1.Exploring Mechanism of Luoshi Neiyi Prescription in Treating Endometriosis Based on Ferroptosis and Serum Metabolomics
Haixia PAN ; Yingqiao ZHONG ; Ting MAO ; Ziyi DENG ; Meilin WU ; Lei HUANG ; Siyang CHEN ; Yong GUO ; Ying ZHOU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):201-212
ObjectiveThis study aimed to investigate the mechanism by which Luoshi Neiyi prescription treats endometriosis (EMs) through regulating ferroptosis, and to screen key metabolites and analyze their association with ferroptosis. MethodsClinical samples of normal endometrium from patients without EMs and eutopic and ectopic endometrium from EMs patients (10 cases each) were collected and divided into control group, eutopic group, and EMs group. Hematoxylin-eosin (HE) staining was performed to observe ectopic lesions of EMs. Immunohistochemistry was used to detect the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Enzyme-linked immunosorbent assay (ELISA) was adopted to determine the levels of malondialdehyde (MDA), ferrous ion (Fe2+), GPX4 and glutathione (GSH) in endometrial tissues, as well as serum levels of Fe2+, GPX4 and GSH. Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the mRNA expression of SLC7A11, GPX4, transferrin receptor (TFR) and ferritin heavy chain 1 (FTH1). In the in vitro experiment, primary stromal cells were isolated from ectopic lesions of EMs patients. Cell counting kit-8 (CCK-8) was used to determine the optimal concentration of drug-containing serum for intervention. The level of reactive oxygen species (ROS) was measured, and Real-time PCR was applied to detect ferroptosis-related indicators. In the animal experiments, an EM rat model was established, and the rats were randomly assigned to the sham operation group, EMs group, low-dose Luoshi Neiyi Formula group (7.87 g·kg-1), high-dose Luoshi Neiyi prescription group (15.74 g·kg-1), and danazol group (42 mg·kg-1). Untargeted metabolomics detection and pathway enrichment analysis were conducted on serum samples from patients and rats. Spearman correlation analysis was performed to assess the relationship between differential metabolites and ferroptosis indicators. The correlations between differential metabolites in patient endometrium and serum and key ferroptosis indicators (GPX4, Fe2+, MDA, GSH) as well as ferroptosis-related mRNAs (GPX4, SLC7A11, FTH1) were analyzed, and correlation heatmaps were generated accordingly. ResultsCompared with normal eutopic endometrium, ectopic lesions in EMs patients showed glandular disorganization and stromal fibrosis. In ectopic endometrium, the contents of MDA, ROS, and Fe2+ decreased, while GPX4 level increased, and the mRNA expression of SLC7A11 and GPX4 was upregulated (P<0.05, P<0.01). In serum, the levels of GPX4 and Fe2+ were elevated, whereas the GSH level declined, suggesting abnormalities in ferroptosis-related pathways in ectopic lesions (P<0.05, P<0.01). After intervention with Luoshi Neiyi prescription-containing serum, the intracellular ROS level in ectopic endometrial stromal cells was elevated, the mRNA expression of SLC7A11 and GPX4 was downregulated, and TFR mRNA expression was upregulated (P<0.05, P<0.01). Metabolomics analysis revealed 1104 and 198 differential metabolites in EMs patients and EMs rats, respectively, compared with their corresponding control groups, and both low-dose and high-dose Luoshi Neiyi prescription were found to regulate this metabolic disturbance, with the core regulatory pathways mainly involving arginine and proline metabolism. Correlation analysis showed that the glycerophospholipids including PI(16∶0/17∶0) and PI[18∶2(9Z,12Z)] were negatively correlated with GPX4 and positively correlated with MDA, while 17α-hydroxyprogesterone was positively correlated with GPX4, SLC7A11, and FTH1 q<0.05). ConclusionLuoshi Neiyi prescription may systematically ameliorate disease-associated metabolic dysregulation via modulation of the serum arginine and proline metabolism pathway, and may regulate ferroptosis in ectopic lesions through a mechanism potentially linked to the serum glycerophospholipid and steroid metabolism pathways. Collectively, these findings provide experimental evidence for the clinical application of Luoshi Neiyi prescription.
