Tobacco control knowledge and beliefs among healthcare workers in respiratory departments in Fujian Province, China: A cross-sectional study.

INTRODUCTION: Smoking prevalence is high in China, and healthcare workers are important for tobacco control. This study aimed to determine the smoking status, cognition of tobacco hazards, and smoking cessation-related knowledge among respiratory healthcare workers, and to explore their ability to provide smoking cessation assistance. METHODS: A cross-sectional study was conducted in 2021 among 1028 respiratory healthcare workers from 89 hospitals in Fujian Province, China. A self-designed electronic questionnaire was used to collect data on smoking status, knowledge of smoking hazards, and smoking cessation knowledge. Descriptive statistics were calculated for all questions. Logistic regression analysis was used to explore the relationship between awareness of the tobacco control goals of Healthy China 2030 and demographic characteristics. RESULTS: Among the healthcare workers surveyed, 3.4% were smokers, all of whom were male. Most respondents (99.4%) were aware of smoking as a cause of lung cancer, but awareness of smoking as a cause of non-respiratory cancer was lower. The awareness rate of smoking cessation support was high (>90%), but only 40.0% of participants were aware of the Healthy China 2030 tobacco control targets. Male (HR=2.16; 95% CI: 1.69-2.80) and participation in the cessation clinic (HR=1.47; 95% CI: 1.10-1.96) were associated with higher awareness of the targets. CONCLUSIONS: Respiratory healthcare workers in Fujian Province demonstrated a high level of awareness regarding behavioral and pharmacotherapy support for smoking cessation. In order to enable healthcare workers to play a more active role in tobacco control, there is a need to increase public awareness of smoking cessation services in Fujian Province.

Longitudinal analysis of quality of life in primary lung cancer patients with chlamydia pneumoniae infection: a time-to-deterioration model.

BACKGROUND: Chlamydia pneumoniae (Cpn) IgG and IgA has been strongly linked to lung cancer, but its impact on patients' quality of life remains unclear. Our objective was to investigate the relationship between pre-treatment Cpn IgG and IgA and time to deterioration (TTD) of the HRQoL in patients with primary lung cancer. METHODS: A prospective hospital-based study was conducted from June 2017 to December 2018, enrolling 82 patients with primary lung cancer admitted to the First Affiliated Hospital of Fujian Medical University for questionnaire surveys. Cpn IgG and IgA was detected by microimmunofluorescence method. HRQoL was assessed at baseline and during follow-up using the EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13). HRQoL scores were calculated using the QoLR package, and TTD events were determined (minimum clinically significant difference = 5 points). Cox regression analysis was used to evaluate the effect of Cpn IgG and IgA on HRQoL. RESULTS: We investigated the relationship between Cpn IgG and IgA and quality of life in patients with primary lung cancer. The study was found that 75.61% of cases were Cpn IgG + and 45.12% were Cpn IgA + . Cpn IgA + IgG + was 41.46%. For EORTC QLQ-C30, Physical function (PF) and Pain (PA) TTD events on the functional scale and Symptom scale were the most common during follow-up. After adjusting for gender and smoking status, Pre-treatment Cpn IgA + was found to signifcantly delay TTD of Physical functioning(HR = 0.539, 95% CI: 0.291-0.996, P = 0.048). In addition, Cpn IgG + before treatment significantly delayed TTD in Emotional functioning (HR = 0.310, 95% CI: 0.115-0.836, P = 0.021). For EORTC QLQ-LC13, deterioration of dyspnea (LC-DY) was the most common event. However, Cpn IgG and IgA before treatment had no effect on the TTD of EORTC QLQ-LC13 items. CONCLUSIONS: According to EORTC QLQ-C30 and EORTC QLQ-LC13, Cpn IgA delayed TTD in Physical functioning and Cpn IgG delayed TTD in Emotional functioning.

Differentiation Potential of Hypodifferentiated Subsets of Nephrogenic Rests and Its Relationship to Prognosis in Wilms Tumor.

