1.Severity Assessment Parameters and Diagnostic Technologies of Obstructive Sleep Apnea
Zhuo-Zhi FU ; Ya-Cen WU ; Mei-Xi LI ; Ping-Ping YIN ; Hai-Jun LIN ; Fu ZHANG ; Yu-Xiang YANG
Progress in Biochemistry and Biophysics 2025;52(1):147-161
Obstructive sleep apnea (OSA) is an increasingly widespread sleep-breathing disordered disease, and is an independent risk factor for many high-risk chronic diseases such as hypertension, coronary heart disease, stroke, arrhythmias and diabetes, which is potentially fatal. The key to the prevention and treatment of OSA is early diagnosis and treatment, so the assessment and diagnostic technologies of OSA have become a research hotspot. This paper reviews the research progresses of severity assessment parameters and diagnostic technologies of OSA, and discusses their future development trends. In terms of severity assessment parameters of OSA, apnea hypopnea index (AHI), as the gold standard, together with the percentage of duration of apnea hypopnea (AH%), lowest oxygen saturation (LSpO2), heart rate variability (HRV), oxygen desaturation index (ODI) and the emerging biomarkers, constitute a multi-dimensional evaluation system. Specifically, the AHI, which measures the frequency of sleep respiratory events per hour, does not fully reflect the patients’ overall sleep quality or the extent of their daytime functional impairments. To address this limitation, the AH%, which measures the proportion of the entire sleep cycle affected by apneas and hypopneas, deepens our understanding of the impact on sleep quality. The LSpO2 plays a critical role in highlighting the potential severe hypoxic episodes during sleep, while the HRV offers a different perspective by analyzing the fluctuations in heart rate thereby revealing the activity of the autonomic nervous system. The ODI provides a direct and objective measure of patients’ nocturnal oxygenation stability by calculating the number of desaturation events per hour, and the biomarkers offers novel insights into the diagnosis and management of OSA, and fosters the development of more precise and tailored OSA therapeutic strategies. In terms of diagnostic techniques of OSA, the standardized questionnaire and Epworth sleepiness scale (ESS) is a simple and effective method for preliminary screening of OSA, and the polysomnography (PSG) which is based on recording multiple physiological signals stands for gold standard, but it has limitations of complex operations, high costs and inconvenience. As a convenient alternative, the home sleep apnea testing (HSAT) allows patients to monitor their sleep with simplified equipment in the comfort of their own homes, and the cardiopulmonary coupling (CPC) offers a minimal version that simply analyzes the electrocardiogram (ECG) signals. As an emerging diagnostic technology of OSA, machine learning (ML) and artificial intelligence (AI) adeptly pinpoint respiratory incidents and expose delicate physiological changes, thus casting new light on the diagnostic approach to OSA. In addition, imaging examination utilizes detailed visual representations of the airway’s structure and assists in recognizing structural abnormalities that may result in obstructed airways, while sound monitoring technology records and analyzes snoring and breathing sounds to detect the condition subtly, and thus further expands our medical diagnostic toolkit. As for the future development directions, it can be predicted that interdisciplinary integrated researches, the construction of personalized diagnosis and treatment models, and the popularization of high-tech in clinical applications will become the development trends in the field of OSA evaluation and diagnosis.
2.The Establishment of a Virus-related Lymphoma Risk Warning System and Health Management Model Based on Traditional Chinese Medicine Conditions
Hanjing LI ; Shunan LI ; Zewei ZHUO ; Shunyong WANG ; Qiangqiang ZHENG ; Bingyu HUANG ; Yupeng YANG ; Chenxi QIU ; Ningning CHEN ; He WANG ; Tingbo LIU ; Haiying FU
Journal of Traditional Chinese Medicine 2025;66(4):335-339
Virus-related lymphoma exhibits a dual nature as both a hematologic malignancy and a viral infectious disease, making it more resistant to treatment and associated with poorer prognosis. This paper analyzes the understanding and therapeutic advantages of traditional Chinese medicine (TCM) in virus-related lymphoma. It proposes a TCM-based approach centered around syndrome differentiation, using standardized measurements of the overall TCM condition, multi-omics research of hematologic tumors, and artificial intelligence technologies to identify the "pre-condition" of virus-related lymphoma. A risk warning model will be established to early identify high-risk populations with viral infections that may develop into malignant lymphoma, thereby establishing a risk warning system for virus-related lymphoma. At the same time, a TCM health management approach will be applied to manage and regulate virus-related lymphoma, interrupting its progression and forming a human-centered, comprehensive, continuous health service model. Based on this, a standardized, integrated clinical prevention and treatment decision-making model for virus-related lymphoma, recognized by both Chinese and western medicine, will be established to provide TCM solutions for primary prevention of major malignant tumors.