2.Exploring Mechanism of Luoshi Neiyi Prescription in Treating Endometriosis Based on Ferroptosis and Serum Metabolomics
Haixia PAN ; Yingqiao ZHONG ; Ting MAO ; Ziyi DENG ; Meilin WU ; Lei HUANG ; Siyang CHEN ; Yong GUO ; Ying ZHOU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):201-212
ObjectiveThis study aimed to investigate the mechanism by which Luoshi Neiyi prescription treats endometriosis (EMs) through regulating ferroptosis, and to screen key metabolites and analyze their association with ferroptosis. MethodsClinical samples of normal endometrium from patients without EMs and eutopic and ectopic endometrium from EMs patients (10 cases each) were collected and divided into control group, eutopic group, and EMs group. Hematoxylin-eosin (HE) staining was performed to observe ectopic lesions of EMs. Immunohistochemistry was used to detect the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Enzyme-linked immunosorbent assay (ELISA) was adopted to determine the levels of malondialdehyde (MDA), ferrous ion (Fe2+), GPX4 and glutathione (GSH) in endometrial tissues, as well as serum levels of Fe2+, GPX4 and GSH. Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the mRNA expression of SLC7A11, GPX4, transferrin receptor (TFR) and ferritin heavy chain 1 (FTH1). In the in vitro experiment, primary stromal cells were isolated from ectopic lesions of EMs patients. Cell counting kit-8 (CCK-8) was used to determine the optimal concentration of drug-containing serum for intervention. The level of reactive oxygen species (ROS) was measured, and Real-time PCR was applied to detect ferroptosis-related indicators. In the animal experiments, an EM rat model was established, and the rats were randomly assigned to the sham operation group, EMs group, low-dose Luoshi Neiyi Formula group (7.87 g·kg-1), high-dose Luoshi Neiyi prescription group (15.74 g·kg-1), and danazol group (42 mg·kg-1). Untargeted metabolomics detection and pathway enrichment analysis were conducted on serum samples from patients and rats. Spearman correlation analysis was performed to assess the relationship between differential metabolites and ferroptosis indicators. The correlations between differential metabolites in patient endometrium and serum and key ferroptosis indicators (GPX4, Fe2+, MDA, GSH) as well as ferroptosis-related mRNAs (GPX4, SLC7A11, FTH1) were analyzed, and correlation heatmaps were generated accordingly. ResultsCompared with normal eutopic endometrium, ectopic lesions in EMs patients showed glandular disorganization and stromal fibrosis. In ectopic endometrium, the contents of MDA, ROS, and Fe2+ decreased, while GPX4 level increased, and the mRNA expression of SLC7A11 and GPX4 was upregulated (P<0.05, P<0.01). In serum, the levels of GPX4 and Fe2+ were elevated, whereas the GSH level declined, suggesting abnormalities in ferroptosis-related pathways in ectopic lesions (P<0.05, P<0.01). After intervention with Luoshi Neiyi prescription-containing serum, the intracellular ROS level in ectopic endometrial stromal cells was elevated, the mRNA expression of SLC7A11 and GPX4 was downregulated, and TFR mRNA expression was upregulated (P<0.05, P<0.01). Metabolomics analysis revealed 1104 and 198 differential metabolites in EMs patients and EMs rats, respectively, compared with their corresponding control groups, and both low-dose and high-dose Luoshi Neiyi prescription were found to regulate this metabolic disturbance, with the core regulatory pathways mainly involving arginine and proline metabolism. Correlation analysis showed that the glycerophospholipids including PI(16∶0/17∶0) and PI[18∶2(9Z,12Z)] were negatively correlated with GPX4 and positively correlated with MDA, while 17α-hydroxyprogesterone was positively correlated with GPX4, SLC7A11, and FTH1 q<0.05). ConclusionLuoshi Neiyi prescription may systematically ameliorate disease-associated metabolic dysregulation via modulation of the serum arginine and proline metabolism pathway, and may regulate ferroptosis in ectopic lesions through a mechanism potentially linked to the serum glycerophospholipid and steroid metabolism pathways. Collectively, these findings provide experimental evidence for the clinical application of Luoshi Neiyi prescription.
