Background While Nordic hamstring exercise(NHE)training has been shown to reduce hamstring strains,the muscle-specific adaptations to NHE across the 4 hamstrings remain unclear.This study investigates architectural an...Background While Nordic hamstring exercise(NHE)training has been shown to reduce hamstring strains,the muscle-specific adaptations to NHE across the 4 hamstrings remain unclear.This study investigates architectural and microstructural adaptations of the biceps femoris short head(BFsh),biceps femoris long head(BFlh),semitendinosus(ST),and semimembranosus(SM)in response to an NHE intervention.Methods Eleven subjects completed 9 weeks of supervised NHE training followed by 3 weeks of detraining.Magnetic resonance imaging was performed at pre-training,post-training,and detraining to assess architectural(volume,fiber tract length,and fiber tract angle)and microstructural(axial(AD),mean(MD),radial(RD)diffusivities,and fractional anisotropy(FA))parameters of the 4 hamstrings.Results NHE training induced significant but non-uniform hamstring muscle hypertrophy(BFsh:22%,BFlh:9%,ST:26%,SM:6%)and fiber tract length increase(BFsh:11%,BFlh:7%,ST:18%,SM:10%).AD(5%),MD(4%),and RD(5%)showed significant increases,but fiber tract angle and FA remained unchanged.After detraining,only ST showed a significant reduction(8%)in volume,which remained higher than the pre-training value.While fiber tract lengths returned to baseline,AD,MD,and RD remained higher than pre-training levels for all hamstrings.Conclusion The 9-week NHE training substantially increased hamstring muscle volume with greater hypertrophy in ST and BFsh.Hypertrophy was accompanied by increases in fiber tract lengths and cross-sections(increased RD).After 3 weeks of detraining,fiber tract length gains across all hamstrings declined,emphasizing the importance of sustained training to maintain all the protective adaptations.展开更多
Objective: To develop and validate a computed tomography(CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2(HER2) status in patients with gastric cancer.Methods: This retrospective st...Objective: To develop and validate a computed tomography(CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2(HER2) status in patients with gastric cancer.Methods: This retrospective study included 134 patients with gastric cancer(HER2-negative: n=87;HER2-positive: n=47) from April 2013 to March 2018, who were then randomly divided into training(n=94) and validation(n=40) cohorts. Radiomics features were obtained from the CT images showing gastric cancer. Least absolute shrinkage and selection operator(LASSO) regression analysis was utilized for building the radiomics signature. A multivariable logistic regression method was applied to develop a prediction model incorporating the radiomics signature and independent clinicopathologic risk predictors, which were then visualized as a radiomics nomogram. The predictive performance of the nomogram was assessed in the training and validation cohorts.Results: The radiomics signature was significantly associated with HER2 status in both training(P<0.001) and validation(P=0.023) cohorts. The prediction model that incorporated the radiomics signature and carcinoembryonic antigen(CEA) level demonstrated good discriminative performance for HER2 status prediction,with an area under the curve(AUC) of 0.799 [95% confidence interval(95% CI): 0.704-0.894] in the training cohort and 0.771(95% CI: 0.607-0.934) in the validation cohort. The calibration curve of the radiomics nomogram also showed good calibration. Decision curve analysis showed that the radiomics nomogram was useful.Conclusions: We built and validated a radiomics nomogram with good performance for HER2 status prediction in gastric cancer. This radiomics nomogram could serve as a non-invasive tool to predict HER2 status and guide clinical treatment.展开更多
Background:Traumatic brain injury can be caused by head impacts,but many brain injury risk estimation models are not equally accurate across the variety of impacts that patients may undergo,and the characteristics of ...Background:Traumatic brain injury can be caused by head impacts,but many brain injury risk estimation models are not equally accurate across the variety of impacts that patients may undergo,and the characteristics of different types of impacts are not well studied.We investigated the spectral characteristics of different head impact types with kinematics classification.Methods:Data were analyzed from 3262 head impacts from lab reconstruction,American football,mixed martial arts,and publicly available car crash data.A random forest classifier with spectral densities of linear acceleration and angular velocity was built to classify head impact types(e.g.,football,car crash,mixed martial arts).To test the classifier robustness,another 271 lab-reconstructed impacts were obtained from 5 other instrumented mouthguards.Finally,with the classifier,type-specific,nearest-neighbor regression models were built for brain strain.Results:The classifier reached a median accuracy of 96% over 1000 random partitions of training and test sets.The most important features in the classification included both low-and high-frequency features,both linear acceleration features and angular velocity features.Different head impact types had different distributions of spectral densities in low-and high-frequency ranges(e.g.,the spectral densities of mixed martial arts impacts were higher in the high-frequency range than in the low-frequency range).The type-specific regression showed a generally higher R2value than baseline models without classification.Conclusion:The machine-learning-based classifier enables a better understanding of the impact kinematics spectral density in different sports,and it can be applied to evaluate the quality of impact-simulation systems and on-field data augmentation.展开更多
