1.Development and evaluation of classification system for drug-related problems in China
Shuang ZOU ; Tingting LU ; Lei BAO ; Yun LIAO ; Ling LI ; Ping ZHANG
China Pharmacy 2026;37(3):371-376
OBJECTIVE To establish a Chinese drug-related problem (DRP) classification system applicable to pharmacist-led pharmaceutical care in China, providing pharmacists with an effective and practical tool for pharmaceutical care. METHODS A multi-stage process was employed to construct the DRP classification system, including literature review and analysis, comparison of existing classification systems, refinement of classification items and framework development, two rounds of standard case validation, expert discussion, and system revision. The Fleiss′ kappa test was used to calculate the consistency coefficient κ, assessing the reliability of pharmacists participating in evaluating the classification system. An electronic questionnaire comprising six items was employed to evaluate the system’s applicability. RESULTS The constructed Chinese DRP classification system comprised six sections [problem(including potential problems), DRP evaluation, cause (including possible causes of potential problems), intervention, acceptance of intervention and DRP status], with 24 primary codes and 96 secondary codes. In the first round of case validation, κ values exceeded 0.4 for all sections except “intervention” and “DRP status”. In the second round, κ values exceeded 0.4 for all sections. In the applicability evaluation of the classification system, positive ratings (“strongly agree” or “agree”) exceeded 85% for all items. Specifically, positive ratings for“the classification system can provide appropriate category selection”,“ the classification system is comprehensive”,“ the classification system is convenient to use” and “the classification system is highly satisfactory” exceeded 92%. CONCLUSIONS The Chinese DRP classification system developed demonstrates both high reliability and applicability, providing an effective and practical classification tool for pharmacists in China to conduct pharmaceutical care.
2.Mechanistic study of mitochondrial dysfunction in renal injury induced by maternal bone lead mobilization during pregnancy in rats
Ling LI ; Lin ZHANG ; Li LI ; Yuting WEI ; Man LYU ; Zeshi ZHANG ; Li MA ; Anxin LU ; Yin LIN ; Shaohua WANG ; Chonghuai YAN
Journal of Environmental and Occupational Medicine 2026;43(3):286-292
Background Lead is a typical persistent environmental pollutant that can accumulate in bones for decades. During pregnancy, alterations in calcium metabolism promote the mobilization of bone lead, resulting in secondary exposure; however, the mechanisms by which pregnancy-associated bone lead mobilization affects maternal renal function remain unclear. Objective To investigate the role of mitochondrial dysfunction in pregnancy-related bone lead mobilization-induced renal injury. Methods Newly weaned female Wistar rats were randomly assigned to a control or a lead-exposed group administered either 0.05% sodium acetate or 0.05% lead acetate in drinking water. Following a 4-week lead exposure and a 4-week washout period, the females were co-housed with healthy age-matched males for mating. Rats were sacrificed at early (gestational day 3) and late (gestational day 17) pregnancystages, respectively. Renal histopathology was assessed using hematoxylin and eosin staining staining. Mitochondria-related indicators, including oxidative stress, inflammatory responses, and energy metabolism, were measured. Differential metabolites were identified using serum metabolomics. Results Renal injury in the lead-exposed pregnant rats progressed in a time-dependent manner, characterized by degeneration of proximal tubular epithelial cells, glomerular hyaline changes, and interstitial inflammatory cell infiltration. Repeated measures ANOVA indicated a significant interaction between the treatment factor (lead exposure) and the temporal factor (gestational stage) on renal injury (P<0.001). Further analysis of mitochondrial function-related indicators in late-pregnancy renal tissue revealed that the lead exposure group exhibited significantly increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS) (P<0.05), accompanied by a reduction in superoxide dismutase (SOD) and reduced glutathione (GSH) activities (P<0.05); regarding inflammatory markers, levels of interleukin-18 (IL-18) and interleukin-1β (IL-1β) were elevated (P<0.01), whereas interleukin-33 (IL-33) was decreased in the lead-exposed group (P<0.05); energy metabolism-related indicators, including adenosine triphosphate (ATP) level, Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities, and mitochondrial respiratory chain complexes I, III, and V activities, were significantly reduced (P<0.05) in the lead-exposed gorup. The typical differential metabolite N-methylisoleucine, identified through serum metabolomics analysis, was negatively correlated with blood lead levels, kidney injury scores, and IL-1β, while positively correlated with catalase (CAT) activity and Ca2+-Mg2+-ATPase. Conclusions Mitochondrial dysfunction may play a critical role in renal injury induced by bone lead mobilization during late gestation.
