1.Research progress on the correlation of dry eye with depression
Feng JIN ; Baoyue MI ; Jingqing MU ; Jingjing CAO ; Xia HUA
International Eye Science 2026;26(1):74-79
Dry eye disease is a chronic ocular surface disorder of multifactorial origin, characterized by a loss of tear film homeostasis and associated with a range of ocular discomfort symptoms. Growing evidence underscores a significant bidirectional relationship between dry eye and depression: individuals with dry eye disease exhibit a higher prevalence of depressive disorders, and conversely, those diagnosed with depression demonstrate an increased susceptibility to developing dry eye. This interplay is mediated through several pathophysiological pathways, such as chronic inflammation, cerebral functional alterations, gut microbiome dysregulation, and sleep disturbances, which may collectively sustain a vicious cycle. The use of antidepressant therapy introduces further complexity, exerting heterogeneous effects on dry eye—some agents may offer symptomatic relief, whereas others can aggravate ocular surface impairment. The mechanisms responsible for these differential outcomes remain incompletely elucidated and merit further investigation. This review systematically consolidates epidemiological data on the dry eye-depression link, examines potential shared pathological mechanisms, and evaluates current therapeutic options. We propose an integrated management approach that combines conventional dry eye treatments, such as traditional Chinese medicine, electroacupuncture, physical activity and antidepressants—a multimodal strategy that may yield synergistic benefits in alleviating both ocular and affective symptoms, thereby improving overall quality of life. Moving forward, research should focus on deciphering the underlying mechanistic pathways and facilitating the translation of these insights into clinical practice to inform targeted, combined treatment regimens for patients with dry eye and depression.
2.Comparison of clinical characteristics between primary bilateral macronodular adrenal hyperplasia and adrenal cortisol-producing adenoma
Bing LI ; Ming-Xiu YANG ; Huai-Jin XU ; Jing-Xuan WANG ; Qing-Zheng WU ; Ya-Jing WANG ; Yi-Jun LI ; Kang CHEN ; Yu CHENG ; Qi NI ; Ya-Qi YIN ; Li ZANG ; Qing-Hua GUO ; Jian-Ming BA ; Wei-Jun GU ; Jing-Tao DOU ; Zhao-Hui LYU ; Yi-Ming MU
Medical Journal of Chinese People's Liberation Army 2025;50(7):779-785
Objective To comparatively analyze the clinical characteristics of primary bilateral macronodular adrenal hyperplasia(PBMAH)and adrenal cortisol-producing Adenoma(CPA),and enhance the understanding of two diseases.Methods The clinical data of 85 PBMAH patients(PBMAH group)and 195 CPA patients(CPA group)diagnosed at Department of Endocrinology,the First Medical Center of Chinese PLA General Hospital,from September 2014 to August 2024 were retrospectively analyzed.The demographic characteristics,comorbidities,biochemical indicators,adrenocorticotropic hormone-cortisol(ACTH-F)levels,and adrenal imaging features and treatment conditions were compared between the two groups.Results(1)General characteristics:Compared with CPA group,PBMAH group had older age at diagnosis and a higher proportion of male patients.(2)Clinical characteristics:Compared with CPA group,PBMAH group had a longer disease duration,a higher proportion of subclinical Cushing's syndrome(CS),and a higher proportion of hypertension,impaired glucose tolerance/diabetes,bone mass reduction or osteoporosis,with higher serum potassium levels,and the differences were statistically significant(P<0.01).(3)Hormone levels:Both PBMAH and CPA groups showed ACTH-F rhythm disorder,significantly increased cortisol levels and suppressed ACTH.Compared with PBMAH group,CPA group had stronger autonomous cortisol secretion ability,manifested by increased midnight serum cortisol(F0:00),16:00 serum cortisol(F16:00),24-hour urinary free cortisol(24 h UFC)levels and lower 8:00 serum ACTH(ACTH8:00)and 16:00 serum ACTH(ACTH16:00)(P<0.01).After low-dose dexamethasone suppression test(LDDST),CPA group showed lower suppression rates of ACTH and cortisol,and higher proportions of paradoxical elevation in serum cortisol and 24 h UFC compared with PBMAH(P<0.01).Conclusions PBMAH has a longer disease course and higher proportions of comorbid metabolic disorders than CPA,mostly manifested as subclinical Cushing's syndrome.CPA has stronger autonomous cortisol secretion ability,with cortisol less likely to be suppressed after LDDST and more obvious paradoxical elevation of cortisol and 24 h UFC.