AIM:To assess the efficacy and safety of non-penetrating deep sclerectomy(NPDS)with uveoscleral implant plus subconjunctival and intrascleral collagen matrix overcoming the superficial scleral flap lips(modified deep ...AIM:To assess the efficacy and safety of non-penetrating deep sclerectomy(NPDS)with uveoscleral implant plus subconjunctival and intrascleral collagen matrix overcoming the superficial scleral flap lips(modified deep sclerectomy technique,DS)and minimal use of mitomycin C in glaucoma surgery.METHODS:A retrospective review of 47 consecutive glaucoma patients who underwent NPDS with DS between January 2017 and May 2018.Best-corrected visual acuity,intraocular pressure(IOP),post-operative need for glaucoma medications,visual field mean deviation(MD),re-interventions,needling revisions and laser goniopuncture were noted.Absolute success was defined as IOP≤18 mm Hg without topical medication.Relative success was defined as the same criteria but with the addition of any antihypertensive medication.IOP over 18 mm Hg on two consecutive followup visits was considered as a failure.RESULTS:Fifty-two eyes of 47 patients were evaluated.Mean preoperative IOP was 25.37±6.47 mm Hg,and decreased to 15.04±4.73 at 12mo and 12.21±4.1 at 24mo(all P<0.0001).Requirement for topical medications dropped from a mean of 3.06±0.25 per patient to 0.51±0.99 and 1.11±1.23 respectively after 12 and 24mo(all P<0.0001).No medications were required in 45.5%of patients after 24mo.Relative and absolute success rate at 24mo were 85.5%±5%and 48.5%±7.4%,respectively.CONCLUSION:DS is a safe and effective nonpenetrating glaucoma surgery variation.It aims to retain the patency of all pathways created for aqueous humor drainage:the intrascleral bleb,the supraciliary space and the open communication between intrascleral and subconjunctival compartments.展开更多
背景与目的神经母细胞瘤(neuroblastoma,NB)是一种异质性疾病,伴有基因组畸变,且临床表现呈多样性。虽然我们对遗传畸变与临床特征之间的关系已有所了解,但对患者的预后预测和制订个体化治疗策略仍是挑战。本研究旨在建立一种有效的NB...背景与目的神经母细胞瘤(neuroblastoma,NB)是一种异质性疾病,伴有基因组畸变,且临床表现呈多样性。虽然我们对遗传畸变与临床特征之间的关系已有所了解,但对患者的预后预测和制订个体化治疗策略仍是挑战。本研究旨在建立一种有效的NB患者预后预测模型。方法我们整合了多种不同算法定义基因特征,反映MYCN活性和染色体畸变,包括染色体1p缺失(deletion of chromosome1p,Chr1p_del)、染色体11q缺失(deletion of chromosome 11q,Chr11q_del)以及染色体11q全部丢失(whole loss of chromosome 11q,Chr11q_wls)。我们评估了由RNA测序和微阵列平台产生的7个NB基因表达数据集(样本量从94到498,共2120)中这些基因特征的预后预测价值。结果MYCN活性评分是比MYCN扩增状态和表达更有效的预后标志物。同样,Chr1p_del评分是比Chr1p状态更好的预后标志物。MYCN、Chr1p_del和Chr11q_del的活性评分与预后不良相关,而Chr11q_wls评分与预后良好相关。我们整合MYCN、Chr1p_del、Chr11q_del和Chr11q_wls评分以及临床变量建立综合预测模型,该模型对NB预后预测效果比单独应用临床变量或每个基因组畸变更佳。结论加入了基因特征的预后预测模型显著提高了预测效果,可作为对NB患者进行分层以评估预后的生物标志物。展开更多
Lung cancer is a leading cause of cancer-related death worldwide,with a very poor overall five-year survival rate.The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used fo...Lung cancer is a leading cause of cancer-related death worldwide,with a very poor overall five-year survival rate.The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used for lung cancer have motivated the development of nanotechnology and nanomedicine approaches,in order to improve early diagnosis rate and develop more effective and safer therapeutic options for lung cancer.Cancer nanomedicines aim to individualize drug delivery,diagnosis,and therapy by tailoring them to each patient’s unique physiology and pathological features—on both the genomic and proteomic levels—and have attracted widespread attention in this field.Despite the successful application of nanomedicine techniques in lung cancer research,the clinical translation of nanomedicine approaches remains challenging due to the limited understanding of the interactions that occur between nanotechnology and biology,and the challenges posed by the toxicology,pharmacology,immunology,and largescale manufacturing of nanoparticles.In this review,we highlight the progress and opportunities associated with nanomedicine use for lung cancer treatment and discuss the prospects of this field,together with the challenges associated with clinical translation.展开更多
Objective:To assess efficacy of Chinese medicine(CM)on insomnia considering characteristics of treatment based on syndrome differentiation.Methods:A total of 116 participants aged 18 to 65 years with moderate and seve...Objective:To assess efficacy of Chinese medicine(CM)on insomnia considering characteristics of treatment based on syndrome differentiation.Methods:A total of 116 participants aged 18 to 65 years with moderate and severe primary insomnia were randomized to the placebo(n=20)or the CM group(n=96)for a 4-week treatment and a 4-week follow-up.Three CM clinicians independently prescribed treatments for each patient based on syndromes differentiation.The primary outcome was change in total sleep time(TST)from baseline.Secondary endpoints included sleep onset latency(SOL),wake time after sleep onset(WASO),sleep efficiency,Pittsburgh Sleep Quality Index(PSQI)and CM symptoms.Results:The CM group had an average 0.6 h more(95%confidence interval(CI):0.3–0.9,P<0.001)TST and 34.1%(10.3%–58.0%,P=0.005)more patients beyond 0.5 h TST increment than that of the placebo group.PSQI was changed–3.3(–3.8 to–2.7)in the CM group,a–2.0(–3.2 to–0.8,P<0.001)difference from the placebo group.The CM symptom score in the CM group decreased–2.0(–3.3 to–0.7,P=0.003)more than the placebo group.SOL and WASO changes were not significantly different between groups.The analysis of prescriptions by these clinicians revealed blood deficiency and Liver stagnation as the most common syndromes.Prescriptions for these clinicians displayed relative stability,while the herbs varied.All adverse events were mild and were not related to study treatment.Conclusions:CM treatment based on syndrome differentiation can increase TST and improve sleep quality of primary insomnia.It is effective and safe for primary insomnia.In future studies,the long-term efficacy validation and the exploratory of eutherapeutic clinicians'fixed herb formulas should be addressed.(Registration No.NCT01613183).展开更多
Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observation...Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands.Adult patients(aged≥18 years)who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries(polytrauma,as defined by Injury Severity Scores of≥16)caused by blunt trauma were eligible for inclusion.Partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition(mod-ified Nutrition Risk in Critically Ill score).Malnutrition was diagnosed based on Subjective Global Assessment scores.The relationship of lipoprotein properties and small metabolite concentrations with malnutrition(during ICU admission)was evaluated using mixed effects logistic regression.Results:Overall,51 patients were included.Lower(very)low-density lipoprotein([V]LDL)(free)cholesterol and phospholipid levels,low particle number,and higher levels of LDL triglycerides were associated with a higher risk of malnutrition(variable importance in projection[VIP]value>1.5).Low levels of most(V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition(VIP value>1.5).Increased levels of dimethyl sulfone,trimethylamine N-oxide,creatinine,N,N-dimethylglycine,and pyruvic acid and decreased levels of creatine,methionine,and acetoacetic acid were also indicative of malnutrition(VIP value>1.5).Overall,14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission(P<0.05);however,the association did not persist after correcting the false discovery rate(P=0.35 for all).Conclusion:Increased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites(involved in the homocysteine cycle,ketone body formation,and muscle metabolism)may be indicative of malnutrition risk.Following validation in larger cohorts,these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.展开更多