3.Effect of hnRNPA2B1-mediated m6A modification of MIR100HG in promoting the proliferation and invasion of gastric cancer MKN-28 cells
Wenwen LU ; Haixia ZHOU ; Jianbo ZHUANG ; Jiemin WANG ; Jing ZHANG
Journal of Chongqing Medical University 2025;50(8):1078-1083
Objective:To investigate the expression of N6-methyladenosine(m6A)reader heterogeneous nuclear ribonucleoprotein A2/B1(hnRNPA2B1)in human gastric cancer(GC)tissue and its effect on the proliferation and invasion of MKN-28 cells.Methods:The Cancer Genome Atlas and Gene Expression Omnibus were used to analyze the expression of hnRNPA2B1 and long noncoding RNA(ln-cRNA)mir-100-let-7a-2-mir-125b-1 cluster host gene(MIR100HG)in GC tissue and their association with the clinical prognosis of patients with GC.Quantitative PCR and Western blotting were used to measure the effect of hnRNPA2B1 on the expression level of MIR100HG and its downstream Wnt/β-catenin signaling pathway;Methylated RNA immunoprecipitation(MeRIP)was used to mea-sure the m6A level of MIR100HG;CCK-8 assay and Transwell assay were used to observe cell proliferation and invasion.Results:Com-pared with paracancerous tissue,human GC tissue showed significant increases in the expression levels of hnRNPA2B1(t=6.101,P<0.001)and MIR100HG(t=2.191,P=0.036 7),and the high expression levels of hnRNPA2B1 and MIR100HG were associated with poor survival in patients with GC.Knockdown of hnRNPA2B1 reduced the mRNA expression level(t=5.156,P=0.007)and m6A level of MIR100HG(t=4.789,P=0.010),inhibited the proliferation and invasion of MKN-28 cells(t=4.915,P=0.008 and t=5.167,P=0.007),and blocked the activity of the Wnt/β-catenin signaling pathway(P<0.05).Overexpression of MIR100HG promoted cell pro-liferation and invasion(t=3.578,P=0.023 and t=8.411,P=0.001),activated the Wnt/β-catenin signaling pathway(P<0.01),and re-versed the antitumor effect induced by hnRNPA2B1 knockdown(t=3.667,P=0.021).Conclusion:This study shows that hnRNPA2B1-mediated m6A modification of MIR100HG promotes the proliferation and invasion of GC MKN-28 cells by activating the Wnt/β-catenin signaling pathway.
4.Study on the mechanism of electroacupuncture in improving lipid metabolism in PCOS based on metabolomics combined with transcriptomics
Haixia PAN ; Peiyi XIAN ; Xiaoying HE ; Hongxia MA ; Ying ZHOU ; Maohua LAI
Chongqing Medicine 2025;54(8):1761-1770
Objective To explore the mechanism of electroacupuncture in improving lipid metabolism in polycystic ovary syndrome(PCOS)based on metabolomics combined with transcriptomics.Methods Eight-een SD rats were divided into the control group,the PCOS group and the electroacupuncture group,with 6 rats in each group.The PCOS group and the electroacupuncture group used intragastric letrozole to establish the PCOS model.After the model was established,the electroacupuncture group was intervened with electroacu-puncture,while the control group was only given sodium carboxymethyl cellulose by gavage.Observed the changes in body weight and estrous cycle of the three groups,detected the sex hormones,blood lipids,liver function,ovarian morphology,plasma metabolism and liver function indicators of the three groups.Metabolo-mics was used to analyze the differences in metabolites in plasma,the differences in gene expression in the liv-er were detected by RT-qPCR.Results Weight gain and estrous cycle disorder occurred in the PCOS group,and the ovarian morphology showed a thinning of the granulosa cell layer,with a significant reduction in the number of corpus luteum and mature follicles.Meanwhile,sex hormones were abnormal(total testosterone and androgen levels were increased,estradiol and progesterone levels were decreased),dyslipidemia occurred(TC,TG,LDL-C were increased,HDL-C level was decreased),and liver function was abnormal(AST,total protein,ALB,TBIL were increased).The electroacupuncture group significantly reduced weight.It improved the estrous cycle,and the granulosa cell layer of the ovary thickened,with a significant increasing in the num-ber of corpus luteum and mature follicles.Meanwhile,sex hormone levels were improved(androgen and total testosterone levels were decreased,estradiol level was increased),lipid balance(TC,TG,LDL-C levels were reduced,HDL-C level was increased)and liver function(AST,total protein,ALB,and TBIL levels were de-creased)was restored.Transcriptomics suggested that electroacupuncture down-regulated the expression of cytochrome P450(CYPs)family genes related to steroid hormones and lipid metabolism,and the results were confirmed by RT-qPCR.Combined omics analysis revealed that electroacupuncture might mainly exert its effect on improving lipid metabolism disorders in PCOS rats through the linoleic acid metabolic pathway.Con-clusion Electroacupuncture can regulate lipid metabolism in rats with PCOS.