3.Characteristics analysis of multimodal metabolic disorders in subclinical Cushing's syndrome patients with different cortisol levels
Ya-Jing WANG ; Bing LI ; Huai-Jin XU ; Qi NI ; Ya-Qi YIN ; Yi-Jun LI ; Li ZANG ; Yu CHENG ; Kang CHEN ; Qing-Hua GUO ; Jian-Ming BA ; Wei-Jun GU ; Jing-Tao DOU ; Zhao-Hui LYU ; Yi-Ming MU
Medical Journal of Chinese People's Liberation Army 2025;50(7):793-799
Objective To characterize multimodal metabolic disorders in subclinical Cushing's syndrome(SCS)patients with different cortisol levels,providing a reference for clinical diagnosis and treatment.Methods A retrospective analysis was conducted on the clinical data of 165 SCS patients diagnosed at the First Medical Center of Chinese PLA General Hospital due to adrenal masses from January 2014 to October 2024.Using the serum cortisol levels after the midnight 1 mg dexamethasone suppression test(1 mg DST)as the cut-off point,SCS patients were divided into high-level group(1 mg DST-F>138 nmol/L,n=96)and low-level group(50 nmol/L<1 mg DST-F≤138 nmol/L,n=69).The differences in age,gender,body mass index(BMI),blood pressure,glucolipid metabolism indices,electrolytes,hormone levels,and imaging features of adrenal adenoma(such as CT values)were compared between the two groups.Multivariate linear regression was used to analyze the correlation between CT values and metabolic indices.Results Compared with low-level group,patients in high-level group were younger(54.0±11.3 vs.57.7±10.3,P=0.034),while there were no statistically significant differences in gender ratio or BMI between the two groups(P>0.05).Both groups exhibited decreased adrenocorticotropic hormone(ACTH)levels and disrupted circadian rhythm.Compared with low-level group,high-level group showed significantly higher F0:00 levels[250.00(170.07,422.53)nmol/L vs.110.00(82.74,133.90)nmol/L]and 24-hour urinary free cortisol(24 h UFC)[568.40(377.80,875.45)nmol/24 h vs.369.40(265.40,494.69)nmol/24 h](P<0.001),with no significant differences in serum F8:00,or 1 mg DST ACTH0:00 levels(P>0.05).Except for the fasting C-peptide level in the high-level group being higher than that in low-level group[(2.88±1.01)ng/ml vs.(2.46±0.78)ng/ml,P=0.024],there were no significant differences in blood pressure,blood lipids,glycated hemoglobin(HbA1c),fasting blood glucose,fasting insulin,serum electrolytes,uric acid,and other indices between the two groups(P>0.05).The CT value of adrenal adenoma during contrast-enhanced scanning was higher in high-level group[80.00(17.80,93.00)Hu vs.52.00(35.50,75.00)Hu,P=0.006]compared with low-level group.Multivariate linear regression analysis revealed that diastolic blood pressure was positively correlated with CT values of adrenal adenomas in both plain scanning(β=0.49,95%CI 0.09-0.90)and contrast-enhanced scanning(β=2.08,95%CI 0.76-3.39),while triglyceride levels were negatively correlated with plain scanning CT values(β=-5.77,95%CI-10.88--0.66).Conclusion Patients with SCS at different cortisol levels differ in age,fasting C-peptide levels,and CT values.CT values may serve as potential imaging markers to assess metabolic risk in SCS patients.