This article is a call to action to address escalating threats to scientific progress that affect academic researchers across the globe.These threats include public mistrust of science,challenges in translating academ...This article is a call to action to address escalating threats to scientific progress that affect academic researchers across the globe.These threats include public mistrust of science,challenges in translating academic research to end-user applications,a disconnect between academics and policymakers,emerging barriers to international collaboration,and a reliance on conventional metrics to evaluate academic performance.This article presents various calls to action informed by exemplary approaches across the globe that serve as frameworks to drive beneficial transformation for researchers,academic institutions,and society.展开更多
Ovo-like transcriptional repressor 1(OVOL1)is a key mediator of epithelial lineage determination and mesenchymal–epithelial transition(MET).The cytokines transforming growth factor-β(TGF-β)and bone morphogenetic pr...Ovo-like transcriptional repressor 1(OVOL1)is a key mediator of epithelial lineage determination and mesenchymal–epithelial transition(MET).The cytokines transforming growth factor-β(TGF-β)and bone morphogenetic proteins(BMP)control the epithelial–mesenchymal plasticity(EMP)of cancer cells,but whether this occurs through interplay with OVOL1 is not known.Here,we show that OVOL1 is inversely correlated with the epithelial–mesenchymal transition(EMT)signature,and is an indicator of a favorable prognosis for breast cancer patients.OVOL1 suppresses EMT.展开更多
Although the role of cathepsin C (Cat C) in inflammation is gradually being elucidated, its function in periapical periodontitis, which is one of the most common infectious diseases worldwide, has not been studied. Th...Although the role of cathepsin C (Cat C) in inflammation is gradually being elucidated, its function in periapical periodontitis, which is one of the most common infectious diseases worldwide, has not been studied. This study evaluated a surgically-induced model of periapical periodontitis in cathepsin C (Cat C) knock-down (KD) mice, which was constructed with a tetracycline operator, to evaluate the role of Cat C in the pathogenesis and progression of periapical periodontitis. Our results showed, for the first time, that there was a statistically significant increase in the expression of Cat C as periapical periodontitis progressed;this increase started from 1 week after surgery and reached a peak at 3 weeks after surgery, before gradually decreasing. The volume of periapical bone resorption in Cat C KD mice was significantly smaller than that in wild-type mice at 3 and 4 weeks after surgery (P<0.05). Inflammatory cell infiltration into the apical tissues of wild-type mice was also significantly higher than that of Cat C KD mice. The expression of receptor activator of nuclear factor-j B ligand (RANKL) in wild-type mice was also higher than that in Cat C KD mice. The difference in the number of osteoclasts in the apical area between the two groups was statistically significant after 2 weeks. Correlation analysis showed that there was a significant correlation between Cat C and RANKL expression (r= 0.835). Therefore, our data indicated that Cat C promoted the apical inflammation and bone destruction in mice.展开更多
Background:Plateau zokor inhabits in sealed burrows from 2,000 to 4,200 meters at Qinghai-Tibet Plateau.This extreme living env ironment makes it a great model to study animal adaptation to hypoxia,low temperature,and...Background:Plateau zokor inhabits in sealed burrows from 2,000 to 4,200 meters at Qinghai-Tibet Plateau.This extreme living env ironment makes it a great model to study animal adaptation to hypoxia,low temperature,and high carbon dioxide concentration.Methods:We provide an integrated resource,ZokorDB,for tissue specific regulatory network annotation for zokor.ZokorDB is based on a high-quality draft genome of a plateau zokor at 3,300 m and its transcriptional profiles in brain,heart,liver,kidney,and lung.The conserved non-coding elements of zokor are annotated by their nearest genes and upstream transcriptional factor motif binding sites.Results:ZokorDB provides a general draft gene regulatory network(GRN),Le?potential transcription factor(TF)binds to non-coding regulatory elements and regulates the expression of target genes(TG).Furthermore,we refined the GRN by incorporating matched RNA-seq and DNase-seq data from mouse ENCODE project and reconstructed five tissue-specific regulatory networks.Conclusions:A web-based,open-access database is developed for easily searching,visualizing,and downloading the annotation and data.The pipeline of non-coding region annotation for zokor will be useful for other non-model species.ZokorDB is free available at the website(bigd.big.ac.cn/zokordb/).展开更多
Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than...Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to T0.Therefore,it is still unclear which calcineurin inhibitor is preferred after LT.We aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first LT.Methods:Patients after first LT were randomized to C2 or T0.tBPAR,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank test.Results:In intention-totreat analysis 84 patients on C2 and 85 on T0 were included.Cumulative incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with C2.Incidence of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and tolerability.Conclusions:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.展开更多