3.Study on the distribution of traditional Chinese medicine syndromes and syndrome elements in lymphoma and the correlation between syndromes and Western medicine clinical indicators
Hanjing LI ; Shunan LI ; Zewei ZHUO ; Shunyong WANG ; Qiangqiang ZHENG ; Bingyu HUANG ; Yupeng YANG ; Chenxi QIU ; Ningning CHEN ; Yanyan QIU ; He WANG ; Tingbo LIU ; Haiying FU
Journal of Beijing University of Traditional Chinese Medicine 2025;48(1):127-137
Objective:
To investigate the distribution of traditional Chinese medicine (TCM) syndromes and syndrome elements in lymphoma, as well as the correlation between TCM syndromes and Western clinical indicators, in order to analyze associations between TCM syndromes and these indicators.
Methods:
From January 2023 to May 2024, 216 patients with lymphoma who met the inclusion criteria in the Department of Hematology, Third People′s Hospital Affiliated to Fujian University of Traditional Chinese Medicine were enrolled. Four diagnostic methods were applied to perform TCM syndrome differentiation and extract syndrome elements. The correlations between various syndromes and blood test indicators of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), white blood cell (WBC), hemoglobin (Hb), platelet count (PLT), neutrophil (NEUT), immunohistochemical markers of B-cell lymphoma-6 (BCL6), B-cell lymphoma-2 (BCL2), proto-oncogene MYC, and Ki67 protein expression, Ann Arbor staging, international prognostic index (IPI) score, bone marrow infiltration, concurrent infections during chemotherapy, and post-chemotherapy bone marrow suppression rate were analyzed.
Results:
Five TCM syndromes, ranked by frequency, were syndromes of yin deficiency with phlegm accumulation(41.67%), qi depression with phlegm obstruction(30.56%), cold-phlegm congelation and stagnation(12.96%), phlegm-blood stasis toxin(12.04%), and lingering pathogen due to deficient vital qi(2.77%). Yin deficiency(50.93%) and phlegm(45.37%) were the more prevalent syndrome elements. The TCM syndromes were correlated with β2-MG, PLT, MYC, BCL2/MYC, Ki67 protein expression, and bone marrow infiltration (P<0.05). No statistically significant differences were observed in Ann Arbor staging or IPI score across the syndromes. Compared to the syndrome of cold-phlegm congelation and stagnation, the syndrome of qi depression with phlegm obstruction exhibited higher levels of NEUT, MYC, BCL2/MYC, and Ki67 protein expression, as well as a higher rate of post-chemotherapy bone marrow suppression (P<0.05); the syndrome of phlegm-blood stasis toxin showed higher MYC and BCL2/MYC protein expression and a higher rate of post-chemotherapy bone marrow suppression rate (P<0.05); the syndrome of yin deficiency with phlegm accumulation demonstrated higher MYC and BCL2/MYC protein expression and bone marrow infiltration rates, whereas PLT level was lower (P<0.05); the syndrome of lingering pathogen due to deficient vital qi had higher MYC, BCL2/MYC, and Ki67 protein expression levels, as well as a higher rate of post-chemotherapy bone marrow suppression rate (P<0.05). Compared to the syndrome of qi depression with phlegm obstruction, the syndrome of phlegm-blood stasis toxin exhibited lower Ki67 protein expression (P<0.05); the syndrome of yin deficiency with phlegm accumulation had higher β2-MG level, bone marrow infiltration rate, and rate of concurrent infections during chemotherapy, whereas PLT and NEUT levels and the rate of post-chemotherapy bone marrow suppression rate were lower (P<0.05). Compared to the syndrome of phlegm-blood stasis toxin, the syndrome of yin deficiency with phlegm accumulation had higher β2-MG level, whereas NEUT and the rate of post-chemotherapy bone marrow suppression were lower(P<0.05); the syndrome of lingering pathogen due to deficient vital qi exhibited a higher Ki67 protein expression (P<0.05). Compared to the syndrome of yin deficiency with phlegm accumulation, the syndrome of lingering pathogen due to deficient vital qi also showed a higher Ki67 protein expression(P<0.05).
