1.Research progress on neuropsychiatric comorbidities in childhood absence epilepsy
Journal of Clinical Neurology 2025;38(4):311-317
Childhood absence epilepsy(CAE)is a common pediatric epilepsy syndrome traditionally considered benign.However,an increasing body of research indicates that children with CAE often present with comorbid neuropsychiatric disorders such as attention deficit hyperactivity disorder,mood disorders,and cognitive dysfunction.These comorbidities not only impair the children's academic performance and social adaptability but also negatively affect their psychological well-being and quality of life.However,the symptoms of these comorbidities are often subtle,and there is a lack of standardized assessment criteria and treatment strategies,making their diagnosis and long-term management a persistent challenge in clinical practice.This review aims to summarize the latest research progress on the comorbidities of CAE,focusing on the types and clinical characteristics of these comorbidities,influencing factors,diagnostic approaches,and treatment strategies,to enhance understanding of CAE comorbidities and provide reference for future research and clinical management.
2.Analysis of Therapeutic Effect of Pelvic Floor Myofascial Trigger Point Release Combined with Biostimulatory Feedback in the Treatment of Female Dyspareu-nia after Vaginal Delivery
Wenjun FAN ; Zhidan LIU ; Yinjie ZHU
Journal of Practical Obstetrics and Gynecology 2025;41(3):237-241
Objective:To evaluate the clinical effect of pelvic floor trigger point release combined with biostimu-lation feedback on dyspareunia in women after vaginal delivery.Methods:A total of 122 patients diagnosed with postpartum dyspareunia were selected from the postpartum rehabilitation department,gynecology department and rehabilitation department of Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine from March 2022 to September 2023,and were randomly divided into the control group(61 cases)and the study group(61 cases)according to the lottery method.The control group received biostimulatory feedback treatment,and the study group received pelvic floor trigger point release combined with biostimulatory feedback treatment.The number of pain points and the total score of visual analog scale(VAS),female sexual function assessment scale(FSFI)and Glazer pelvic floor surface electromyography were compared between the two groups before and after treatment to evaluate the efficacy of pelvic floor trigger point release combined with biostimulatory feed-back.Results:After treatment,the study group showed significantly fewer pain points(3.36±2.01 points vs.8.79±3.12 points),lower VAS scores(4.31±2.93 points vs.10.07±4.24 points),and reduced Glazer electromyogra-phy values during both pre-resting(3.01±0.78 μV vs.6.16±1.09 μV,P<0.05)and post-resting stages(3.56±0.81 μV vs.6.53±1.13 μV,P<0.05)compared to the control group.Additionally,the study group demonstrated significantly higher FSFI scores and total scores(P<0.05).Conclusions:Pelvic floor trigger point release com-bined with biostimulation feedback therapy can relieve the pain of sexual intercourse and improve the sexual dys-function of women after vaginal delivery.
3.Analysis of Therapeutic Effect of Pelvic Floor Myofascial Trigger Point Release Combined with Biostimulatory Feedback in the Treatment of Female Dyspareu-nia after Vaginal Delivery
Wenjun FAN ; Zhidan LIU ; Yinjie ZHU
Journal of Practical Obstetrics and Gynecology 2025;41(3):237-241
Objective:To evaluate the clinical effect of pelvic floor trigger point release combined with biostimu-lation feedback on dyspareunia in women after vaginal delivery.Methods:A total of 122 patients diagnosed with postpartum dyspareunia were selected from the postpartum rehabilitation department,gynecology department and rehabilitation department of Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine from March 2022 to September 2023,and were randomly divided into the control group(61 cases)and the study group(61 cases)according to the lottery method.The control group received biostimulatory feedback treatment,and the study group received pelvic floor trigger point release combined with biostimulatory feedback treatment.The number of pain points and the total score of visual analog scale(VAS),female sexual function assessment scale(FSFI)and Glazer pelvic floor surface electromyography were compared between the two groups before and after treatment to evaluate the efficacy of pelvic floor trigger point release combined with biostimulatory feed-back.Results:After treatment,the study group showed significantly fewer pain points(3.36±2.01 points vs.8.79±3.12 points),lower VAS scores(4.31±2.93 points vs.10.07±4.24 points),and reduced Glazer electromyogra-phy values during both pre-resting(3.01±0.78 μV vs.6.16±1.09 μV,P<0.05)and post-resting stages(3.56±0.81 μV vs.6.53±1.13 μV,P<0.05)compared to the control group.Additionally,the study group demonstrated significantly higher FSFI scores and total scores(P<0.05).Conclusions:Pelvic floor trigger point release com-bined with biostimulation feedback therapy can relieve the pain of sexual intercourse and improve the sexual dys-function of women after vaginal delivery.