4.Clinical characteristics of clinical and subclinical Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia
Huai-Jin XU ; Bing LI ; Kang CHEN ; Hui-Xin ZHOU ; Ya-Jing WANG ; Li ZANG ; Xian-Ling WANG ; Yu CHENG ; Jin DU ; Qing-Hua GUO ; Wei-Jun GU ; Zhao-Hui LYU ; Jian-Ming BA ; Jing-Tao DOU ; Yi-Ming MU
Medical Journal of Chinese People's Liberation Army 2025;50(7):800-807
Objective To investigate the clinical characteristics of patients with clinical and subclinical Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia(PBMAH).Methods A retrospective analysis was performed on the clinical data of 198 patients with Cushing's syndrome caused by PBMAH diagnosed in the First Medical Center of Chinese PLA General Hospital from January 2004 to October 2024.According to clinical manifestations,the patients were classified into clinical type Cushing's syndrome(n=61)and subclinical type Cushing's syndrome(n=137),and the clinical characteristics of the two types were compared.Results The mean age at diagnosis of patients with PBMAH-induced Cushing's syndrome was(53.5±10.4)years,including 118 males and 80 females,with a male-to-female ratio of 1.475:1.Compared with the subclinical type,the clinical type had a higher proportion of females,higher levels of serum cortisol,24-hour urine free cortisol(24 h UFC),and inhibited serum cortisol after low-dose dexamethasone suppression.Additionally,the clinical type had lower plasma ACTH,larger adrenal nodules and a higher risk of surgery(P<0.05)compared with those in subclinical type.The incidences of hypertension,dyslipidemia,obesity,diabetes mellitus,hypokalemia,vitamin D deficiency,osteoporosis,coronary heart disease,and cerebrovascular disease in patients with Cushing's syndrome caused by PBMAH were 87.9%,50.5%,37.1%,36.9%,27.8%,25.9%,18.7%,18.7%and 12.1%,respectively.Among them,compared with subclinical type patients,clinical type patients had higher incidence of hypokalaemia,vitamin D deficiency and osteoporosis(P<0.05),while there were no statistically significant differences in the incidences of other comorbidities between the two types(P>0.05).The results of postoperative follow-up for PBMAH patients showed that the short-term biochemical remission rate of unilateral total adrenalectomy was 41.5%(22/53)and the long-term biochemical remission rate was 32.0%(8/25).The short-term biochemical remission rate of unilateral partial(or nodular)adrenalectomy was 52.9%(9/17),and the long-term biochemical remission rate was 14.3%(1/7).All patients who underwent unilateral total adrenalectomy plus contralateral partial resection developed adrenal insufficiency(3/3),and 1 patient(1/3)relapsed 3.4 years after surgery.Conclusion Clinical and subclinical types of Cushing's syndrome caused by PBMAH have their distinct clinical characteristics.Surgery is an effective treatment for PBMAH,but a certain proportion of patients fail to achieve biochemical remission after non-bilateral total adrenalectomy.