The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into...The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network(CNEReg)to investigate the ruminant multi-chambered stomach innovation.We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep,and revealed 1601 active ruminantspecific conserved non-coding elements(active-RSCNEs).To interpret the function of these activeRSCNEs,we defined toolkit transcription factors(TTFs)and modeled their regulation on rumenspecific genes via batteries of active-RSCNEs during development.Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules.Notably,6 TTFs(OTX1,SOX21,HOXC8,SOX2,TP63,and PPARG),as well as 16 active-RSCNEs,functionally distinguished the rumen from the esophagus.Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.展开更多
Aim:Neuroblastoma is the most common extracranial solid tumor in children.Recent advances in immunotherapy Approaches,including in neuroblastoma,have shown the important role of the immune system in mounting an effect...Aim:Neuroblastoma is the most common extracranial solid tumor in children.Recent advances in immunotherapy Approaches,including in neuroblastoma,have shown the important role of the immune system in mounting an effective anti-tumor response.In this study,we aimed to provide a comprehensive investigation of immune cell infiltration in neuroblastoma utilizing a large number of gene expression datasets.Methods:We inferred immune cell infiltration using an established immune inference method and evaluated the association between immune cell abundance and patient prognosis as well as common chromosomal abnormalities found in neuroblastoma.In addition,we evaluated co-infiltration patterns among distinct immune cell types.Results:The infiltration of naïve B cells,NK cells,and CD8+T cells was associated with improved patient prognosis.Naïve B cells were the most consistent indicator of prognosis and associated with an active immune tumor microenvironment.Patients with high B cell infiltration showed high co-infiltration of other immune cell types and the enrichment of immune-related pathways.The presence of high B cell infiltration was associated with both recurrence-free and overall survival,even after adjusting for clinical variables.Conclusion:In this study,we have provided a comprehensive evaluation of immune cell infiltration in neuroblastoma using gene expression data.We propose an important role for B cells in the neuroblastoma tumor microenvironment and suggest that B cells can be used as a prognostic biomarker to predict recurrence-free and overall survival independently of currently utilized prognostic variables.展开更多
Background:Neuroblastoma(NB)is a heterogeneous disease with respect to genomic abnormalities and clinical behaviors.Despite recent advances in our understanding of the association between the genetic aberrations and c...Background:Neuroblastoma(NB)is a heterogeneous disease with respect to genomic abnormalities and clinical behaviors.Despite recent advances in our understanding of the association between the genetic aberrations and clinical features,it remains one of the major challenges to predict prognosis and stratify patients for determining personalized therapy in this disease.The aim of this study was to develop an effective prognosis prediction model for NB patients.Methods:We integrated diverse computational analyses to define gene signatures that reflect MYCN activity and chromosomal aberrations including deletion of chromosome 1p(Chr1p_del)and chromosome 11q(Chr11q_del)as well as chromosome 11q whole loss(Chr11q_wls).We evaluated the prognostic and predictive values of these signatures in seven NB gene expression datasets(the number of samples ranges from 94 to 498,with a total of 2120)generated from both RNA sequencing and microarray platforms.Results:MYCN signature was a more effective prognostic marker than MYCN amplification status and MYCN expression.Similarly,the Chr1p_del score was more prognostic than Chr1p status.The activity scores of MYCN,Chr1p_del and Chr11q_del were associated with poor prognosis,while the Chr11q_wls score was linked to good outcome.We integrated the activity scores of MYCN,Chr1p_del,Chr11q_del,and Chr11q_wls and clinical variables into an integrative prognostic model,which displayed significant performance over the clinical variables or each genomic aberration alone.Conclusions:Our integrative gene signature model shows a significantly improved forecast performance with prognostic and predictive information,and thereby can be served as a biomarker to stratify NB patients for prognosis evaluation and surveillance programs.展开更多
基金financial support from the general electric (GE) healthcareAustralian Research Council Discovery Project (DP200101476)+5 种基金in parts by National Institutes of Health (NIH) grants (R01 AR077604, R01 EB002524, R01 AR079431, P41 EB02706)Stanford Graduate FellowshipThe University of Queensland Graduate ScholarshipNational Health and Medical Research Council of Australia Fellowship (#1194937)Wu Tsai Human Performance Alliance at Stanford Universitythe Joe and Clara Tsai Foundation
文摘Background While Nordic hamstring exercise(NHE)training has been shown to reduce hamstring strains,the muscle-specific adaptations to NHE across the 4 hamstrings remain unclear.This study investigates architectural and microstructural adaptations of the biceps femoris short head(BFsh),biceps femoris long head(BFlh),semitendinosus(ST),and semimembranosus(SM)in response to an NHE intervention.Methods Eleven subjects completed 9 weeks of supervised NHE training followed by 3 weeks of detraining.Magnetic resonance imaging was performed at pre-training,post-training,and detraining to assess architectural(volume,fiber tract length,and fiber tract angle)and microstructural(axial(AD),mean(MD),radial(RD)diffusivities,and fractional anisotropy(FA))parameters of the 4 hamstrings.Results NHE training induced significant but non-uniform hamstring muscle hypertrophy(BFsh:22%,BFlh:9%,ST:26%,SM:6%)and fiber tract length increase(BFsh:11%,BFlh:7%,ST:18%,SM:10%).AD(5%),MD(4%),and RD(5%)showed significant increases,but fiber tract angle and FA remained unchanged.After detraining,only ST showed a significant reduction(8%)in volume,which remained higher than the pre-training value.While fiber tract lengths returned to baseline,AD,MD,and RD remained higher than pre-training levels for all hamstrings.Conclusion The 9-week NHE training substantially increased hamstring muscle volume with greater hypertrophy in ST and BFsh.Hypertrophy was accompanied by increases in fiber tract lengths and cross-sections(increased RD).After 3 weeks of detraining,fiber tract length gains across all hamstrings declined,emphasizing the importance of sustained training to maintain all the protective adaptations.