Background Wilms tumor (WT) is highly curable, although anaplastic histology or relapse imparts a worse prognosis. Nephrogenic rests (NR) associated with a high risk of developing WT are abnormally retained embryonic kidney precursor cells. Methods After pseudo-time analysis using single-cell RNA sequencing (scRNA-seq) data, we generated and validated a WT differentiation-related gene (WTDRG) signature to predict overall survival (OS) in children with a poor OS. Results A differentiation trajectory from NR to WT was identified and showed that hypodifferentiated subsets of NR could differentiate into WT. Classification of WT children with anaplastic histology or relapse based on the expression patterns of WTDRGs suggested that patients with relatively high levels of hypodifferentiated NR presented a poorer prognosis. A WTDRG-based risk model and a clinically applicable nomogram was developed. Conclusions These findings may inform oncogenesis of WT and interventions directed toward poor prognosis in WT children of anaplastic histology or relapse.

Predictive Model of CK7 Expression in Patients With Clear Cell Renal Cell Carcinoma by Combined Multimodal Ultrasound Diagnostic Techniques: A Retrospective Study.

OBJECTIVE: The aim of the work described here was to develop and validate a predictive model for cytokeratin 7 (CK7) expression in clear cell renal cell carcinoma (ccRCC) patients by combining multimodal ultrasound diagnostic techniques. METHODS: This retrospective study enrolled 157 surgically confirmed ccRCC patients. All patients underwent pre-operative multimodal ultrasound diagnostic examinations, including B-mode ultrasound (US), color Doppler flow imaging (CDFI) and contrast-enhanced ultrasound (CEUS). The patients were randomly divided into a training group (103 cases) and a testing group (54 cases). Univariate and multivariate logistic regression analyses were performed in the training group to identify independent indicators associated with CK7 positivity. These indicators were included in the predictive model. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the model's discriminative ability and accuracy. Decision curve analysis (DCA) and nomogram visualization were used to assess the clinical utility of the predictive model. RESULTS: Univariate logistic regression analysis revealed that US and CDFI observations were not correlated with CK7 expression and could not predict it. Multivariate logistic regression analysis identified age (odds ratio [OR] = 0.953, 95% confidence interval [CI]: 0.909-0.999), wash-in pattern (OR = 0.180, 95% CI: 0.063-0.513) and enhancement homogeneity (OR = 11.610, 95% CI: 1.394-96.675) as independent factors related to CK7 positivity in ccRCC. Incorporating these variables into the predictive model resulted in areas under the receiver operating characteristic curve of 0.812 (95% CI: 0.711-0.913) for the training group and 0.792 (95% CI: 0.667-0.924) for the testing group. The calibration curve and DCA revealed that the model had good accuracy and clinical utility of the model. CONCLUSION: The combination of multimodal ultrasound diagnostic techniques in constructing a predictive model for CK7 expression in ccRCC patients has significant predictive value.

The efficacy of robotic-assisted laparoscopic pyeloplasty for pediatric ureteropelvic junction obstruction: a systematic review and meta-analysis.

To evaluate the safety and effectiveness of robotic-assisted laparoscopic pyeloplasty (RALP) for treating pediatric ureteropelvic junction obstruction through an extensive comparison of RALP, open pyeloplasty (OP) and laparoscopic pyeloplasty (LP). We conducted a comprehensive search of the following databases: PubMed, Excerpta Medica Database, Cochrane Library, Web of Science database, China National Knowledge Infrastructure, WanFang Data, and China Biology Medical Disc. Baseline data were compared, the sources of heterogeneity were assessed, and publication biases were detected. This study was registered with PROSPERO (CRD42023415667). 26 studies with 6074 cases performing pyeloplasty were included, and the overall data are comparable. Our analysis showed no significant difference in success rate and postoperative complications between RALP and OP, and RALP is associated with a shorter length of stay (LOS) (MD - 1.00 95%CI - 1.45 to - 0.55, p < 0.0001). In addition, compared to LP, RALP was associated with a shorter anastomosis time (MD - 18.35 95%CI - 29.88 to - 6.82, p = 0.002) and fewer postoperative analgesics (MD - 0.09 95% CI - 0.18 to - 0.01, p = 0.03); however, RALP has a longer operative time (OT) (MD 52.39, 95% CI 39.75-65.03, p < 0.00001) and higher cost. The heterogeneity of OT may be influenced by factors, such as age and region, while the heterogeneity of LOS primarily stems from regional differences. No significant publication bias was detected. Our meta-analysis shows that RALP can be an alternative to OP and LP with a high success rate, minimal postoperative complications, and shorter LOS. In addition, RALP contributes to reduce anastomosis time and postoperative analgesic drugs. However, further well-designed, large-scale, randomized controlled trials with additional parameters are needed to conduct a more comprehensive analysis of heterogeneity.