3.Expert consensus on neoadjuvant PD-1 inhibitors for locally advanced oral squamous cell carcinoma (2026)
LI Jinsong ; LIAO Guiqing ; LI Longjiang ; ZHANG Chenping ; SHANG Chenping ; ZHANG Jie ; ZHONG Laiping ; LIU Bing ; CHEN Gang ; WEI Jianhua ; JI Tong ; LI Chunjie ; LIN Lisong ; REN Guoxin ; LI Yi ; SHANG Wei ; HAN Bing ; JIANG Canhua ; ZHANG Sheng ; SONG Ming ; LIU Xuekui ; WANG Anxun ; LIU Shuguang ; CHEN Zhanhong ; WANG Youyuan ; LIN Zhaoyu ; LI Haigang ; DUAN Xiaohui ; YE Ling ; ZHENG Jun ; WANG Jun ; LV Xiaozhi ; ZHU Lijun ; CAO Haotian
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(2):105-118
Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.
4.Influence and mechanism of curcumin on the biological behavior of oral squamous cell carcinoma cells based on network pharmacology and transcriptomics
LIU Ji' ; an ; XU Bo ; ZHANG Ling
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(9):871-885
Objective:
To investigate the effects of curcumin on the biological behavior of oral squamous cell carcinoma (OSCC) cells and its potential molecular mechanisms, as well as to provide experimental evidence for the application of curcumin in the prevention and treatment of OSCC.
Methods:
All animal experiments in this study were approved by the Institutional Animal Welfare and Ethics Committee and strictly adhered to relevant animal ethics guidelines. Potential intersecting targets of curcumin and OSCC were screened using TCMSP, SwissTargetPrediction, DrugBank, and GeneCards databases, followed by construction of a protein-protein interaction network and gene ontology(GO) /Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Scratch and clone formation experiments were conducted using CAL-27 and SCC-9 cells to detect the effect of curcumin on cell migration and proliferation ability. Combining RNA sequencing analysis of differentially expressed genes, and verifying the changes in mRNA and protein expression of key cellular molecules by curcumin through real-time fluorescence quantitative PCR and Western blot, respectively. Simultaneously establish a CAL-27 xenograft BALB/c nude mouse transplant tumor model and use immunohistochemistry to detect the effect of curcumin treatment on the expression of related proteins in the transplant tumor tissue.
Results:
A total of 178 intersecting targets were identified, mainly enriched in the PI3K/AKT signaling pathway and lipid metabolism-related pathways. Curcumin significantly inhibited migration and colony formation of CAL-27 and SCC-9 cells in vitro. Transcriptomic analysis identified 828 differentially expressed genes enriched in lipid metabolism and PI3K/AKT pathways. Real-time fluorescence quantitative PCR showed downregulation of PIK3CA, CCND1, BCL2, and FASN, while western blot demonstrated decreased expression of p-AKT and FASN. In vivo, curcumin markedly suppressed tumor growth and reduced the expression of Ki-67, BCL2, and p-AKT in tumor tissues.
Conclusion
Curcumin may inhibit the migration and proliferation of OSCC cells by regulating the PI3K/AKT signaling pathway and the expression of lipid metabolism-related genes.