基金supported by the National Key Research and Development Program of China (No. 2017YFC1309100)National Natural Scientific Foundation of China (No. 81771912, 81601469, and 81701782)+1 种基金the Science and Technology Planning Project of Guangdong Province (No. 2017B020227012)the Science and Technology Planning Project of Guangzhou (No. 20191A011002).
文摘Objective: To develop and validate a computed tomography(CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2(HER2) status in patients with gastric cancer.Methods: This retrospective study included 134 patients with gastric cancer(HER2-negative: n=87;HER2-positive: n=47) from April 2013 to March 2018, who were then randomly divided into training(n=94) and validation(n=40) cohorts. Radiomics features were obtained from the CT images showing gastric cancer. Least absolute shrinkage and selection operator(LASSO) regression analysis was utilized for building the radiomics signature. A multivariable logistic regression method was applied to develop a prediction model incorporating the radiomics signature and independent clinicopathologic risk predictors, which were then visualized as a radiomics nomogram. The predictive performance of the nomogram was assessed in the training and validation cohorts.Results: The radiomics signature was significantly associated with HER2 status in both training(P<0.001) and validation(P=0.023) cohorts. The prediction model that incorporated the radiomics signature and carcinoembryonic antigen(CEA) level demonstrated good discriminative performance for HER2 status prediction,with an area under the curve(AUC) of 0.799 [95% confidence interval(95% CI): 0.704-0.894] in the training cohort and 0.771(95% CI: 0.607-0.934) in the validation cohort. The calibration curve of the radiomics nomogram also showed good calibration. Decision curve analysis showed that the radiomics nomogram was useful.Conclusions: We built and validated a radiomics nomogram with good performance for HER2 status prediction in gastric cancer. This radiomics nomogram could serve as a non-invasive tool to predict HER2 status and guide clinical treatment.
基金supported by the Pac-12 Conference’s Student-Athlete Health and Well-Being Initiative,the National Institutes of Health (R24NS098518)Stanford Department of Bioengineering。
文摘Background:Traumatic brain injury can be caused by head impacts,but many brain injury risk estimation models are not equally accurate across the variety of impacts that patients may undergo,and the characteristics of different types of impacts are not well studied.We investigated the spectral characteristics of different head impact types with kinematics classification.Methods:Data were analyzed from 3262 head impacts from lab reconstruction,American football,mixed martial arts,and publicly available car crash data.A random forest classifier with spectral densities of linear acceleration and angular velocity was built to classify head impact types(e.g.,football,car crash,mixed martial arts).To test the classifier robustness,another 271 lab-reconstructed impacts were obtained from 5 other instrumented mouthguards.Finally,with the classifier,type-specific,nearest-neighbor regression models were built for brain strain.Results:The classifier reached a median accuracy of 96% over 1000 random partitions of training and test sets.The most important features in the classification included both low-and high-frequency features,both linear acceleration features and angular velocity features.Different head impact types had different distributions of spectral densities in low-and high-frequency ranges(e.g.,the spectral densities of mixed martial arts impacts were higher in the high-frequency range than in the low-frequency range).The type-specific regression showed a generally higher R2value than baseline models without classification.Conclusion:The machine-learning-based classifier enables a better understanding of the impact kinematics spectral density in different sports,and it can be applied to evaluate the quality of impact-simulation systems and on-field data augmentation.
文摘AIM:To assess the efficacy and safety of non-penetrating deep sclerectomy(NPDS)with uveoscleral implant plus subconjunctival and intrascleral collagen matrix overcoming the superficial scleral flap lips(modified deep sclerectomy technique,DS)and minimal use of mitomycin C in glaucoma surgery.METHODS:A retrospective review of 47 consecutive glaucoma patients who underwent NPDS with DS between January 2017 and May 2018.Best-corrected visual acuity,intraocular pressure(IOP),post-operative need for glaucoma medications,visual field mean deviation(MD),re-interventions,needling revisions and laser goniopuncture were noted.Absolute success was defined as IOP≤18 mm Hg without topical medication.Relative success was defined as the same criteria but with the addition of any antihypertensive medication.IOP over 18 mm Hg on two consecutive followup visits was considered as a failure.RESULTS:Fifty-two eyes of 47 patients were evaluated.Mean preoperative IOP was 25.37±6.47 mm Hg,and decreased to 15.04±4.73 at 12mo and 12.21±4.1 at 24mo(all P<0.0001).Requirement for topical medications dropped from a mean of 3.06±0.25 per patient to 0.51±0.99 and 1.11±1.23 respectively after 12 and 24mo(all P<0.0001).No medications were required in 45.5%of patients after 24mo.Relative and absolute success rate at 24mo were 85.5%±5%and 48.5%±7.4%,respectively.CONCLUSION:DS is a safe and effective nonpenetrating glaucoma surgery variation.It aims to retain the patency of all pathways created for aqueous humor drainage:the intrascleral bleb,the supraciliary space and the open communication between intrascleral and subconjunctival compartments.