Near complete response to ceritinib in a pediatric patient with metastatic ALK-rearranged lung adenocarcinoma.

Anaplastic lymphoma kinase (ALK) inhibitors have significant efficacies in ALK-rearranged non-small cell lung cancers (NSCLC). In regard to pediatric NSCLC patients, however, there is a paradox in that on the one hand, they may have a higher probability of ALK-rearrangement positive, but on the other hand, there is no sufficient data for efficacies of ALK inhibitors in pediatric NSCLC patients. Here, we present an 11-year-old boy diagnosed with metastatic ALK-rearranged lung adenocarcinoma. He was treated with ceritinib 450 mg with food once daily and has obtained near complete response in 18th month, with a largely regressed intrathoracic lesion and only localized residual distant metastatic disease. Meanwhile, he showed continued good tolerance after a short period of side effects at the beginning of the dose. This is the first report of the use of ceritinib in pediatric patient with NSCLC.

Association between physical activity and health-related quality of life: time to deterioration model analysis in lung adenocarcinoma.

BACKGROUND AND PURPOSE : Health-related quality of life (HRQoL) is a key aspect of care for cancer survivors that can be improved by physical activity. Our aim was to explore the relationship between physical activity and time to deterioration (TTD) of the HRQoL in patients with lung adenocarcinoma (LUAD). METHODS: We conducted a hospital-based prospective study. The International Physical Activity Questionnaire long-form (IPAQ-L) was used to investigate the pre-treatment physical activity levels, and the EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13) were used to assess HRQoL at baseline and during follow-up. The QoLR package was used to calculate the HRQoL scores and determine TTD events (minimal clinically important difference=5 points). The effect of physical activity on the HRQoL was assessed using Cox regression analysis. RESULTS: For EORTC QLQ-C30, TTD events of physical functioning (PF) and dyspnea (DY) in functional scales and symptom scales were the most common during follow-up. Pre-treatment physical activity was found to significantly delay TTD of insomnia (HR=0.635, 95%CI: 0.437-0.922, P=0.017) and diarrhea (HR=0.475, 95%CI: 0.291-0.774, P=0.003). For EORTC QLQ-LC13 scales, deterioration of dyspnea (LC-DY) was the most common event. Physical activity was found to delay the TTD of dyspnea (HR=0.654, 95%CI: 0.474-0.903, P=0.010), sore mouth (HR=0.457, 95%CI: 0.244-0.856, P=0.015), and dysphagia (HR=0.315, 95%CI: 0.172-0.580, P<0.001). CONCLUSIONS: Pre-treatment physical activity of LUAD patients may delay the TTD of multiple HRQoL indicators in EORTC QLQ-C30 and EORTC QLQ-LC13. IMPLICATION FOR CANCER SURVIVORS: Health-related quality of life (HRQoL) is a key aspect of care for cancer survivors (someone who is living with or beyond cancer), that can be improved by physical activity. Our aim was to explore the relationship between physical activity and time to deterioration (TTD) of the HRQoL in patients with lung adenocarcinoma (LUAD).

Beliefs and perceptions of electronic cigarettes among medical staff in respiratory departments of Fujian Province, China, in 2021.