4.Research progress on neuropsychiatric comorbidities in childhood absence epilepsy
Journal of Clinical Neurology 2025;38(4):311-317
Childhood absence epilepsy(CAE)is a common pediatric epilepsy syndrome traditionally considered benign.However,an increasing body of research indicates that children with CAE often present with comorbid neuropsychiatric disorders such as attention deficit hyperactivity disorder,mood disorders,and cognitive dysfunction.These comorbidities not only impair the children's academic performance and social adaptability but also negatively affect their psychological well-being and quality of life.However,the symptoms of these comorbidities are often subtle,and there is a lack of standardized assessment criteria and treatment strategies,making their diagnosis and long-term management a persistent challenge in clinical practice.This review aims to summarize the latest research progress on the comorbidities of CAE,focusing on the types and clinical characteristics of these comorbidities,influencing factors,diagnostic approaches,and treatment strategies,to enhance understanding of CAE comorbidities and provide reference for future research and clinical management.
5.Effect of high-dose vitamin B6 on stress-induced liver cell death in rats with severe trauma and the possible mechanism
Yinjie ZHANG ; Zhihuai WANG ; Xuelin TANG ; Haiyang ZHOU ; Peng GAO ; Chunfu ZHU ; Zhongzhi JIA ; Maoxing YUE ; Xihu QIN
Chinese Journal of Trauma 2024;40(6):558-568
Objective:To investigate the effect of high-dose vitamin B6 on stress-induced liver cell death in rats with severe trauma and its possible mechanism.Methods:Thirty-two male SD rats were selected and divided into sham surgery group, sham surgery+B6 group, trauma group, and trauma+B6 group by using a random number table, with 8 rats in each group. Rat models of severe trauma were established by inducing abdominal wall injury, bilateral femoral fractures, unilateral cranial injury, and withdrawal of 4 ml blood from the femoral artery. The sham surgery+B6 group and trauma+B6 group were treated with saline solution plus high-dose vitamin B6, while the sham surgery group and trauma group with infusion of saline solution only. At 36 hours after injury, rat liver tissues were collected for the following experiments: (1) the genes differentially expressed in the liver tissues of the rats of the trauma group and the trauma+B6 group were screened with next-generation sequencing, followed by an analysis of the possible involvement of cell death pathways; (2) validation was conducted to ascertain whether high-dose vitamin B6 could influence various cell death pathways in the liver cells in the sham surgery group, sham surgery+B6 group, trauma group, and trauma+B6 group: apoptosis was confirmed through terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining; necroptosis was verified by mixed lineage kinase domain-like protein (MLKL) immunohistochemical staining; autophagy was examined via transmission electron microscopy; ferroptosis was confirmed by detecting oxidative malondialdehyde (MDA) levels, oxidized glutathione levels, Prussian blue staining with diaminobenzidine (DAB) enhancement, transmission electron microscopy, and immunohistochemical staining for acyl-CoA synthetase long-chain family member 4 (ACSL4); (3) Biological information analyses [Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Enrichment analysis (GSEA)] were performed for biological processes and signaling pathways represented by liver tissue sequencing results of rats between the trauma group and the trauma+B6 group.Results:(1) In the liver tissues of rats, there were 344 significantly differentially expressed genes between the trauma group and trauma+B6 group, comprising 137 upregulated genes and 207 downregulated genes, of which 18 genes were associated with apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. (2) No significant differences were found in TUNEL staining among the sham surgery group, sham surgery+B6 group, trauma group or trauma+B6 group; MLKL protein expression levels in the liver tissues after trauma were improved, of which the trauma+B6 group was lower than that of the trauma group; Electron microscopy showed that autophagic activity in the liver cells were significantly increased after trauma, which was significantly lower of the trauma+B6 group than that of the trauma group; MDA levels in the rat liver tissues were (0.20±0.05)nmol/mg, (0.17±0.07)nmol/mg, (0.69±0.11)nmol/mg and (0.52±0.07)nmol/mg in the sham surgery group, sham surgery+B6 group, trauma group, and trauma+B6 group respectively ( P<0.01), with the trauma group having the highest MDA levels and trauma+B6 group having lower MDA levels than the trauma group; Oxidized glutathione levels in the liver tissues of the four groups were (11.75±2.09)μmol/g, (11.69±1.66)μmol/g, (19.75±3.40)μmol/g, and (14.51±1.46)μmol/g respectively ( P<0.01), with the trauma group having the highest levels and trauma+B6 group having lower levels than the trauma group; Significantly increased iron deposition was observed in the liver tissues after trauma, with lower iron deposition in trauma+B6 group than the trauma group; Electron microscopy revealed significantly lower mitochondrial membrane density in the trauma+B6 group compared to the trauma group. ACSL4 protein expression level was lower in the trauma+B6 group compared to the trauma group; (3) GO, KEGG and GSEA enrichment analyses suggested that high-dose vitamin B6 may enhance cholesterol synthesis metabolism in the liver cells and alleviate oxidative stress to reduce liver cell damage and restore normal liver cell function after trauma. Conclusions:High-dose vitamin B6 attenuates stress-induced liver injury in rats with severe trauma by inhibiting the progression of necroptosis, autophagy and ferroptosis. Its molecular mechanism may be associated with enhanced hepatic cholesterol synthesis metabolism and alleviation of oxidative stress in the liver cells.