基金Amer ican Cancer Societ y(No.IRG-82-003-30)National Center for Advancing Translational Sciences of the National Institutes of Health(No.KL2TR001088)国家自然科学基金(No.81201543)的支持。
文摘背景与目的神经母细胞瘤(neuroblastoma,NB)是一种异质性疾病,伴有基因组畸变,且临床表现呈多样性。虽然我们对遗传畸变与临床特征之间的关系已有所了解,但对患者的预后预测和制订个体化治疗策略仍是挑战。本研究旨在建立一种有效的NB患者预后预测模型。方法我们整合了多种不同算法定义基因特征,反映MYCN活性和染色体畸变,包括染色体1p缺失(deletion of chromosome1p,Chr1p_del)、染色体11q缺失(deletion of chromosome 11q,Chr11q_del)以及染色体11q全部丢失(whole loss of chromosome 11q,Chr11q_wls)。我们评估了由RNA测序和微阵列平台产生的7个NB基因表达数据集(样本量从94到498,共2120)中这些基因特征的预后预测价值。结果MYCN活性评分是比MYCN扩增状态和表达更有效的预后标志物。同样,Chr1p_del评分是比Chr1p状态更好的预后标志物。MYCN、Chr1p_del和Chr11q_del的活性评分与预后不良相关,而Chr11q_wls评分与预后良好相关。我们整合MYCN、Chr1p_del、Chr11q_del和Chr11q_wls评分以及临床变量建立综合预测模型,该模型对NB预后预测效果比单独应用临床变量或每个基因组畸变更佳。结论加入了基因特征的预后预测模型显著提高了预测效果,可作为对NB患者进行分层以评估预后的生物标志物。
基金supported in part by a grant(GM108337)from the National Institutes of Health and the National Science Foundation(Tang and Tu)a pilot grant(UR-CTSI GR500208)from the Clinical and Translational Sciences Institute at the University of Rochester Medical Center(Feng and Tu)
基金This work was supported by the National Program on Key Basic Research Project(2020YFA0211100)National Natural Science Foundation of China(51872205,51922077,and 81602412)+3 种基金Fundamental Research Funds for the Central Universities,Training Plan of Outstanding Young Medical Talents,Shanghai Municipal Commission of Health and Family Planning(2017YQ050)Scientific Research Project of Shanghai Municipal Commission of Health and Family Planning(2016Y0121)Natural Scientific Foundation of Shanghai(134119b1002)Outstanding Young Scientific Researcher of Shanghai Pulmonary Hospital.
文摘Lung cancer is a leading cause of cancer-related death worldwide,with a very poor overall five-year survival rate.The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used for lung cancer have motivated the development of nanotechnology and nanomedicine approaches,in order to improve early diagnosis rate and develop more effective and safer therapeutic options for lung cancer.Cancer nanomedicines aim to individualize drug delivery,diagnosis,and therapy by tailoring them to each patient’s unique physiology and pathological features—on both the genomic and proteomic levels—and have attracted widespread attention in this field.Despite the successful application of nanomedicine techniques in lung cancer research,the clinical translation of nanomedicine approaches remains challenging due to the limited understanding of the interactions that occur between nanotechnology and biology,and the challenges posed by the toxicology,pharmacology,immunology,and largescale manufacturing of nanoparticles.In this review,we highlight the progress and opportunities associated with nanomedicine use for lung cancer treatment and discuss the prospects of this field,together with the challenges associated with clinical translation.
基金Supported by the National Natural Science Foundation of China(No.81973713 and No.81303149)。
文摘Objective:To assess efficacy of Chinese medicine(CM)on insomnia considering characteristics of treatment based on syndrome differentiation.Methods:A total of 116 participants aged 18 to 65 years with moderate and severe primary insomnia were randomized to the placebo(n=20)or the CM group(n=96)for a 4-week treatment and a 4-week follow-up.Three CM clinicians independently prescribed treatments for each patient based on syndromes differentiation.The primary outcome was change in total sleep time(TST)from baseline.Secondary endpoints included sleep onset latency(SOL),wake time after sleep onset(WASO),sleep efficiency,Pittsburgh Sleep Quality Index(PSQI)and CM symptoms.Results:The CM group had an average 0.6 h more(95%confidence interval(CI):0.3–0.9,P<0.001)TST and 34.1%(10.3%–58.0%,P=0.005)more patients beyond 0.5 h TST increment than that of the placebo group.PSQI was changed–3.3(–3.8 to–2.7)in the CM group,a–2.0(–3.2 to–0.8,P<0.001)difference from the placebo group.The CM symptom score in the CM group decreased–2.0(–3.3 to–0.7,P=0.003)more than the placebo group.SOL and WASO changes were not significantly different between groups.The analysis of prescriptions by these clinicians revealed blood deficiency and Liver stagnation as the most common syndromes.Prescriptions for these clinicians displayed relative stability,while the herbs varied.All adverse events were mild and were not related to study treatment.Conclusions:CM treatment based on syndrome differentiation can increase TST and improve sleep quality of primary insomnia.It is effective and safe for primary insomnia.In future studies,the long-term efficacy validation and the exploratory of eutherapeutic clinicians'fixed herb formulas should be addressed.(Registration No.NCT01613183).