5.Effects and Regulation of Glycosylation Modifications on G Protein-coupled Receptor Function
Fang-Ming WU ; Sheng-Long LING ; Pan SHI ; Yu SUN ; Chang-Lin TIAN
Progress in Biochemistry and Biophysics 2026;53(9):2352-2364
Glycosylation constitutes a critical, highly intricate, and diverse co- and post-translational modification characterized by the covalent attachment of sugar moieties to proteins, lipids, or small RNAs. Complex glycans are ubiquitously present across nearly all living organisms. Despite their prevalence, our comprehension of glycan diversity remains limited, likely due to the inherent challenges associated with elucidating their structural complexity. Among post-translational modifications, protein glycosylation is notably prevalent, involving the enzymatic transfer of oligosaccharides to specific amino acid residues by glycosyltransferases. This modification plays a pivotal role in modulating protein function, including participation in various biological and biochemical recognition processes. G protein-coupled receptors (GPCRs), encoded by approximately one thousand genes, share a conserved architecture comprising seven transmembrane helices interconnected by three intracellular and three extracellular loops. Representing the largest family of human membrane proteins, GPCRs regulate a vast array of physiological and pathological processes, thereby constituting the most extensive class of therapeutic targets. In mammalian systems, the majority of GPCRs undergo glycosylation predominantly at their extracellular N-terminus or extracellular loops, primarily through N-linked and O-linked glycosylation. These covalent carbohydrate modifications exert profound effects on multiple facets of GPCR biology, including endoplasmic reticulum folding and quality control, membrane trafficking and surface expression, receptor internalization and recycling or degradation, ligand binding and signal transduction, biased signaling, and receptor dimerization. Notably, glycosylation can exert both positive and negative regulatory influences on these processes. Dysregulation of GPCR glycosylation has been implicated in a range of pathological conditions, such as cancer, diabetes, and neurological disorders, underscoring its physiological and pathological significance. Aberrant glycosylation patterns may lead to dysfunctional receptor signaling, thereby contributing to disease progression. Consequently, elucidating the precise roles of glycosylation in GPCR function not only enhances fundamental understanding of receptor biology but also facilitates the development of novel therapeutic strategies targeting glycosylation pathways or specific GPCR glycoforms. Although the functional consequences of glycosylation have been investigated for several decades, delineating their exact structural underpinnings has remained challenging due to the intrinsic flexibility and heterogeneity of carbohydrate structures. Recent advances in structural biology, particularly single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography, have catalyzed a paradigm shift in our understanding of GPCR glycosylation. The integration of these sophisticated structural techniques with biochemical approaches has redefined glycosylation as a complex structural element integral to receptor function. These developments provide a molecular framework for comprehending how glycans influence receptor pharmacology and open new avenues for the rational design of glyco-engineered biologics and allosteric modulators targeting specific extracellular motifs. This mini-review concentrates on glycosylation within the GPCR superfamily, summarizing the impact of glycosylation modifications on receptor function and regulatory mechanisms, recent progress in the structural biology of GPCR glycosylation, and prospective directions for future research in this field.
6.Effects of Modified Baohe Pill (保和丸) Formula on Thoracic Drainage Volume,Chest Tube Duration, and Inflammatory Indices After Thoracoscopic Surgery for Lung Cancer:A Randomized Parallel-Controlled Study
Yi LIU ; Ling XU ; Zhiyi DONG ; Xuanting YE ; Yiyun HE ; Zhiying WANG ; Yabin GONG ; Lijing JIAO
Journal of Traditional Chinese Medicine 2026;67(20):2202-2209
ObjectiveTo evaluate the effects of modified Baohe Pill (保和丸) formula added to conventional pulmonary rehabilitation on thoracic drainage volume, chest tube duration, and peripheral blood inflammatory indices after video-assisted thoracoscopic surgery (VATS) for lung cancer. MethodsIn this randomized parallel-controlled study, 118 post-VATS patients were enrolled, with 59 cases in each group. The control group received conventional pulmonary rehabilitation, while the treatment group additionally received an oral decoction of modified Baohe Pill formula until chest tube removal and discharge. The primary outcome was total postoperative thoracic drainage volume, while the secondary outcomes included chest tube duration and inflammatory indices including the pre-treatment and post-treatment levels and relative changes in platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), aggregate index of systemic inflammation (AISI), and systemic inflammation response index (SIRI). Adverse events during the treatment period were recorded. ResultsThe total postoperative thoracic drainage volume was 850 (430, 1410) ml in the treatment group, lower than 1085 (660, 1720) ml in the control group (P<0.05). Total postoperative chest tube duration was 8 (6, 11) days in the treatment group, shorter than 10 (7, 11) days in the control group (P<0.05), whereas the interval from enrollment to removal did not differ significantly between groups (P>0.05). The postoperative NLR in the treatment group was lower than that in the control group, and the relative change in NLR was greater than that in the control group (P<0.05). No significant between-group differences were found in post-treatment levels or relative changes of the other five inflammatory indices (P>0.05). No treatment-related serious adverse events were reported in either group. ConclusionModified Baohe Pill formula plus conventional pulmonary rehabilitation has lower total postoperative thoracic drainage volume, shorter total postoperative chest tube duration, and lower NLR levels in lung cancer patients following VATS, while demonstrating a more favorable safety profile than conventional pulmonary rehabilitation alone.