6.Research on neural network in childhood absence epilepsy based on multi-frequency magnetoencephalography
Yingfan WANG ; Mingyang DU ; Minghao LI ; Jing LU ; Yinjie ZHU ; Xiaoshan WANG
Chinese Journal of Neurology 2024;57(10):1101-1110
Objective:To investigate alterations in functional connectivity network and brain function activity in childhood absence epilepsy (CAE) based on neuromagnetic signals by using multi-frequency magnetoencephalography.Methods:Twenty-five drug-naive children diagnosed with CAE from the Affiliated Brain Hospital of Nanjing Medical University and the Affiliated Children′s Hospital of Nanjing Medical University during October 2022 and March 2024 and 25 healthy controls matched for age and sex from community were recruited in this cross-sectional study. The interictal data, ictal data of CAE and healthy control children were collected using a CTF-275 channel magnetoencephalography system. Corrected amplitude envelope correlation was used to construct functional connectivity network, and network-based statistics were used to compare network differences between groups. Relative power spectral density was used to describe the distribution characteristics of whole-brain spectral power. Nonparametric permutation tests were conducted 1 000 times to compare spectral power differences between groups.Results:In terms of functional connectivity, significant increases in network activity were observed in the low-frequency bands (δ, θ) during interictal periods in children with CAE. A sub-network with significantly increased functional connectivity, including key nodes of the default mode network, was observed in the δ band. Compared with interictal periods, functional connectivity in the δ band decreased during absence seizures in children with CAE, while connectivity in the mid-to-high-frequency bands (α-γ2) increased. In terms of spectral power, children with CAE during interictal periods exhibited widespread magnetic source activation in the δ band, activation in parts of the parietal and occipital lobes in the θ band, and significantly decreased magnetic source intensity in most areas of the parietal, occipital, and temporal lobes in the α-γ2 band. Compared with interictal periods, children with CAE during absence seizures exhibited widespread magnetic source activation in the δ band, and significantly decreased activation in the θ-γ2 band. According to the magnetic source distribution map, during absence seizures, the frontal lobe replaced the parieto-occipital region in cortical activation in the α band.Conclusion:In the analysis of functional network and spectral power based on multi-frequency neuromagnetic signals, the network pattern and magnetic source activation of children with CAE during interictal periods were significantly different from those of healthy children, and there were characteristic changes in neuromagnetic signals during consciousness impairment caused by absence seizures in children with CAE.
7.Analysis of clinical characteristic of children with progressive familial intrahepatic cholestasis type 3
Lili CAO ; Jianguo YAN ; Danni FENG ; Yi DONG ; Zhiqiang XU ; Fuchuan WANG ; Yinjie GAO ; Shishu ZHU ; Min ZHANG
Chinese Journal of Pediatrics 2024;62(5):462-466
Objective:To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3).Methods:This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity.Results:Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment.Conclusions:Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.