5.Effects of Deduhonghua-7 powder and its main components on CCR1 and DNMT1 proteins in mice with liver fibrosis
Zhi-Qiang HAN ; Yan-Hua XU ; Ren MU ; Da AN
The Chinese Journal of Clinical Pharmacology 2024;40(7):1004-1008
Objective To elucidate the effect of Deduhonghua-7 powder and its main components on liver fibrosis induced by carbon tetrachloride(CCl4)by regulating chemokine receptor 1(CCR1)and DNA methyltransferase 1(DNMT1).Methods C57BL/6 mice were randomly divided into blank group,model group,Deduhonghua-7 powder group(0.75 g·kg-1 Deduhonghua-7 powder),Scabiosa Atropurea group(0.75 g·kg-1 Scabiosa Atropurea)and Luteolin-L,-H groups(0.02 and 0.04 g·kg-1 Luteolin,respectively).Except the blank group,the other groups were intrabitoneally injected with 10%CC14 olive oil solution to establish liver fibrosis model,and all groups were given 0.5%CMC-Na dissolved intragastric drug once a day for 4 weeks,and blood and liver tissues were collected after the last administration.The serum CCR1,DNMT1,α-smooth muscle actin(α-smA)and precollagen Ⅲ contents were detected by enzyme linked immunosorbent assay;the CCR1,DNMT1,α-smA,Collagen Ⅰprotein expression were detected by Western blot.Result The contents of serum DNMT1 in blank group,model group,Deduhonghua-7 powder group,Luteotin-L,-H groups and Scabiosa Atropurea group were(4.56±0.69),(6.09±0.59),(5.21±0.33),(4.99±0.68),(5.03±0.45)and(5.17±0.61)pg·mL-1;the contents of CCR1 were(13.38±0.47),(11.20±0.73),(12.97±0.80),(12.89±0.75)(12.88±0.95)and(12.92±0.58)pg·mL-1;the contents of α-smA were(181.80±24.50),(281.30±26.60),(220.90±22.30),(193.70±16.10),(199.30±17.70)and(205.80±14.70)pg·mL-1;the contents of procollagen Ⅲ were(49.29±8.26),(77.56±8.61),(67.56±5.63),(55.47±7.07),(64.93±8.66)and(59.66±8.51)pg·mL-1;the relative expression levels of DNMT1 protein in liver tissues were 0.08±0.03,0.26±0.08,0.13±0.01,0.12±0.05,0.13±0.05 and 0.15±0.03;the CCR1 protein relative expression levels were 0.18±0.03,0.13±0.02,0.21±0.06,0.22±0.07,0.17±0.07 and 0.18±0.06;the α-smA protein relative expression levels were 0.03±0.01,0.27±0.11,0.09±0.05,0.12±0.08,0.09±0.07 and 0.11±0.07;the expression of Colagen Ⅰ protein were 0.09±0.04,0.65±0.22,0.28±0.12,0.26±0.19,0.30±0.22 and 0.25±0.12.The differences of above indicators between the model group and the blank group,between the Deduhonghua-7 powder group,Luteotin-L,-H groups,Scabiosa Atropurea group and the model group were statistically significant(all P<0.05).Conclusion Luteotein is one of the pharmacodynamic substance bases of Deduhonghua-7 powder to alleviate liver fibrosis induced by CC14.It can inhibit or delay the formation of liver fibrosis through CCR1,DNMT1,α-smA and Collagen Ⅰ proteins.
6. Effects of metabolites of eicosapentaenoic acid on promoting transdifferentiation of pancreatic OL cells into pancreatic β cells
Chao-Feng XING ; Min-Yi TANG ; Qi-Hua XU ; Shuai WANG ; Zong-Meng ZHANG ; Zi-Jian ZHAO ; Yun-Pin MU ; Fang-Hong LI
Chinese Pharmacological Bulletin 2024;40(1):31-38
Aim To investigate the role of metabolites of eicosapentaenoic acid (EPA) in promoting the transdifferentiation of pancreatic α cells to β cells. Methods Male C57BL/6J mice were injected intraperitoneally with 60 mg/kg streptozocin (STZ) for five consecutive days to establish a type 1 diabetes (T1DM) mouse model. After two weeks, they were randomly divided into model groups and 97% EPA diet intervention group, 75% fish oil (50% EPA +25% DHA) diet intervention group, and random blood glucose was detected every week; after the model expired, the regeneration of pancreatic β cells in mouse pancreas was observed by immunofluorescence staining. The islets of mice (obtained by crossing GCG
7.Relationship between GLI1 expression and tumor immune infiltration and clinical prognosis of gastric cancer
Wen-Shuai ZHU ; Jing-Guo SUN ; Yi LU ; Mu-Hua LUAN ; Xiao-Li MA ; Yan-Fei JIA
Chinese Journal of Current Advances in General Surgery 2024;27(1):8-13