Conclusion
The syndrome of yin deficiency with phlegm accumulation is relatively common in lymphoma. There is a correlation between TCM syndromes and Western medicine clinical indicators. The presence of heat signs in the syndromes may indicate active disease and poor prognosis, while the presence of strong pathogenic factors and weak vital qi in the syndromes may indicate a severer chemotherapy-related bone marrow suppression.
4.Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism
Xiaomin ZHU ; Wei CHEN ; Yulan FU ; Guifeng ZHUO ; Yingrui HUANG ; Ying ZHANG ; Lin WU
China Pharmacy 2025;36(9):1046-1051
OBJECTIVE To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula (WPTL) against neuronal necroptosis in Alzheimer’s disease (AD) mice based on the Z-DNA binding protein 1 (ZBP1)/mixed lineage kinase domain-like protein (MLKL) signaling pathway. METHODS Forty APP/PS1 transgenic AD mice were randomly divided into model group, WPTL low-dose (WPTL-L) group (10.4 g/kg, calculated by the raw medicine), WPTL high-dose (WPTL-H) group (20.8 g/kg, calculated by the raw medicine) and donepezil hydrochloride group (3 mg/kg), with 10 mice in each group; another 10 C57BL/6J mice were selected as normal control group. Intragastric administration, once a day, for 30 consecutive days. Twenty-four hours after the last administration, Morris water maze test was performed to evaluate learning and memory abilities; the pathological morphology of hippocampal tissues was observed; the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) were determined; the expressions of amyloid precursor protein (APP), Tau protein, and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected; the positive expression of phosphorylated receptor-interacting protein kinase 3 (p-RIPK3) in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues. RESULTS Compared with normal control group, the escape latency of mice in model group was prolonged significantly on day 3 to 5 (P<0.05), the times of crossing platform reduced significantly (P<0.05), and obvious pathological changes were observed in the hippocampal tissue. The level of TNF- α, the expressions of APP, p-Tau and ZBP1, the phosphorylation levels of RIPK1, RIPK3 and MLKL, the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased (P<0.05), while the serum level of IL-4 was decreased significantly (P<0.05). Compared with model group, above indexes were reversed significantly in administration groups (P<0.05), and pathological damage of hippocampal tissue was alleviated. CONCLUSIONS WPTL can inhibit the ZBP1/MLKL signaling pathway, reduce neuronal necroptosis in AD mice, and inhibit inflammatory responses, thereby improving learning and spatial memory abilities in AD mice.