INTRODUCTION: Due to the popularity of e-cigarettes, more and more patients ask about e-cigarettes, and it is particularly important to understand doctors' beliefs and perceptions on e-cigarettes. The aim was to evaluate the belief and perception of electronic cigarettes among medical staff in the respiratory department of medical institutions located in Fujian Province. METHODS: The electronic questionnaires were conveyed to the medical staff of the respiratory department in Fujian Province during March to April 2021. Descriptive statistics were calculated for all questions, and the relationship between relevant factors and the perception of e-cigarette-related statements was analyzed by logistic regression analysis. RESULTS: Among 1028 medical staff in the respiratory departments of Fujian Province, 90.5% of medical staff agreed that electronic cigarettes are harmful to the human body; 61.4% of medical staff agreed that e-cigarettes cannot be regarded as a type of smoking cessation treatment; 71.7% of medical staff agreed that e-cigarettes could be a 'gateway' to other tobacco use; and 69.2% of medical staff agreed that electronic cigarettes are in 'Three No' states. The multivariate logistic regression analysis showed that the respondents' perception of 'e-cigarettes cannot be regarded as a type of smoking cessation treatment' were related to gender, professional title and whether they participated in the cessation clinic. CONCLUSIONS: The medical staff of the respiratory department in Fujian Province put more emphasis on the adverse effects of e-cigarettes on health, but lack the cognition of the effect of e-cigarette smoking cessation. In order to better carry out smoking cessation work, it is necessary to strengthen the training of respiratory medical staff at all levels of medical institutions on e-cigarette knowledge.

Construction of an immune-related lncRNA signature pair for predicting oncologic outcomes and the sensitivity of immunosuppressor in treatment of lung adenocarcinoma.

BACKGROUND: Although immunotherapy has shown clinical activity in lung adenocarcinoma (LUAD), LUAD prognosis has been a perplexing problem. We aimed to construct an immune-related lncRNA pairs (IRLPs) score for LUAD and identify what immunosuppressor are appropriate for which group of people with LUAD. METHODS: Based on The Cancer Genome Atlas (TCGA)-LUAD cohort, IRLPs were identified to construct an IRLPs scoring system by Cox regression and validated in the Gene Expression Omnibus (GEO) dataset using log-rank test and the receiver operating characteristic curve (ROC). Next, we used spearman's correlation analysis, t-test, signaling pathways analysis and gene mutation analysis to explore immune and molecular characteristics in different IRLP subgroups. The "pRRophetic" package was used to predict the sensitivity of immunosuppressant. RESULTS: The IRLPs score was constructed based on eight IRLPs calculated as 2.12 × (MIR31HG|RRN3P2) + 0.43 × (NKX2-1-AS1|AC083949.1) + 1.79 × (TMPO-AS1|LPP-AS2) + 1.60 × (TMPO-AS1|MGC32805) + 1.79 × (TMPO-AS1|PINK1-AS) + 0.65 × (SH3BP5-AS1|LINC01137) + 0.51 × (LINC01004|SH3PXD2A-AS1) + 0.62 × (LINC00339|AGAP2-AS1). Patients with a lower IRLPs risk score had a better overall survival (OS) (Log-rank test P TCGA train dataset < 0.001, P TCGA test dataset = 0.017, P GEO dataset = 0.027) and similar results were observed in the AUCs of TCGA dataset and GEO dataset (AUC TCGA train dataset = 0.777, AUC TCGA test dataset = 0.685, AUC TCGA total dataset = 0.733, AUC GEO dataset = 0.680). Immune score (Cor = -0.18893, P < 0.001), stoma score (Cor = -0.24804, P < 0.001), and microenvironment score (Cor = -0.22338, P < 0.001) were significantly decreased in the patients with the higher IRLP risk score. The gene set enrichment analysis found that high-risk group enriched in molecular changes in DNA and chromosomes signaling pathways, and in this group the tumor mutation burden (TMB) was higher than in the low-risk group (P = 0.0015). Immunosuppressor methotrexate sensitivity was higher in the high-risk group (P = 0.0052), whereas parthenolide (P < 0.001) and rapamycin (P = 0.013) sensitivity were lower in the high-risk group. CONCLUSIONS: Our study established an IRLPs scoring system as a biomarker to help in the prognosis, the identification of molecular and immune characteristics, and the patient-tailored selection of the most suitable immunosuppressor for LUAD therapy.

Immune-Related Molecular Profiling of Thymoma With Myasthenia Gravis.