5.Application of optical surface monitoring system in intensity-modulated radiotherapy for thoracic tumors
Haixia YANG ; Menglu SUN ; Xiaosha ZHOU ; Yaxuan HAN ; Baolong REN ; Jianying LI ; Yi LI
The Journal of Practical Medicine 2025;41(9):1345-1351
Objective To evaluate the effect of optical body surface monitoring system(OSMS)in setup of intensity modulated radiotherapy(IMRT)for thoracic tumorsand to analyze its relationship with BMI.Methods Thesetup errors of CBCT and location CT with body membrane and the registration errors of OSMS and first body surface reference image without body membrane were obtained in 49 patients with thoracic tumor who received routine intensity modulated radiotherapy.The paired t-test was used to analyze the difference of registration errors between the two image guidance methods.Pearson′s correlation analysis was used to analyze the correlation between CBCT errors and OSMS errors,and Bland-Altman analysis was employed to evaluatethe agreement of the two errors.The correlation and consistency of the two registration errors in patients with different BMI index were analyzed.PTV external marginsby the two registration methods were calculated using Van Herk formula.Results The OSMS and CBCT groups demonstrated significant differences in setup errors in the ventrodorsal direction(P<0.05),while no significant differences were found in the left-right,head-foot translation directions,or RTN rota-tion directions(P>0.05).Although the two methods showed a significant correlation in setup errors(P<0.05),this correlation was only moderate in the head-foot and left-right directions(r=0.500,0.408),weak in the RTN rotation direction(r=0.339),and very weak in the ventrodorsal direction(r=0.152).The limits of agreement(LOA,95%CI)between the two methods were[-0.45,0.45]cm in the left-right direction,[-0.59,0.57]cm in the head-foot direction,and[-0.48,0.40]cm in the ventrodorsal direction,with(-2.08°~2.19°)in the RTN rotation direction.Different BMI levels influenced the results of the two registration methods,particularly in patients with a BMI of 18.5~23.9 kg/m2.In this group,OSMS and CBCT exhibited a strong correlation in the head-foot direction(r=0.731),a moderate correlation in the left-right direction(r=0.512),and weak correlations in the ventrodorsal and RTN rotation directions(r=0.345,0.267).The absolute difference in setup errors between the two imaging systems was 0.4~0.5 cm/2°.Using CBCT and OSMS image guidance,the margins in the left-right,head-foot,and ventrodorsal directions were[0.5 cm,0.7 cm,0.3 cm]for CBCT,and[0.5 cm,0.7 cm,0.5 cm]for OSMS.Conclusion In chest tumor patients with a BMI of 18.5~23.9 kg/m2,OSMS and CBCT image guidance methods show good correlation in the head-foot and left-right directions,but their limits of agreement exceed the clinically acceptable range.OSMS cannot yet replace CBCT for image guidance in chest tumor intensity-modulated radiotherapy.Further improvements to tumor motion surrogates are necessary to enhance the accuracy of OSMS image guidance.