7.The value of serum and sputum Galectin-7 expression in evaluating the therapeutic effect of omalizumab in children with moderate asthma
Xiuya ZHANG ; Wei HUANG ; Ling LIU ; Jiao CHEN
International Journal of Laboratory Medicine 2025;46(4):457-461
Objective To investigate the value of serum and sputum Galectin-7 expression in evaluating the therapeutic effect of omalizumab in children with moderate asthma.Methods A total of 210 children with moderate asthma admitted to the hospital from January 2021 to August 2023 were selected as the study ob-jects.All the children were treated with omazumab,and the efficacy was evaluated according to the clinical control criteria of asthma,and they were divided into effective group and ineffective group.The expression of Galectin-7 in serum and sputum before treatment was detected in the two groups.Multivariate Logistic regres-sion was used to analyze the relationship between serum and sputum Galectin-7 and the efficacy of omalizumab in the treatment of moderate asthma children.Receiver operating characteristic(ROC)curve was used to ana-lyze the value of serum and sputum Galectin-7 in evaluating the efficacy of omalizumab in the treatment of children with moderate asthma.Results There was statistical significance in the proportion of passive smok-ing between the two groups(P<0.05).The expression of Galectin-7 in serum and sputum before treatment in the effective group was lower than that in the ineffective group,and the difference was statistically signifi-cant(P<0.05).Multivariate Logistic regression analysis showed that passive smoking history,serum Galec-tin-7 expression and sputum Galectin-7 expression were independent risk factors affecting the efficacy of oma-lizumab in the treatment of moderate asthma children(P<0.05).ROC curve analysis results showed that,The area under the curve of serum Galectin-7,sputum Galectin-7 and their combination to evaluate the efficacy of omalizumab in the treatment of children with moderate asthma were 0.791(95%CI:0.673-0.849),0.845(95%CI:0.766-0.925),0.910(95%CI:0.844-0.976),respectively.Conclusion The combined detection of serum Galectin-7 and sputum Galectin-7 has a higher value in evaluating the therapeutic effect of omazumab in children with moderate asthma.
8.Clinical phenotype and genetic analysis of a child with CAKUTHED syndrome due to variant of PBX1 gene.
Jiao TANG ; Chuan ZHANG ; Ruiqiong YANG ; Xinyuan TIAN ; Bingbo ZHOU ; Yupei WANG ; Ling HUI
Chinese Journal of Medical Genetics 2025;42(12):1471-1476
UNLABELLED:
OBJECTIVE:To explore the clinical characteristics and genetic etiology of a child with CAKUTHED syndrome.
METHODS:
A child who was admitted to the neonatal department of Gansu Provincial Maternal and Child Health Care Hospital due to "neonatal asphyxia" in May 2021 was selected as the study subject. Genomic DNA was extracted from peripheral venous blood samples from the child and his parents, and whole exome sequencing (WES) was carried out. Sanger sequencing was used to verify the candidate variant of the PBX1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital [Ethics No.: 2021GSFY (65)].
RESULTS:
The proband, a male neonate, manifested renal dysplasia, congenital heart disease, pulmonary dysplasia, mediastinal hernia, cryptorchidism, and clavicle dysplasia. WES revealed that he had harbored a heterozygous c.863G>A (p.Arg288Gln) missense variant in exon 6 of PBX1 gene, which resulted substitution of Arginine at position 288 by Glutamine, for which both parents were of the wild type. The variant was unreported previously and rated as pathogenic (PS2+PM1+PM2_Supporting+PP2+PP3) based on the ACMG guidelines.
CONCLUSION
The c.863G>A variant of the PBX1 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PBX1 gene.