Background: Approximately 50% of thymoma patients also show myasthenia gravis (MG), which is an autoimmune disease; however, the pathogenesis of MG-associated thymoma remains elusive. Our aim was to investigate immune-related lncRNA profiles of a set of candidate genes for better understanding of the molecular mechanism underlying the pathogenesis of thymoma with or without MG. Methods: Molecular profiles of thymoma with or without MG were downloaded from The Cancer Genome Atlas, and Pearson's correlation analysis was performed to identify immune-related lncRNAs. T test was used to examine the differential expression and differential methylation between thymoma patients with or without MG. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the function of target genes of immune-related lncRNAs. Results: Analyses of the 87 thymoma samples with complete MG information revealed that 205 mRNAs and 56 lncRNAs showed up-regulated expression in thymoma with MG patients, while 458 mRNAs and 84 lncRNAs showed down-regulated expression. The methylation level of three immune-related lncRNAs (AP000787.1, AC004943.1, WT1-AS, FOXG1-AS1) was significantly decreased in thymoma tissues, and the methylation level of these immune-related lncRNAs (WT1-AS: Cor = 0.368, p < 0.001; FOXG1-AS1: Cor = 0.288, p < 0.01; AC004943.1: Cor = -0.236, p < 0.05) correlated with their expression. GO and KEGG pathway analysis revealed that targets of the immune-related lncRNA FOXG1-AS1 were enriched in small GTPase binding and herpes simplex virus 1 infection. Transcription coregulator activity and cell cycle were the most enriched pathways for targets of lncRNA AC004943.1. LncRNA WT1-AS targets were most enriched in actin binding and axon guidance. Conclusion: Our results revealed the immune-related molecular profiling of thymoma with MG and without MG and identified key pathways involved in the underlying molecular mechanism of thymoma-related MG. These findings provide insights for further research of potential markers for thymoma-related MG.

Overexpression of close homolog of L1 enhances the chemosensitivity of lung cancer cells via inhibition of the Akt pathway.

Drug resistance leads to tumor relapse and further progression during chemotherapy in lung cancer. Close homolog of L1 (CHL1) has been identified as a tumor suppressor in most malignancies. However, to the best of our knowledge, whether CHL1 mediates chemoresistance remains unknown. The present study observed that CHL1 was significantly downregulated in cisplatin (DDP)-resistant cells (A549/DDP) and paclitaxel (PTX)-resistant cells (A549/PTX) compared with A549 cells. When treated with or without DDP and PTX, silencing of CHL1 in A549 cells promoted the cell survival rate and clone formation, and decreased apoptosis. Whereas overexpression of CHL1 in A549/DDP and A549/PTX cells impeded the cell survival and clone formation and promoted apoptosis. Additionally, CHL1 overexpression enhanced the chemosensitivity of A549/DDP cells to DDP in vivo. Notably, the chemoresistance induced by CHL1 depletion was reversed by the Akt inhibitor SC66 in A549 cells. The results of the present study demonstrated that CHL1 enhanced sensitivity of lung cancer cells by suppressing the Akt pathway, which suggested that CHL1 may be a potential target for overcoming chemoresistance in lung cancer.

Outcomes and Adverse Effects of Deep Brain Stimulation on the Ventral Intermediate Nucleus in Patients with Essential Tremor.

Objective: This study was aimed at identifying the potential outcome predictors, comparing the efficacy in patients with different tremor characteristics, and summarizing the adverse effect rates (AERs) of deep brain stimulation on the ventral intermediate nucleus (VIM-DBS) for essential tremor (ET). Methods: An extensive search of articles published to date in 2019 was conducted, and two main aspects were analyzed. Improvement was calculated as a percentage of change in any objective tremor rating scale (TRS) and analyzed by subgroup analyses of patients' tremor characteristics, laterality, and stimulation parameters. Furthermore, the AERs were analyzed as follows: the adverse effects (AEs) were classified as stimulation-related, surgical-related, or device-related effects. A simple regression analysis was used to identify the potential prognostic factors, and a two-sample mean-comparison test was used to verify the statistical significance of the subgroup analyses. Results: Forty-six articles involving 1714 patients were included in the meta-analysis. The pooled improvement in any objective TRS score was 61.3% (95% CI: 0.564-0.660) at the mean follow-up visit (20.0 ± 17.3 months). The midline and extremity symptoms showed consistent improvement (P = 0.440), and the results of the comparison of postural and kinetic tremor were the same (P = 0.219). In addition, the improvement in rest tremor was similar to that in action tremor (OR = 2.759, P = 0.120). In the simple regression analysis, the preoperative Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS) scores and follow-up time were negatively correlated with the percentage change in any objective TRS score (P < 0.05). The most common adverse event was dysarthria (10.5%), which is a stimulation-related AE (23.6%), while the rates of the surgical-related and device-related AEs were 6.4% and 11.5%, respectively. Conclusion: VIM-DBS is an efficient and safe surgical method in ET, and the efficacy was not affected by the body distribution of tremor, age at surgery, and disease duration. Lower preoperative FTM-TRS scores likely indicate greater improvement, and the effect of VIM-DBS declines over time.