6.The Initial Evaluation of the Safety and Impact on Cardiac Electrical Synchronization Post Low Ventricular Septum Implantation of Leadless Pacemaker
Jifang MA ; You ZHOU ; Yonghui ZHAO ; Haitao YANG ; Xiaobiao ZANG ; Juan HU ; Weifeng SONG ; Xianqing WANG ; Haixia FU
Chinese Circulation Journal 2025;40(1):69-75
Objective:This study aims to investigate the feasibility and safety of implanting leadless pacemakers in the low septum and its impact on cardiac electrical synchronization.Methods:A total of 36 patients who received leadless pacemaker implantation at Fuwai Central China Cardiovascular Hospital from January 2021 to August 2023 were included in this study.According to implantation sites of leadless pacemakers,patients were divided into mid-septal group(n=16)and low-septal group(n=20).The clinical characteristics and cardiac electrical synchronization were compared between the two groups.Results:There were 21 male patients,mean age was(68±13)years old.There was no statistical difference in the type of brady-arrhythmia between the two groups(P=0.73).There were 61 implant attempts in these 36 patients,and there was no significant difference in the number of attempts,procedure time,and pacemaker parameters between the two groups,but the average procedure time tended to be shorter in the low-septal group([84±37]minutes vs.[105±35]minutes,P=0.09).In terms of electrical synchronization,there was no statistical difference in QRS duration between the low-septal group and the mid-septal group([162.0±21.1]ms vs.[174.0±14.8]ms,P=0.20).There were no vascular puncture complications,cardiac perforation,or pericardial tamponade during the procedure.There were no complications and readmissions related to the leadless pacemaker during follow-up period.Conclusions:Our results show that the implantation of a leadless pacemaker in the low ventricular septum is safe and effective,has a similar impact on cardiac electrical synchronization as mid-septal pacing.
7.Application of optical surface monitoring system in intensity-modulated radiotherapy for thoracic tumors
Haixia YANG ; Menglu SUN ; Xiaosha ZHOU ; Yaxuan HAN ; Baolong REN ; Jianying LI ; Yi LI
The Journal of Practical Medicine 2025;41(9):1345-1351
Objective To evaluate the effect of optical body surface monitoring system(OSMS)in setup of intensity modulated radiotherapy(IMRT)for thoracic tumorsand to analyze its relationship with BMI.Methods Thesetup errors of CBCT and location CT with body membrane and the registration errors of OSMS and first body surface reference image without body membrane were obtained in 49 patients with thoracic tumor who received routine intensity modulated radiotherapy.The paired t-test was used to analyze the difference of registration errors between the two image guidance methods.Pearson′s correlation analysis was used to analyze the correlation between CBCT errors and OSMS errors,and Bland-Altman analysis was employed to evaluatethe agreement of the two errors.The correlation and consistency of the two registration errors in patients with different BMI index were analyzed.PTV external marginsby the two registration methods were calculated using Van Herk formula.Results The OSMS and CBCT groups demonstrated significant differences in setup errors in the ventrodorsal direction(P<0.05),while no significant differences were found in the left-right,head-foot translation directions,or RTN rota-tion directions(P>0.05).Although the two methods showed a significant correlation in setup errors(P<0.05),this correlation was only moderate in the head-foot and left-right directions(r=0.500,0.408),weak in the RTN rotation direction(r=0.339),and very weak in the ventrodorsal direction(r=0.152).The limits of agreement(LOA,95%CI)between the two methods were[-0.45,0.45]cm in the left-right direction,[-0.59,0.57]cm in the head-foot direction,and[-0.48,0.40]cm in the ventrodorsal direction,with(-2.08°~2.19°)in the RTN rotation direction.Different BMI levels influenced the results of the two registration methods,particularly in patients with a BMI of 18.5~23.9 kg/m2.In this group,OSMS and CBCT exhibited a strong correlation in the head-foot direction(r=0.731),a moderate correlation in the left-right direction(r=0.512),and weak correlations in the ventrodorsal and RTN rotation directions(r=0.345,0.267).The absolute difference in setup errors between the two imaging systems was 0.4~0.5 cm/2°.Using CBCT and OSMS image guidance,the margins in the left-right,head-foot,and ventrodorsal directions were[0.5 cm,0.7 cm,0.3 cm]for CBCT,and[0.5 cm,0.7 cm,0.5 cm]for OSMS.Conclusion In chest tumor patients with a BMI of 18.5~23.9 kg/m2,OSMS and CBCT image guidance methods show good correlation in the head-foot and left-right directions,but their limits of agreement exceed the clinically acceptable range.OSMS cannot yet replace CBCT for image guidance in chest tumor intensity-modulated radiotherapy.Further improvements to tumor motion surrogates are necessary to enhance the accuracy of OSMS image guidance.