5.Summary of 16-Year Observation of Reflux Esophagitis-Like Symptoms in A Natural Village in A High-Incidence Area of Esophageal Cancer
Junqing LIU ; Lingling LEI ; Yaru FU ; Xin SONG ; Jingjing WANG ; Xueke ZHAO ; Min LIU ; Zongmin FAN ; Fangzhou DAI ; Xuena HAN ; Zhuo YANG ; Kan ZHONG ; Sai YANG ; Qiang ZHANG ; Qide BAO ; Lidong WANG
Cancer Research on Prevention and Treatment 2025;52(6):461-465
Objective To investigate the screening results and factors affecting abnormal detection rates among high-risk groups of esophageal cancer and to explore effective intervention measures. Methods We investigated and collected the information on gender, education level, age, marital status, symptoms of reflux esophagitis (heartburn, acid reflux, belching, hiccup, foreign body sensation in the pharynx, and difficulty swallowing), consumption of pickled vegetables, salt use, and esophageal cancer incidence of villagers in a natural village in Wenfeng District, Anyang City, Henan Province. Changes in reflux esophagitis symptoms in the high-incidence area of esophageal cancer before and after 16 years were observed, and the relationship of such changes with esophageal cancer was analyzed. Results In 2008, 711 cases were epidemiologically investigated, including
6.Anti-vascular dementia effect of Yifei xuanfei jiangzhuo formula by inhibiting mitochondrial fission
Yulan FU ; Wei CHEN ; Guifeng ZHUO ; Xiaomin ZHU ; Yingrui HUANG ; Jinzhi ZHANG ; Fucai YANG ; Ying ZHANG ; Lin WU
China Pharmacy 2025;36(15):1859-1865
OBJECTIVE To investigate the intervention effect and its potential mechanism of Yifei xuanfei jiangzhuo formula by inhibiting mitochondrial fission in a vascular dementia (VaD) model rats. METHODS VaD rat model was established by bilateral common carotid artery ligation. The experimental animals were randomly divided into sham operation group (SHAM), model group (MOD),Yifei xuanfei jiangzhuo formula low-dose group (YFXF-L), Yifei xuanfei jiangzhuo formula high-dose group (YFXF-H), and Donepezil hydrochloride group (positive control), with 9 animals in each group. After 30 days of intervention, the spatial learning memory ability was assessed by Morris water maze experiment; HE staining was used to observe histopathological changes in CA1 area of hippocampus; ELISA was used to detect the levels of serum inflammatory factors [interleukin-1β (IL-1β) and IL-4]; Western blot was used to detect the expressions of heat shock protein 90 (HSP90)/mixed lineage kinase domain-like protein (MLKL)/dynamin-related protein 1 (Drp1) pathway-related proteins, mitochondrial fusion proteins (MFN1, MFN2), and adenosine triphosphate synthase 5A (ATP5A) in hippocampal tissues. The immunohistochemistry was used to detect the level of phosphorylated MLKL (p-MLKL); real-time fluorescence quantitative PCR was adopted to detect mRNA expressions ofHSP90, MFN1, MFN2 and ATP5A. RESULTS Compared with SHAM group, the escape latency of rats in the MOD group was significantly prolonged, the number of crossing the platform was significantly reduced, and the hippocampal tissues showed typical neuronal damage characteristics, the positive expression level of p-MLKL and the serum level of IL-1β significantly increased, while the serum level of IL-4 significantly decreased, the protein and mRNA expression of HSP90, as well as the protein expressions of p-MLKL/MLKL and p-Drp1(Ser616)/Drp1 were all significantly increased in hippocampal tissue, the protein and mRNA expressions of MFN1, MFN2 and ATP5A, and protein expression of p-Drp1(Ser637)/Drp1 were all significantly decreased (P<0.05). After the intervention of Yifei xuanfei jiangzhuo formula, above indicators in each treatment group were all significantly reversed (P<0.05). CONCLUSIONS Yifei xuanfei jiangzhuo formula may alleviate neuronal damage and neuroinflammatory responses in VaD rats by regulating the HSP90/MLKL/Drp1 signaling pathway, inhibiting mitochondrial fission, thereby maintaining mitochondrial dynamic balance and improving mitochondrial function.
7. Konjac Mannan Oligosaccharides enhanced intestinal barrier function to improve alcoholic nervous injury
Jing-Jing CHEN ; Wen-Yan ZHONG ; Wen-Zhuo SHEN ; Li XIAO ; Cheng-Fu YUAN ; Wen-Yan ZHONG ; Li XIAO ; Cheng-Fu YUAN
Chinese Pharmacological Bulletin 2024;40(3):447-454
Aim Excessive cerebral inflammation caused by chronic alcohol intake is an important risk factor for central nervous system injury. The purpose of this study was to explore the protective effect of konjac mannan oligosaccharide (KMOS) on central nervous system inflammation in alcohol-fed mice and its mechanism. Methods The chronic alcohol fed model of C57BL/6J mice was established using Gao-binge method. And the different doses of KMOS were gavaged every day for 6 weeks. The neuronal damage and microglia activation were evaluated in cerebral cortex and hippocampus. The damage of colon tissue was assessed and serum LPS concentrations were measured. In vitro, Caco-2 cells were stimulated with LPS to establish intestinal mucosal injury model. Results Chronic alcohol intake can cause brain neuron damage in mice, and different doses of KMOS effectively reduced the activation state of microglia, decreased the expression of inflammatory factors caused by the activation of the NLRP3 inflammasome and alleviated neuronal damage in the brain tissue of alcohol-fed mice. The results of colon tissue analysis showed that the use of KMOS effectively reduced the concentration of endotoxin LPS in serum of alcohol-fed mice, alleviated the pathological injury and inflammatory response of colon tissue, and enhanced the expression of Occludin in intestinal tissue. In vitro experiments also showed that KMOS significantly inhibited the inflammatory reaction of Caco-2 cells exposed to alcohol and increased the expression of Occludin protein. Conclusions KMOS treatment effectively inhibited intestinal inflammation caused by alcohol intake, repaired intestinal barrier to prevent the entry of intestinal LPS into brain tissue, decreased the activation of microglia, and then improved brain neuron damage. KMOS had the potential to prevent alcoholic nerve injury.
