgender heterosexual females. Conclusion:The Transsexualism Screening Questionnaire exhibits acceptable reliability, validity, sensitivity, and specificity, and is suitable for screening transsexualism in the Chinese population.
7.Effect of Guanxinning injection on myocardial infarction by regulating cardiac immunity through CCL21
Yu-xin BAI ; Ying-xue ZHANG ; Ting-ting SHI ; Si-nan ZHU ; Zhen-kun XU ; Hong WANG ; Lu CHEN
Chinese Pharmacological Bulletin 2025;41(5):960-969
Aim To investigate the mechanism of Guanxinning injection regulating cardiac immune mi-croenvironment to improve myocardial infarction in mice.Methods In this study,MI model was estab-lished by permanent ligation of left anterior descending coronary artery in mice.The mice were divided into five groups:sham operation group,model group,Guanxinning injection low dose group,Guanxinning in-jection high dose group and positive drug captopril group.Hearts were weighed,heart tissues were collect-ed,and Masson staining was used for pathological anal-ysis of heart tissues;immunofluorescence staining was used to detect apoptosis and CCL21 expression in the infarct border zone;flow cytometry was used to detect the proportion of immune cells in myocardial ischemia tissues and lymph nodes;PCR was used to detect CCL21 expression in heart and in vitro human lymphat-ic endothelial cells(HLEC).Results Compared with the model group,the low and high dose groups of Guanxinning injection significantly improved cardiac hypertrophy.Apoptosis in the border zone of myocardi-al infarction was reduced in the low and high dose groups of Guanxinning injection and captopril group.Compared with the model group,the proportion of leu-kocytes in the infarct border zone was dreduced and the proportion of CD4+T cells,Treg cells,and CD8+T cells in the mediastinal lymph nodes and infarct border zone of the heart was regulated in the low and high dose groups of Guanxinning injection;CCL21 secretion by the heart and lymphatic vessels increased.Conclu-sions Guanxinning injection can significantly improve cardiac hypertrophy and fibrosis in MI mice,reduce ap-optosis in the infarct border zone,and play a role in an-ti-myocardial ischemia injury by promoting CCL21 ex-pression in lymphatic vessels to regulate the proportion of mediastinal lymph nodes and cardiac T cells after myocardial infarction.
8.Expert consensus on intraoperative repositioning for patients with spine fracture and dislocation (version 2025)
Dongmei BIAN ; Ke SUN ; Ningbo CHEN ; Caixia BAI ; Miao WANG ; Yafeng QIAO ; Fei WANG ; Hong WANG ; Feng TIAN ; Mei YAN ; Meng BAI ; Linjuan ZHANG ; Liyan ZHAO ; Yaqing CUI ; Xue JIANG ; Leling FENG ; Ning NING ; Junqin DING ; Lan WEI ; Yonghua ZHAI ; Yu ZENG ; Zengmei ZHANG ; Jiqun HE ; Fenggui BIE ; Hong CHEN ; Zengyan WANG ; Li LI ; Li ZHANG ; Yaying ZHOU ; Bing SHAO ; Ying WANG ; Caixia XIE ; Yanfeng YAO ; Jingjing AN ; Wen SHI ; Xiongtao LIU ; Xiaoyan AN ; Ning NAN ; Lan LI ; Xiaohui GOU ; Qiaomei LI ; Xiuting WU ; Yuqin ZHANG ; Jing LIU ; Fusen XIANG ; Xu XU ; Na MEI ; Jiao ZHOU ; Shan FAN ; Qian WANG ; Shuixia LI
Chinese Journal of Trauma 2025;41(2):138-147
Spine fracture and dislocation are common traumatic spinal conditions that often require surgical intervention due to compromised spinal stability. Surgical approaches include anterior, posterior, and combined anterior-posterior spinal procedures. According to the specific surgical requirements, patients may be placed in the prone position or repositioned between prone and supine positions during surgery. Intraoperative repositioning has become an essential step in patient positioning. However, during repositioning, patients with spinal fracture and dislocation are at increased risk for complications such as hemodynamic instability, nerve injury, and pressure injuries to the skin and soft tissue. Notably, due to the instability of the spinal cord, even minor manipulations can further exacerbate the damage, potentially leading to severe outcomes like paraplegia. Although the current clinical guidelines provide instructive recommendations for standard position, there remains no specific protocols for intraoperative repositioning in patients with spine fracture and dislocation. With a concern for the lack of clinical studies on positioning techniques, risk prevention, and operational norms for special patients, no applicable guidelines or standards are available. A consensus was required to provide clinical reference, meet the requirements of surgical treatment, and minimize the safety risks of patients caused by improper placement of positions. Professional Committee of Operating Room Nursing of Shaanxi Nursing Association organized experts in nursing management and operating room nursing from major hospitals across China to formulate Expert consensus on intraoperative repositioning for patients with spinal fracture and dislocation ( version 2025). The consensus provides 11 recommendations covering pre-repositioning preparation, intraoperative maneuvers, and post-repositioning observation, aiming to provide references for clinical standardization of the intraoperative repositioning process and protection of patients′ safety.