8.The efficacy of ganciclovir combined with spleen aminopeptide in treating infectious mononucleosis and its impact on the immune function of diseased children
Youjia SUN ; Guijuan ZHOU ; Yuee JIA ; Haixia LI ; Xue FANG
Immunological Journal 2025;41(5):356-361
Objective To investigate the efficacy of ganciclovir combined with spleen aminopeptide in treating infectious mononucleosis(IM)and its impact on the immune function of diseased children.Methods Totally 120 diseased children with IM accepted by our hospital from February 2022 to August 2024 were stochastically assigned into a treatment group and a monotherapy group.The monotherapy group received treatment with ganciclovir,while the treatment group received treatment with spleen aminopeptide in addition to the monotherapy group.The efficacy,symptom improvement time,serum inflammatory factors,immune indicators,and biochemical indicators before and after treatment were compared between the two groups.Results The efficacy of the treatment group was better than that of the monotherapy group,and the symptom relief time was shorter than that of the monotherapy group(P<0.05).After treatment,the serum amyloid A,TNF-α,IL-6,procalcitonin,CD3+T,CD8+T,lactate dehydrogenase,alanine aminotransferase,EBV-DNA,creatine kinase,and white blood cell count in both groups decreased,while CD4+T and CD4+T/CD8+T increased.The amplitude of the treatment group was greater than that of the monotherapy group(P<0.05).Conclusion The combination of ganciclovir and spleen aminopeptide in treating IM is beneficial for enhancing the immune function of T lymphocytes of diseased children,alleviating inflammatory reactions,improving biochemical indicators,and enhancing efficacy.
9.Consensus of experts on the management of thoracic anesthesia with spontaneous respiration
Qisen FAN ; Lan LAN ; Jingxiang WU ; Yuan QIU ; Guiping XU ; Jiang WANG ; Duozhi WU ; Jinhui LUO ; Jian RAN ; Ying-fen LI ; Peng PAN ; Bing ZHANG ; Yuelan ZHOU ; Yiwen ZHANG ; Xuebing XU ; Yatao LIU ; Yingbin WANG ; Yan WANG ; Yulong WANG ; Youyang HU ; Shoushi WANG ; Hongwei MENG ; Haixia XU ; Peijia TANG ; Xia-oxue ZHUANG ; Canzhou ZHANG
The Journal of Practical Medicine 2025;41(13):1945-1951
Thoracic anesthesia with spontaneous respiration represents a form of precision anesthesia meticulously customized to individual patients.Considering the more stringent requirements this anesthesia approach imposes on the regulation of respiratory function,the writing group of the"Consensus of Experts on the Management of Thoracic Anesthesia with Spontaneous Respiration"has formulated elaborate guidelines regarding indications and contraindications,preoperative evaluation,anesthesia implementation,common complications,and treatment strategies.This was accomplished by referencing relevant domestic and international literature and integrating it with actual clinical requirements.The objective is to standardize the rational application of this anesthesia method.
10.Summary of the best evidence for intense pulsed light therapy in dry eye
Haixia SHI ; Chang ZHOU ; Xiu YAO ; Mei YANG ; Furong LI
Chinese Journal of Modern Nursing 2025;31(30):4093-4100
Objective:To summarize the best evidence for intense pulsed light therapy in dry eye.Methods:Literature on intense pulsed light therapy for dry eye was electronically retrieved from databases and websites, including the National Guideline Clearinghouse, Guidelines International Network, British Medical Journal (BMJ) Best Practice, UpToDate, Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and China Biology Medicine disc. The search period was from database establishment to December 3, 2024. Two researchers independently conducted quality evaluation of the literature, and extracted and summarized the evidence.Results:A total of 22 articles were ultimately included, including four guidelines, seven expert consensus, and eleven systematic reviews. Twenty-seven piecesof evidence were summarized from six aspects of the mechanism of action, clinical indications, treatment protocols, operation and maintenance, therapeutic efficacy evaluation, adverse reactions, and precautions.Conclusions:The best evidence for intense pulsed light therapy in dry eye is evidence-based and scientific. Healthcare providers are advised to apply this evidence in conjunction with clinical context and patient preferences.

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