Effect of fat particle-to-SVF ratio on graft survival rates in rabbits.

OBJECTIVE: This study aimed to compare the graft survival rates of various ratios of fat particles to stromal vascular fraction (SVF) in rabbits. METHODS: Fifteen purebred white rabbits of the same brood were used. In the study, the grafts of equal weight (0.8 g) were mixtures of fat particles with various proportions of SVF (1/3, 1/4, 1/5, and 1/6) to form 4 treated groups (I, II, III, and IV), whereas merely fat particles formed 1 control group. They were randomly autoimplanted into subcutaneous pockets on both sides of the dorsal midlines of the rabbits. Animals were killed 3 months after surgery. The grafts were harvested and weighed. Comparisons were performed between the groups for survival rates. RESULTS: The treated group II (fat particle-to-SVF ratio was 3:1) revealed the greatest weight maintenance in all of the groups, showing the greatest survival rate [87.94% (1.30%), P < 0.01 or P < 0.05]. CONCLUSIONS: It was suggested that the optimal fat particle-to-SVF ratio might be 3:1, with a low resorption rate.

Effect of ASCs on the graft survival rates of fat particles in rabbits.

This study was conducted to explore the effect of adipose-derived stem cells (ASCs) on the graft survival rates of fat particles in rabbits. Six domestic rabbits were used for a 3-month study; 1.4 grams of fat tissues were harvested from the bilateral inguinal regions of each animal. They were cut into granules and divided into three parts (A = 0.4 g, B = 0.4 g, and C = 0.6 g). Part A was centrifuged after 0.075% collagenase digestion for isolation of the stromal vascular fraction (SVF). About 0.2 grams of SVF containing ASCs was obtained, and then incorporated with part B to create a treated group, whereas part C was treated as a control group. The tissues in both groups were randomly transplanted into a subcutaneous space that had been created on each side of the dorsal midline of the rabbit. The grafts were taken out after 3 months for calculation of the survival rates. The graft survival rate in the treated group was 23.56 ± 2.49%, while that in the control group was 11.06 ± 2.10%. The graft survival rate in the treated group increased significantly, compared with in the control group (p < 0.01). Improved transplantation effects may be obtained by implanting the fat particles mixed with ASCs. It is suggested that this approach has the potential for becoming a new method of fat graft in clinical practice.

[Proliferation of the mesenchymal stem cells in a delayed fat flap: an experimental study in rabbits].

OBJECTIVE: To investigate the possibility to enhance the proliferation of adipose-derived stem cells (ASCs) in a delayed fat flap in rabbits. METHODS: A delayed fat flap was formed in one side of inguinal region of a rabbit. 21 days after operation, the fat tissues at the delayed flaps and at the unoperated side were harvested and digested with 0.25% collagenase and sieved. The cell suspensions were centrifuged. The cells were obtained from tissue precipitate after centrifugation. The expression rates of the surface marker (CD29, CD44, CD14 and CD45) were measured by FCM and compared between the experimental and control groups. RESULTS: Expression rates of CD29 and CD44 were higher in the delayed fat flap (74.06% and 90.74%) than in the contralateral fat tissue (62.88% and 77.54%, P < 0.05), while those of CD14 and CD45 were lower in the delayed fat flap (57.66% and 4.84%) than in the contralateral fat tissue (72.10% and 75.82%, P < 0.05 and P < 0.01). CONCLUSIONS: Tissue hypoxic ischemia such as fat tissue in a delayed fat flap can promote proliferation of ASCs. It indicates that tissue in the delayed flap may be transplanted with better survival rate. The ischemia pretreatment of fat tissue may become a new method for fat transplantation.