8.Exploring Central Regulatory Effect of Chaishao Liujuntang on Chronic Atrophic Gastritis Rats with Liver Depression and Spleen Deficiency Syndrome Based on Metabolomics
Yinjie HONG ; Wenling TU ; Jingru ZHU ; Wenqian LUO ; Kaiyue HUANG ; Huijuan GAN
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(2):148-155
ObjectiveBased on ultra performance liquid chromatography-mass spectrometry(UPLC-MS) and non-targeted metabolomics technology to discuss the central regulatory effect of Chaishao Liujuntang on chronic atrophic gastritis(CAG) rats with liver-depression and spleen-deficiency, and to look for the correlation between cerebral cortex, hypothalamus and metabolic status of gastric tissues. MethodA CAG rat model with liver-depression and spleen-deficiency was established by chemical induction, hunger and satiety disorders, chronic restraint and tail clamping stimulation, lasting for 16 weeks. Twenty-eight Wistar rats were randomly divided into a blank group of 8 rats and a model group of 20 rats. After the completion of modeling, 4 rats in the model group were taken to observe the pathological changes of gastric mucosa. The remaining model rats were randomly divided into a model group of 8 rats and a Chaishao Liujuntang group of 8 rats. Chaishao Liujuntang group rats were given 5.1 g·kg-1 by gavage, and the remaining rats were given equal volume sterilized water by gavage for 4 weeks. Macroscopic characteristics, behavioral indicators and histopathological changes of the gastric mucosa of rats in each group were observed and compared. UPLC-MS non-targeted metabolomics was used to explore the metabolic regulation effect of Chaishao Liujuntang on the cerebral cortex, hypothalamus and stomach tissues of CAG rats with liver-depression and spleen-deficiency. Pearson correlation coefficient method was used to analyze the correlation between different tissue metabolites. ResultCompared with the model group, the macroscopic characteristics of rats in Chaishao Liujuntang group were improved, such as hair color, mental state and stool properties, and the number of times of crossing and standing in the open field experiment was significantly increased, and the static time of forced swimming was significantly reduced(P<0.01), and the gastric mucosa atrophy was reduced. The metabolic data from the cerebral cortex of rats in each group identified a total of 3 common potential biomarkers, but not enriched in pathways, 26 common potential biomarkers were identified in the hypothalamus, and the key metabolic pathways involved were mainly enriched in purine metabolism, glycerol phospholipid metabolism, D-glutamine and D-glutamic acid metabolism. Seventeen common potential biomarkers were identified in the stomach, and the key metabolic pathways involved were mainly enriched in thiamine metabolism, valine, leucine and isoleucine biosynthesis, and taurine and taurine metabolism. Correlation analysis of metabolites in different tissues revealed that multiple amino acids and their derivatives mediated metabolic connections between the cerebral cortex, hypothalamus and stomach of rats. ConclusionThe metabolic disorders in the cerebral cortex, hypothalamus and stomach of CAG rats with liver-depression and spleen-deficiency have their own characteristics, mainly manifested by changes in the content of glycerol phospholipids, fatty acids and bile acid metabolites. Moreover, Chaishao Liujuntang may play a central regulatory role in CAG rats with liver-depression and spleen-deficiency by correcting the metabolic disorders of amino acids.
9.The efficacy and safety comparison of radium-223 in the treatment of mCRPC patients with and without homologous recombination repair gene mutation
Binbin XIA ; Xinxing DU ; Liancheng FAN ; Chenfei CHI ; Yinjie ZHU ; Jiahua PAN ; Baijun DONG ; Wei XUE
Chinese Journal of Urology 2023;44(5):330-336
Objective:To compare the efficacy and safety of radium-223 in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients with and without homologous recombination repair (HRR) gene mutation.Methods:The clinical data of 27 patients with mCRPC bone metastases who received radium-223 therapy from April 2021 to November 2022 in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were retrospectively analyzed. Among the 27 mCRPC patients, 18 patients carrying HRR gene mutations belonged to the HRD(+ ) group, and 9 patients without HRR gene mutation belonged to the HRD(-) group. The age of patients in HRD(+ ) group was 69.5 (63.8, 77.0) years old, alkaline phosphatase (ALP) was 243.0 (82.8, 301.3) U/L, prostate specific antigen (PSA) was 71.6 (7.3, 329.8) ng/ml, pain score was 3.0 (1.0, 5.0) points. Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1 points in 7 cases, and 2 points in 11 cases. In the HRD(-) group, the median age was 72.0 (64.5, 76.5) years old, ALP was 88.0 (67.5, 260.6) U/L, PSA was 19.1 (1.1, 117.8) ng/ml, and pain score was 2.0 (0, 4.5) points. The ECOG score ranged from 0 to 1 in 4 cases, and 2 in 5 cases in the HRD(-) group. There was no significant difference in the above general data between the two groups ( P>0.05). All patients received radium-223 treatment every 4 weeks, no more than 6 times. The changes of ALP, PSA, pain score and hematological adverse reactions were compared between the two groups. Results:In the HRD(+ ) group, the median number of radium-223 treatment was 4.5 (3.0, 5.3) couses, 4 patients (22.2%) completed 6 courses, and 6 patients died of prostate cancer during follow-up. In the HRD(-) group, the median number of radium treatment was 4.0 (2.5, 6.0) couses, 3 patients (33.3%) completed 6 courses, and 1 patient died of prostate cancer during follow-up. There was no significant difference in the number of radium treatment courses between the two groups ( P=0.320). ALP in HRD(+ ) group was 101.8 (61.3, 147.0) U/L after radium-223 treatment, which was significantly lower than that before treatment ( P=0.002). ALP in HRD(-) group was 73.0 (64.0, 113.5) U/L after radium-223 treatment, and it was not significantly different from that before treatment ( P=0.327). The rate of ALP response (ALP decrease >10%) in HRD(+ ) group was significantly higher than that in HRD(-) group [83.3% (15/18) vs. 44.4% (4/9), P=0.037]. PSA was 105.9(5.2, 798.4) ng/ml in HRD (+ ) group after radium-223 treatment, and was 25.6(0.8, 1 031.0) ng/ml in HRD(-) group, and they were not significantly different from that before treatment ( P=0.145, P=0.386). There were no significant differences in the rate of PSA response (PSA decrease>10%) between HRD(+ ) group and HRD(-) group [38.9% (7/18) vs. 22.2% (2/9), P=0.386]. The median pain score of HRD(+ ) group was 3.0 (0, 4.0) points after treatment, which was significantly lower than that before treatment ( P=0.028). The pain score of HRD(-) group was 1.0(0, 3.0) points after treatment, and it was not significantly different from that before treatment ( P=0.129). There was no significant difference in pain relief rate between HRD(+ ) group and HRD(-) group [66.7% (12/18) vs. 44.4% (4/9), P=0.411]. The incidence of at least one hematological adverse event during radium-223 treatment in the HRD(+ ) group was higher than that in the HRD(-) group [77.8% (14/18) vs. 33.3% (3/9), P=0.039]. There was no significant difference in the incidence of grade 1-2 hematological adverse events between the two groups [72.2%(13/18) vs. 33.3%(3/9), P=0.097]. Only 1 patient in the HRD(+ ) group experienced grade 3 anemia during treatment which was recovered after blood transfusion. Conclusions:Compared to mCRPC patients without HRR gene mutation, patients with HRR gene mutations had better ALP response and bone pain relief after radium-223 treatment. The overall incidence of adverse events in the HRD(+ ) group is higher than that in HRD(-) group, and there was no significant difference in grade 1-2 hematological adverse events between the two goups. It is necessary to expand the sample size to further verify the conclusion.
10.Early Plasma Circulating Tumor DNA as a Potential Biomarker of Disease Recurrence in Non-metastatic Prostate Cancer
Xiaochen FEI ; Xinxing DU ; Yiming GONG ; Jiazhou LIU ; Liancheng FAN ; Jiayi WANG ; Yanqing WANG ; Yinjie ZHU ; Jiahua PAN ; Baijun DONG ; Wei XUE
Cancer Research and Treatment 2023;55(3):969-977
Purpose:
In non-metastatic prostate cancer (nmPCa) setting, it is important to early identify the patients at risk of biochemical recurrence (BCR) for immediate postoperative intervention. Our study aimed to evaluate the potential clinical utility of circulating tumor DNA (ctDNA) for predicting disease recurrence.
Materials and Methods:
This real-world observational study evaluated 161 cases of nmPCa undergoing next-generation sequencing at our institution. A total of 139 ctDNA samples and 31 biopsied tumor tissue underwent genomic profiling. The study endpoint was BCR after radical prostatectomy. Relationships between the ctDNA status and the biochemical progression-free survival (bPFS) were analyzed by log-rank test and multivariate Cox regression.
Results:
Of 161 enrolled patients, 19 (11.8%) harbored deleterious alterations in NCOR2, followed by BRCA2 (3.7%), ATR (2.5%), and CDK12 (2.5%). Of available pre-operative blood samples (n=139), ctDNA was detectable in 91 (65.5%). Until last follow-up, 56 of 68 patients (85.3%) with detectable ctDNA had achieved BCR, whereas only eight of 39 patients (20.5%) with undetectable ctDNA had achieved BCR. Patients who had undetectable ctDNA experienced significantly longer bPFS compared with those who had detectable ctDNA (not available vs. 8.2 months; hazard ratio, 0.14; p < 0.01). Pre-operative ctDNA status was a significant prognostic factor of disease recurrence.
Conclusion
Pre-operative ctDNA detection could identify patients at high risk of recurrence and has the potential to inform immediate postoperative interventions, but these approaches remain to be validated in prospective studies. ctDNA studies can provide insights into accurate monitoring and precise treatment rather than simply following routine clinical care.

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