Humans
;
Male
;
Pre-B-Cell Leukemia Transcription Factor 1/genetics*
;
Phenotype
;
Infant, Newborn
;
Exome Sequencing
;
Mutation, Missense
;
Heart Defects, Congenital/genetics*
;
Abnormalities, Multiple/genetics*
9.Effect of flexible endoscopic evaluation of swallowing on clinical functional outcomes in patients with intensive care unit-acquired swallowing disorders
Yandong SUN ; Lixia HAO ; Yan ZHANG ; Naqi ZHOU ; Zhiyu JIAO ; Ying JIAO ; Yihuan DONG ; Ling XU ; Huri LETEMUER
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2025;60(11):1383-1388
Objective:To evaluate the effect of fiberoptic endoscopic evaluation of swallowing (FEES) on clinical functional outcomes of patients with intensive care unit-acquired swallowing disorders (ICU-ASD).Methods:This retrospective cohort study analyzed clinical data of patients diagnosed with post-extubation dysphagia (PED) in the intensive care unit (ICU) and respiratory intensive care unit (RICU) of the Affiliated Hospital of Inner Mongolia Medical University from February 2020 to February 2025. Patients were categorized into a FEES group of 60 cases [34 males, 26 females, aged 37-80 years (median age 62 years)] and a control group without FEES of 58 cases [32 males, 26 females, aged 39-77 years (median age 61 years)].The patients in two groups received swallowing function and feeding training based on the results of the FEES assessment and the Volume-Viscosity Swallow Test-Clinical Version (VVST-CV), respectively. Clinical functional outcome measures included pneumonia incidence, clinical pulmonary infection score (CPIS), pneumonia severity index (PSI), Functional Oral Intake Scale (FOIS), and dietary method at discharge. χ2 test, Mann-Whitney U test, and Wilcoxon signed-rank test, were employed for statistical analysis of the outcome measures. Results:Compared with the control group, the FEES group had significantly lower aspiration pneumonia incidence at discharge [3.3% (2/60) vs 15.5% (9/58), χ2=5.179, P=0.023]. Regarding dietary methods,a significantly higher proportion of patients in the FEES group achieved complete oral feeding compared with the control group [75.0% (45/60) vs 67.3% (39/58), χ2=8.065, P<0.05]. After training, the FEES group had higher median FOIS scores than the control group (7.00 vs 6.00, Z=-2.370, P=0.018), and lower CPIS scores (2.50 vs 5.00, Z=-2.216, P=0.027) and PSI scores (59.00 vs 73.00, Z=-2.251, P=0.024). Within-group comparisons revealed that FOIS scores significantly improved post-training in both groups (both P<0.001). Conclusion:Early FEES examination for ICU patients with acquired swallowing disorders is associated with a lower incidence of pneumonia, improved swallowing function, and superior clinical functional outcomes.
10.Study on Tongue Manifestations of Patients with Different Syndromes in Non-Small Cell Lung Cancer and Their Correlation with Laboratory Indicators
Jiayi LIU ; Liping TU ; Yulin SHI ; Yu WANG ; Ling XU ; Yun YANG ; Wen JIAO ; Changle ZHOU ; Jiatuo XU
Chinese Journal of Information on Traditional Chinese Medicine 2025;32(3):136-143
Objective To study the tongue manifestation of patients with different syndromes in non-small cell lung cancer(NSCLC)and the correlation between tongue characteristics of different syndromes and tumor markers and coagulation indicators.Methods Totally 497 patients with NSCLC were grouped according to syndrome differentiation,and the differences in tongue characteristics of different syndromes were compared.Bivariate correlation analysis was used to study the correlation between tongue characteristics and serum tumor markers and coagulation indicators in patients with NSCLC of different syndromes.Results Compared with healthy people of different syndromes,in TB-a,yin deficiency and phlegm-heat syndrome>healthy group>qi-yin deficiency syndrome>spleen deficiency and phlegm-dampness syndrome>lung stagnation and phlegm-stasis syndrome(P<0.001).In TB-L,healthy group>spleen deficiency and phlegm-dampness syndrome>qi-yin deficiency syndrome>lung stagnation and phlegm-stasis syndrome>yin deficiency and phlegm-heat syndrome(P<0.001).In TB-b,yin deficiency and phlegm-heat syndrome>qi-yin deficiency syndrome>spleen deficiency and phlegm-dampness syndrome>healthy group>lung stagnation and phlegm-stasis syndrome(P<0.001).Yin deficiency and phlegm-heat syndrome had the highest TB-a and the lowest Per-all.Spleen deficiency and phlegm-dampness syndrome had the highest TB-L and Per-all.Lung stagnation and phlegm-stasis syndrome had lower TB-b and TC-b than other groups,lower TB-a than the healthy group,and a high Per-all index(P<0.05).In terms of tumor markers,Per-all in spleen deficiency and phlegm-dampness syndrome was positively correlated with Ca199,Ca50 and Ca242(P<0.05).In terms of coagulation indicators,the tongue texture index of lung stagnation and phlegm-stasis syndrome had a high correlation with the coagulation indicator Fg(P<0.01).Conclusion Different TCM syndromes of NSCLC have their own typical tongue characteristics.Tongue manifestations of different syndromes are correlated with tumor markers and coagulation indicators,respectively,which can reflect changes in clinical status.


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