Objective:To investigate the correlation between the expression of GLI1 and im-mune invasion and clinical prognosis in gastric cancer.To study the effect of GLI1 expression on drug resistance in gastric cancer.Methods:The expression difference of GLI1 in gastric cancer and normal tissues was analyzed by using TCGA database,and the effect of clinical features and GLI1 gene ex-pression level on prognosis of patients with gastric cancer was analyzed.The correlation between GLI1 gene expression and tumor immune cell infiltration in gastric cancer tissues was analyzed to explore its influence on drug resistance of chemotherapy drugs and targeted drugs.Clinical samples were collect-ed to analyze the difference of GLI1 expression in gastric cancer and paracancer tissues.Results:The expression of GLI1 in gastric cancer tissues was 1.7 times that in normal tissues,and the overall sur-vival and disease-free survival of patients with high expression are shorter than those with low ex-pression(P<0.05).The interstitial score,immune score and abundance of immunoinfiltrating cells were higher in the high expression of GLI1 in gastric cancer tissues.High expression of GLI1 reduces drug sensitivity and is positively correlated with the expression of immune checkpoint markers PDCD1(P<0.05).GLI1 expression was significantly increased in patients with subdifferentiated gastric cancer.Conclusions:GLI1 expression is associated with the prognosis and immune infiltration of patients with gastric cancer,and it may lead to poor prognosis of patients by regulating chemotherapy resis-tance,which may be a potential therapeutic target and molecular marker for gastric cancer.
8.Reference values of carotid intima-media thickness and arterial stiffness in Chinese adults based on ultrasound radio frequency signal: A nationwide, multicenter study
Changyang XING ; Xiujing XIE ; Yu WU ; Lei XU ; Xiangping GUAN ; Fan LI ; Xiaojun ZHAN ; Hengli YANG ; Jinsong LI ; Qi ZHOU ; Yuming MU ; Qing ZHOU ; Yunchuan DING ; Yingli WANG ; Xiangzhu WANG ; Yu ZHENG ; Xiaofeng SUN ; Hua LI ; Chaoxue ZHANG ; Cheng ZHAO ; Shaodong QIU ; Guozhen YAN ; Hong YANG ; Yinjuan MAO ; Weiwei ZHAN ; Chunyan MA ; Ying GU ; Wu CHEN ; Mingxing XIE ; Tianan JIANG ; Lijun YUAN
Chinese Medical Journal 2024;137(15):1802-1810
Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.
9.Mortality, morbidity, and care practices for 1750 very low birth weight infants, 2016-2021
Yang HE ; Meng ZHANG ; Jun TANG ; Wanxiu LIU ; Yong HU ; Jing SHI ; Hua WANG ; Tao XIONG ; Li ZHANG ; Junjie YING ; Dezhi MU
Chinese Medical Journal 2024;137(20):2452-2460
Background::Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges. The study aimed to analyze the clinical characteristics of VLBW infants.Methods::A retrospective cohort study was conducted in West China Second Hospital between January 2016 and December 2021. Neonates with a birth weight of <1500 g were included. Mortality, care practices, and major morbidities were analyzed, and compared with those of previous 7 years (2009-2015).Results::Of the total 1750 VLBW, 1386 were infants born with birth weight between 1000-1499 g and 364 infants were born with weight below 1000 g; 42.9% (751/1750) required delivery room resuscitation; 53.9% (943/1750) received non-invasive ventilation only; 38.2% (669/1750) received invasive ventilation; 1517 VLBW infants received complete treatment. Among them, 60.1% (912/1517) of neonates had neonatal respiratory distress syndrome (NRDS), 28.7% (436/1517) had bronchopulmonary dysplasia (BPD), 22.0% (334/1517) had apnea, 11.1% (169/1517) had culture-confirmed sepsis, 8.4% (128/1517) had pulmonary hemorrhage, 7.6% (116/1517) had severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL), 5.7% (87/1517) had necrotizing enterocolitis (NEC), and 2.0% (31/1517) had severe retinopathy of prematurity. The total and in-hospital mortality rates were 9.7% (169/1750) and 3.0% (45/1517), respectively. The top three diagnoses of death among those who had received complete treatment were sepsis, NRDS, and NEC. In 2009-2015, 1146 VLBW were enrolled and 895 infants received complete treatment. The proportions of apnea, IVH, and IVH stage ≥3/PVL, were higher in 2009-2015 compared with those in 2016-2021, while the proportions of NRDS and BPD were characterized by significant increases in 2016-2021. The total and in-hospital mortality rates were 16.7% (191/1146) and 5.6% (50/895) respectively in 2009-2015.Conclusion::Among VLBW infants born in 2016-2021, the total and in-hospital mortality rates were lower than those of neonates born in 2009-2015. Incidences of NRDS and BPD increased in 2016-2021, which affected the survival rates and long-term prognosis of VLBW.