9.Study on the development and reliability and validity of Transsexualism Screening Questionnaire
Na LIU ; Jingyi BAI ; Junjuan ZHU ; Nan HUANG ; Yi XU ; Jing CHEN ; Jie ZHANG ; Zheng LU
Chinese Journal of Psychiatry 2025;58(5):365-372
Objective:This study aims to develop a questionnaire for transsexualism screening and validate its reliability and validity, to provide a culturally adapted screening tool for Chinese clinicians.Methods:Referencing internationally validated instruments related to transsexualism, items closely aligned with the diagnostic criteria of the International Classification of Diseases, 10th Revision (ICD-10) for transsexualism were extracted. Items reflecting Chinese family cultural characteristics were integrated. The overall structure of the questionnaire was refined through expert consultations. A total of 111 patients diagnosed with transsexualism according to ICD-10 diagnostic criteria (78 male-to-female (MtF), 33 female-to-male (FtM)) were recruited from the outpatient clinic of Shanghai Mental Health Center between June 2021 and April 2024. Additionally, 232 cisgender participants, whose self-reported gender identity aligned with their birth sex, were recruited via the Wenjuanxing platform from June 14 to 22, 2022, comprising 64 heterosexual males, 16 non-heterosexual males, 120 heterosexual females, and 32 non-heterosexual females. Both the transsexual and cisgender groups completed the screening questionnaire. The internal consistency reliability was assessed using Cronbach′s α coefficient, and the corrected item-total correlation (CITC) was employed to measure the relationship between individual items and the total score. Structural validity was verified through structural equation modeling (SEM) using AMOS software. The receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal screening cutoff value, with the area under the curve (AUC) used to evaluate diagnostic accuracy. Effect sizes (Cohen's d) were calculated to compare the average scores of the questionnaire across groups. Results:The Transsexualism Screening Questionnaire consists of 15 items including 4 reverse-scored questions, rated on a 5-point Likert scale. The Cronbach′s α coefficient was 0.953 and the CITC for all items exceeded the recommended threshold of 0.3. After rotation based on eigenvalues>1, one principal component explained 61.67% of the total variance. Confirmatory factor analysis indicated acceptable model fit (χ2/ df = 3.887, standardized root mean square residual (SRMR) = 0.064, root mean square error of approximation (RMSEA)=0.092, comparative fit index (CFI)=0.952, normed fit index (NFI)=0.936, Tucker-Lewis index (TLI)=0.943, incremental fit index (IFI)=0.952). Factor loadings for each item ranged from 0.435 to 0.914. ROC curve analysis revealed that the optimal cutoff values were a mean score of 2.83 and a total score of 42.5, achieving 100% sensitivity and 98.7% specificity, with a Youden index of 0.987. Effect size comparisons showed a Cohen′s d of 6.112 between MtF individuals and cisgender heterosexual males, and a Cohen′s d of 9.287 between FtM individuals and cisgender heterosexual females. Conclusion:The Transsexualism Screening Questionnaire exhibits acceptable reliability, validity, sensitivity, and specificity, and is suitable for screening transsexualism in the Chinese population.
10.Association of product of platelet and neutrophil count with monoclonal gammopathy of undetermined significance:a cross‑sectional analysis of the NHANES
Lijie WANG ; Peiyao YANG ; Huijie NAN ; Wenqian LI ; Yuanyuan LIU ; Fangfang XU ; Mingyue SHI ; Yanliang BAI
Blood Research 2025;60():46-
Background:
Inflammation indices are emerging predictors of diseases. Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous state and chronic inflammation may drive MGUS progression. This study aimed to evaluate the association between inflammatory markers and MGUS.
Methods:
Data from the National Health and Nutrition Examination Survey (NHANES) III and 1999–2004 were collected from 6,383 participants. MGUS subtypes were identified using immunofixation electrophoresis. Seven inflammatory indices [lymphocyte count (LC), neutrophil count (NC), platelet-neutrophil product (PPN), systemic immune inflammation index (SII), platelet-lymphocyte ratio (PLR), and C-reactive protein (CRP)] were calculated. Weighted multivariate regression and subgroup analyses assessed the relationships, reported as odds ratios (ORs) and 95% confidence intervals (CIs).
Results:
Of the 6383 patients included in the study, 157 (2.45%) underwent MGUS. There was a significant correlation trend between ln PPN level and the development of MGUS, especially at low levels (OR: 2.62, 95% CI: 1.54–4.75, p-trend = 0.001), while the correlation between PLR level and MGUS was not obvious. In the subgroup analysis, a significant association between PPN level and MGUS was mainly found in the overall population, female sex, nonHispanic black, non-hypercholesterolemia, non-type 2 diabetes (T2D), high school education or above, and divorced or widowed; however, there was no significant interaction between PPN level and MGUS in each subgroup.
Conclusion
PPN levels were significantly associated with MGUS development. Our study identified PPN as a novel and convenient inflammatory marker with potential clinical relevance. Although preliminary, the observed associations highlight the need for validation through longitudinal studies before considering their clinical applications.

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