文摘Background:This study aimed to identify plasma lipoproteins and small metabolites associated with high risk of malnutrition during intensive care unit(ICU)stay in patients with severe injuries.Methods:This observational prospective exploratory study was conducted at two level-1 trauma centers in the Netherlands.Adult patients(aged≥18 years)who were admitted to the ICU for more than 48 h between July 2018 and April 2022 owing to severe injuries(polytrauma,as defined by Injury Severity Scores of≥16)caused by blunt trauma were eligible for inclusion.Partial least squares discriminant analysis was used to analyze the relationship of 112 lipoprotein-related components and 23 small metabolites with the risk of malnutrition(mod-ified Nutrition Risk in Critically Ill score).Malnutrition was diagnosed based on Subjective Global Assessment scores.The relationship of lipoprotein properties and small metabolite concentrations with malnutrition(during ICU admission)was evaluated using mixed effects logistic regression.Results:Overall,51 patients were included.Lower(very)low-density lipoprotein([V]LDL)(free)cholesterol and phospholipid levels,low particle number,and higher levels of LDL triglycerides were associated with a higher risk of malnutrition(variable importance in projection[VIP]value>1.5).Low levels of most(V)LDL and intermediate-density lipoprotein subfractions and high levels of high-density lipoprotein Apo-A1 were associated with the diagnosis of malnutrition(VIP value>1.5).Increased levels of dimethyl sulfone,trimethylamine N-oxide,creatinine,N,N-dimethylglycine,and pyruvic acid and decreased levels of creatine,methionine,and acetoacetic acid were also indicative of malnutrition(VIP value>1.5).Overall,14 lipoproteins and 1 small metabolite were significantly associated with a high risk of malnutrition during ICU admission(P<0.05);however,the association did not persist after correcting the false discovery rate(P=0.35 for all).Conclusion:Increased triglyceride in several lipoprotein subfractions and decreased levels of other lipoprotein subfraction lipids and several small metabolites(involved in the homocysteine cycle,ketone body formation,and muscle metabolism)may be indicative of malnutrition risk.Following validation in larger cohorts,these indicators may guide institution of preventive nutritional measures in patients admitted to the ICU with severe injuries.
基金funded by the Academy of Medical Sciences(UK)under award number SBF007\100176(R.Z.J.)UK Research and Innovation under award number MR/X032914/1(R.Z.J.)the Swiss National Science Foundation under award number PR00P3_185742(D.L.).
文摘This article is a call to action to address escalating threats to scientific progress that affect academic researchers across the globe.These threats include public mistrust of science,challenges in translating academic research to end-user applications,a disconnect between academics and policymakers,emerging barriers to international collaboration,and a reliance on conventional metrics to evaluate academic performance.This article presents various calls to action informed by exemplary approaches across the globe that serve as frameworks to drive beneficial transformation for researchers,academic institutions,and society.
基金We acknowledge the support of the Chinese Scholarship Council(CSC)to Chuannan Fan and Qian Wang,and the Cancer Genomics Centre in the Netherlands(CGC,NL)and the ZonMW grant(09120012010061)to Peter ten Dijke.We thank Maarten van Dinther and Martijn Rabelink for excellent technical assistance and Slobodan Vukicevic(University of Zagreb,Croatia),and Andrew Hinck(University of Pittsburgh,USA)for generously providing human recombinant BMP6 and TGF-β3,respectively.We acknowledge A.G.Jochemsen for providing the FH1tUTG vector.We are grateful to Midory Thorikay for help with testing effect of compounds on OVOL1 expression and checking the expression of OVOL1 in breast cancer cell lines,Jing Zhang for the help with GSEA,Sijia Liu for instructions on how to perform the zebrafish xenograft assay,and all other members in ten Dijke’s laboratory and Yuva Oz for their kind support.
文摘Ovo-like transcriptional repressor 1(OVOL1)is a key mediator of epithelial lineage determination and mesenchymal–epithelial transition(MET).The cytokines transforming growth factor-β(TGF-β)and bone morphogenetic proteins(BMP)control the epithelial–mesenchymal plasticity(EMP)of cancer cells,but whether this occurs through interplay with OVOL1 is not known.Here,we show that OVOL1 is inversely correlated with the epithelial–mesenchymal transition(EMT)signature,and is an indicator of a favorable prognosis for breast cancer patients.OVOL1 suppresses EMT.
基金This work was supported by the Open Research Fund Program of State Key Laboratory of Oral Disease,Sichuan Univeristy,China(SKLOD2019OF06).
文摘Although the role of cathepsin C (Cat C) in inflammation is gradually being elucidated, its function in periapical periodontitis, which is one of the most common infectious diseases worldwide, has not been studied. This study evaluated a surgically-induced model of periapical periodontitis in cathepsin C (Cat C) knock-down (KD) mice, which was constructed with a tetracycline operator, to evaluate the role of Cat C in the pathogenesis and progression of periapical periodontitis. Our results showed, for the first time, that there was a statistically significant increase in the expression of Cat C as periapical periodontitis progressed;this increase started from 1 week after surgery and reached a peak at 3 weeks after surgery, before gradually decreasing. The volume of periapical bone resorption in Cat C KD mice was significantly smaller than that in wild-type mice at 3 and 4 weeks after surgery (P<0.05). Inflammatory cell infiltration into the apical tissues of wild-type mice was also significantly higher than that of Cat C KD mice. The expression of receptor activator of nuclear factor-j B ligand (RANKL) in wild-type mice was also higher than that in Cat C KD mice. The difference in the number of osteoclasts in the apical area between the two groups was statistically significant after 2 weeks. Correlation analysis showed that there was a significant correlation between Cat C and RANKL expression (r= 0.835). Therefore, our data indicated that Cat C promoted the apical inflammation and bone destruction in mice.
基金ZokorDB is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB13000000)The authors are also supported by the National Natural Science Foundation of China(NSFC)(Nos.11871463,11871462,61671444 and 61621003)+1 种基金We thank all the lab members for discussions on data collection,genome alignment,annotation,GRN reconstructionWe thank Dr.Yilei Wu and his group for help on database design and management.