8.Study on the mechanism of Yifei xuanfei jiangzhuo formula against vascular dementia
Guifeng ZHUO ; Wei CHEN ; Jinzhi ZHANG ; Deqing HUANG ; Bingmao YUAN ; Shanshan PU ; Xiaomin ZHU ; Naibin LIAO ; Mingyang SU ; Xiangyi CHEN ; Yulan FU ; Lin WU
China Pharmacy 2024;35(18):2207-2212
OBJECTIVE To investigate the mechanism of Yifei xuanfei jiangzhuo formula (YFXF) against vascular dementia (VD). METHODS The differentially expressed genes of YFXF (YDEGs) were obtained by network pharmacology. High-risk genes were screened from YDEGs by using the nomogram model. The optimal machine learning models in generalized linear, support vector machine, extreme gradient boosting and random forest models were screened based on high-risk genes. VD model rats were established by bilateral common carotid artery occlusion, and were randomly divided into model group and YFXF group (12.18 g/kg, by the total amount of crude drugs), and sham operation group was established additionally, with 6 rats in each group. The effects of YFXF on behavior (using escape latency and times of crossing platform as indexes), histopathologic changes of cerebral cortex, and the expression of proteins related to the secreted phosphoprotein 1 (SPP1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (aka Akt) signaling pathway and the mRNA expression of SPP1 in cerebral cortex of VD rats were evaluated. RESULTS A total of 6 YDEGs were obtained, among which SPP1, CCL2, HMOX1 and HSPB1 may be high-risk genes of VD. The generalized linear model based on high-risk genes had the highest prediction accuracy (area under the curve of 0.954). Compared with the model group, YFXF could significantly shorten the escape latency of VD rats, significantly increase the times of crossing platform (P<0.05); improve the pathological damage of cerebral cortex, such as neuronal shrinkage and neuronal necrosis; significantly reduce the expressions of SPP1 protein and mRNA (P<0.05), while significantly increase the phosphorylation levels of PI3K and Akt (P<0.05). CONCLUSIONS VD high-risk genes SPP1, CCL2, HMOX1 and HSPB1 may be the important targets of YFXF. YFXF may play an anti-VD role by down-regulating the protein and mRNA expressions of SPP1 and activating PI3K/Akt signaling pathway.