10.Analysis of the application effect of hemoperfusion combined with continuous hemodialysis in patients with acute organophosphorus pesticide poisoning
Shiwei MU ; Xin WANG ; Ling LIU ; Peng ZHANG ; Yan HUA ; Yong TANG
Chinese Journal of Integrated Traditional and Western Medicine in Intensive and Critical Care 2024;31(1):68-72
Objective To observe the effects of hemoperfusion(HP)combined with hemodialysis on cholinesterase(ChE)activity and inflammatory factors in patients with acute organophosphorus pesticide poisoning(AOPP).Methods A retrospective cohort study was conducted.Seventy-three AOPP patients admitted to the department of emergency of Yingshang People's Hospital from January 2020 to December 2022 were enrolled.The patients were divided into HP group(31 cases)and HP+continuous renal replacement therapy(CRRT)group(42 cases)according to different treatment regimens.All patients were given supportive treatment according to the standard protocol after admission.HP was given to the patients as soon as possible after admission,and the treatment time was between 2 hours and 3 hours,with an interval of 24 hours.Patients in HP+CRRT group were treated with continuous veno-venous hemodiafiltration(CVVHDF)after HP.The serum ChE,tumor necrosis factor-α(TNF-α),and interleukins(IL-1,IL-6)levels were compared between the two groups after admission(T0),at the end of the first HP/HP+CRRT(T1),at the end of the second HP/HP+CRRT(T2),and at the end of the third HP/HP+CRRT(T3).The ChE recovery time,the incidence of intermediate syndrome(IMS),the length of hospital stay,and the rate of admission to ICU were also compared.Results With the extension of treatment time,the ChE activity at T1,T2,and T3 in the two groups was significantly higher than that at T0,and the levels of TNF-α,IL-1,and IL-6 were significantly lower than those at T0,reaching the trough value at T3,and the changes in HP+CRRT group were more significant than those in HP group[ChE activity(U/L):2 903.26±164.43 vs.2 292.98±350.96,TNF-α(ng/L):78.24±10.75 vs.100.55±15.58,IL-1(ng/L):95.98±22.56 vs.127.94±18.74,IL-6(ng/L):34.36±8.66 vs.58.74±10.46,all P<0.05].The recovery time of ChE activity and length of hospital stay in HP+CRRT group were significantly shorter than those in HP group[ChE activity recovery time(days):4.42±1.17 vs.7.31±1.46,length of hospital stay(days):9.25±2.14 vs.12.75±2.30,both P<0.05],the incidence of IMS and ICU admission rate were significantly lower than those in HP group[the incidence of IMS:33.33%(14/42)vs.61.29%(19/31),ICU admission rate:9.52%(4/42)vs.29.03%(9/31),both P<0.05].Conclusion For AOPP patients,HP+CRRT is superior to HP alone in the clearance of inflammatory factors,restoring ChE activity,reducing the incidence of IMS,and shortening the length of hospital stay,making it a valuable option for clinical application.

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