文摘Background:Plateau zokor inhabits in sealed burrows from 2,000 to 4,200 meters at Qinghai-Tibet Plateau.This extreme living env ironment makes it a great model to study animal adaptation to hypoxia,low temperature,and high carbon dioxide concentration.Methods:We provide an integrated resource,ZokorDB,for tissue specific regulatory network annotation for zokor.ZokorDB is based on a high-quality draft genome of a plateau zokor at 3,300 m and its transcriptional profiles in brain,heart,liver,kidney,and lung.The conserved non-coding elements of zokor are annotated by their nearest genes and upstream transcriptional factor motif binding sites.Results:ZokorDB provides a general draft gene regulatory network(GRN),Le?potential transcription factor(TF)binds to non-coding regulatory elements and regulates the expression of target genes(TG).Furthermore,we refined the GRN by incorporating matched RNA-seq and DNase-seq data from mouse ENCODE project and reconstructed five tissue-specific regulatory networks.Conclusions:A web-based,open-access database is developed for easily searching,visualizing,and downloading the annotation and data.The pipeline of non-coding region annotation for zokor will be useful for other non-model species.ZokorDB is free available at the website(bigd.big.ac.cn/zokordb/).
基金This study was funded by Novartis Pharma,producer of Neoral ciclosporin.
文摘Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting results.Most used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to T0.Therefore,it is still unclear which calcineurin inhibitor is preferred after LT.We aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first LT.Methods:Patients after first LT were randomized to C2 or T0.tBPAR,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank test.Results:In intention-totreat analysis 84 patients on C2 and 85 on T0 were included.Cumulative incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with C2.Incidence of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and tolerability.Conclusions:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.
基金supported by the National Key R&D Program of China(Grant No.2020YFA0712402)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDPB17)+3 种基金the CAS Project for Young Scientists in Basic Research(Grant No.YSBR-077)the National Natural Science Foundation of China(Grant Nos.12025107,11871463,11688101,and 61621003)the National Thousand Youth Talents Plan,and the CAS“Light of West China”Program(Grant No.xbzg-zdsys-201913)China.We thank High Performance Computing(HPC)of Northwest A&F University(NWAFU)for providing computing resources。
文摘The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network(CNEReg)to investigate the ruminant multi-chambered stomach innovation.We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep,and revealed 1601 active ruminantspecific conserved non-coding elements(active-RSCNEs).To interpret the function of these activeRSCNEs,we defined toolkit transcription factors(TTFs)and modeled their regulation on rumenspecific genes via batteries of active-RSCNEs during development.Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules.Notably,6 TTFs(OTX1,SOX21,HOXC8,SOX2,TP63,and PPARG),as well as 16 active-RSCNEs,functionally distinguished the rumen from the esophagus.Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.
基金supported by the Cancer Prevention Research Institute of Texas(CPRIT)(RR180061 to Cheng C)the National Cancer Institute of the National Institutes of Health(1R21CA227996 to Cheng C)the T32 training grant of the National Institutes of Health(T32 AI007363 to Schaafsma E).Cheng C is a CPRIT Scholar in Cancer Research.
文摘Aim:Neuroblastoma is the most common extracranial solid tumor in children.Recent advances in immunotherapy Approaches,including in neuroblastoma,have shown the important role of the immune system in mounting an effective anti-tumor response.In this study,we aimed to provide a comprehensive investigation of immune cell infiltration in neuroblastoma utilizing a large number of gene expression datasets.Methods:We inferred immune cell infiltration using an established immune inference method and evaluated the association between immune cell abundance and patient prognosis as well as common chromosomal abnormalities found in neuroblastoma.In addition,we evaluated co-infiltration patterns among distinct immune cell types.Results:The infiltration of naïve B cells,NK cells,and CD8+T cells was associated with improved patient prognosis.Naïve B cells were the most consistent indicator of prognosis and associated with an active immune tumor microenvironment.Patients with high B cell infiltration showed high co-infiltration of other immune cell types and the enrichment of immune-related pathways.The presence of high B cell infiltration was associated with both recurrence-free and overall survival,even after adjusting for clinical variables.Conclusion:In this study,we have provided a comprehensive evaluation of immune cell infiltration in neuroblastoma using gene expression data.We propose an important role for B cells in the neuroblastoma tumor microenvironment and suggest that B cells can be used as a prognostic biomarker to predict recurrence-free and overall survival independently of currently utilized prognostic variables.
基金This work was supported by the American Cancer Society(IRG-82-003-30)the National Center for Advancing Translational Sciences of the National Institutes of Health(KL2TR001088)the National Natural Science Foundation of China(81201543).
文摘Background:Neuroblastoma(NB)is a heterogeneous disease with respect to genomic abnormalities and clinical behaviors.Despite recent advances in our understanding of the association between the genetic aberrations and clinical features,it remains one of the major challenges to predict prognosis and stratify patients for determining personalized therapy in this disease.The aim of this study was to develop an effective prognosis prediction model for NB patients.Methods:We integrated diverse computational analyses to define gene signatures that reflect MYCN activity and chromosomal aberrations including deletion of chromosome 1p(Chr1p_del)and chromosome 11q(Chr11q_del)as well as chromosome 11q whole loss(Chr11q_wls).We evaluated the prognostic and predictive values of these signatures in seven NB gene expression datasets(the number of samples ranges from 94 to 498,with a total of 2120)generated from both RNA sequencing and microarray platforms.Results:MYCN signature was a more effective prognostic marker than MYCN amplification status and MYCN expression.Similarly,the Chr1p_del score was more prognostic than Chr1p status.The activity scores of MYCN,Chr1p_del and Chr11q_del were associated with poor prognosis,while the Chr11q_wls score was linked to good outcome.We integrated the activity scores of MYCN,Chr1p_del,Chr11q_del,and Chr11q_wls and clinical variables into an integrative prognostic model,which displayed significant performance over the clinical variables or each genomic aberration alone.Conclusions:Our integrative gene signature model shows a significantly improved forecast performance with prognostic and predictive information,and thereby can be served as a biomarker to stratify NB patients for prognosis evaluation and surveillance programs.