9.The Multicenter Cross-sectional Study on the Distribution Characteristics of Traditional Chinese Medicine Syndrome Elements in Type 2 Diabetes Macroangiopathy
Yulin LENG ; Hong GAO ; Xiaoxu FU ; Gang XU ; Hongyan XIE ; Xingwei ZHUO ; Xiaoqin ZHOU ; Yi YANG ; Xiaoli YUAN ; Zhibiao WANG ; Chunguang XIE
Journal of Traditional Chinese Medicine 2024;65(17):1794-1801
ObjectiveTo explore the distribution characteristics of traditional Chinese medicine (TCM) syndrome elements of macroangiopathy in patients with type 2 diabetes mellitus (T2DM) and the key elements of occurrence, development and progression of disease. MethodsA multicenter cross-sectional study was conducted to enroll 445 T2DM patients from five hospitals, and according to the presence or absence of macroangiopathy, the patients were divided into a T2DM group (120 cases) and a diabetic macroangiopathy (DM) group (325 cases). Patients in DM group were divided into grade Ⅰ, Ⅱ, Ⅲ and Ⅳ according to the peripheral vascular color Doppler ultrasound results and the vascular anomalies classification standard. The general data including gender, age, duration of T2DM and body mass index (BMI) were collected, and the data of four examinations were obtained for syndrome differentiation. According to the diagnostic criteria of TCM syndrome elements, the patients can be divided into 9 patterns including qi deficiency, blood deficiency, yin deficiency, yang deficiency, qi stagnation, blood stasis, excess heat, and excess cold. The general data and distribution of TCM syndrome elements were compared between the two groups. The distribution of TCM syndrome elements in different vascular anomalies grades in the DM group was analyzed. Logistic regression analysis was used to explore the influence of various TCM syndrome elements on the occurrence of macroangiopathy in T2DM. ResultsThere was no significant difference in gender and BMI between groups (P>0.05). The age and duration of diabetes in the DM group were older and longer than those in the T2DM group (P<0.01). With the increase of age and prolonged course of disease, the severity of diabetic macroangiopathy increases gradually (P<0.05 or P<0.01). There was no significant difference in BMI and course of disease among the different TCM syndrome elements (P>0.05). The average age of patients with blood stasis syndrome was the oldest (P<0.05). There was significant difference in gender distribution between the excess heat syndrome and yin deficiency syndrome (P<0.05). A total of 240 TCM syndrome elements were extracted from the T2DM group, while 731 TCM syndrome elements extracted from the DM group. The top two high-frequency syndrome elements in the two groups were qi deficiency and yin deficiency, with a frequency of larger than 50%. The distribution of phlegm-damp syndrome and blood-stasis syndrome were significantly higher in the DM group than in the T2DM group (P<0.01). There were significant differences in the distribution of qi deficiency syndrome, yin deficiency syndrome, phlegm-damp syndrome, blood stasis syndrome, and excess heat syndrome among different grades of vascular anomalies (P<0.01); qi deficiency and yin deficiency were both high-frequency TCM syndrome elements in patients at grades 0 to Ⅲ; phlegm-damp syndrome increased in frequency with the progression of the disease from grades 0 to Ⅳ, and the frequency of blood stasis syndrome showed an overall upward trend. The frequency of phlegm-dampness syndrome increased from grades 0 to Ⅳ with the progression of the disease, and the frequency of blood stasis syndrome showed an overall upward trend. Logistic regression analysis showed that phlegm-damp syndrome and blood stasis syndrome were important TCM syndrome elements related to the vascular anomalies degree of macrovascular disease in T2DM (P<0.05 or P<0.01). ConclusionQi deficiency and yin deficiency are the basic TCM syndrome elements throughout the whole process of T2DM and diabetic macrovascular disease. Phlegm-damp and blood stasis are related to the degree of vascular anomalies in diabetic macrovascular disease and are the key TCM syndrome elements in the progression of macroangiopathy in T2DM.
10.Research progress of phage therapy in orthopedic implant-related infection
Zulipikaer MAIMAITI ; Zhuo LI ; Chi XU ; Jun FU ; Libo HAO ; Liang LIU ; Jiying CHEN ; Wei CHAI
Chinese Journal of Surgery 2024;62(1):81-85
The widespread application of implantable materials has brought about a corresponding increase in implant-related complications, with implant-associated infections being the most critical. Biofilms, which often form on these implants, can significantly impede the effectiveness of traditional antibiotic therapies. Therefore, strategies such as surgical removal of infected implants and prolonged antibiotic treatment have been acknowledged as effective measures to eradicate these infections. However,the challenges of antibiotic resistance and biofilm persistence often result in recurrent or hard-to-control infections, posing severe health threats to patients. Recent studies suggest that phages, a type of virus, can directly eliminate pathogenic bacteria and degrade biofilms. Furthermore, clinical trials have demonstrated promising therapeutic results with the combined use of phages and antibiotics. Consequently, this innovative therapy holds significant potential as an effective solution for managing implant-associated infections. This paper rigorously investigates and evaluates the potential value of phage therapy in addressing orthopedic implant-associated infections, based on a comprehensive review of relevant scientific literature.


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