BACKGROUND:Arthroscopic anchor repair has become the main treatment method for rotator cuff tears at present.Among them,the insertion status of the anchor is a key factor in the success or failure of the operation.However,currently,the impact of the insertion depth of the anchor on the stress of the bone tunnel and the anchor under different bone density conditions remains unclear.OBJECTIVE:To explore the stress distribution of the bone tunnel and the anchor when the insertion depth of the anchor varies under different bone density conditions by using three-dimensional finite element analysis technology.METHODS:The CT image data of the humerus of volunteers were collected,and the models of the humerus and the anchor were constructed by using Mimics,3-Matic,and Solidworks software.In 3-Matic,holes with distances of 0,2,4,6,and 8 mm from the surface of the humerus were respectively created at the same position of the humerus and assembled with the anchor.In Mimics,values were assigned based on the CT gray value to obtain a model with normal bone mass(T value ≥-1.0).The parameters were changed to construct models with reduced bone mass(-2.5＜T value＜-1.0)and osteoporosis(T value＜-2.5).In each model,a 70 N pulling force was applied to the anchor along the direction tangent to the inner edge of the bone tunnel.The stress distribution and magnitude of the bone tunnel and the anchor when inserted at different depths under different bone density conditions were observed.RESULTS AND CONCLUSION:(1)When the insertion depth was the same,as the bone density decreased,the maximum equivalent stress of the anchor increased,while the maximum equivalent stress of the bone tunnel decreased.(2)When the bone density was the same,as the insertion depth of the anchor increased,the maximum equivalent stress of the anchor decreased.When the insertion depth was 4 mm,the stress of the bone tunnel was the smallest and the distribution was relatively uniform.The stress of the anchor was mainly distributed around the lower anchor hole and the proximal thread,and the stress of the bone tunnel was mainly at the part in contact with the proximal thread.The increase in the insertion depth would change the uniformity and pattern of the stress distribution,while the bone density had a relatively small impact on the stress distribution pattern.(3)It is concluded that the bone density of the humerus is crucial for the anchor repair of rotator cuff tears.It is recommended that clinicians measure the bone density of the greater tuberosity of the humerus before the operation.Excessive insertion depth of the anchor does not significantly increase its stability.Clinicians can conduct personalized preoperative assessments by using the finite element analysis method in combination with the actual situation of patients to achieve the best surgical results.

BACKGROUND:Due to the complex movement of the scapula,which is a six-degree-of-freedom activity in three-dimensional space,it is difficult to measure it accurately using traditional methods.The image and model matching technology based on dual-plane X-ray is a three-dimensional measurement method that has gradually developed and matured in recent years.Two high-speed cameras are used to project and shoot from orthogonal directions.Compared with a single perspective,this method has advantages in observation range and reduction of out-of-plane errors,and is suitable for the study of scapula kinematics.OBJECTIVE:X-ray biplane and image-model registration technology were used to explore the differences in scapular kinematics between normal individuals and patients with rotator cuff tears,providing a basis for the treatment and rehabilitation of rotator cuff tear patients.METHODS:From April 2023 to January 2024,10 patients with normal shoulders and 10 patients with rotator cuff tears who met the inclusion criteria were enrolled from Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine.The subjects underwent a shoulder CT scan to create a 3D model and a local scapular coordinate system.X-ray biplane images were taken during shoulder abduction with two C-arm machines.The 2D and 3D images were registered to compare scapular kinematic differences between the two groups at 0°,15°,30°,45°,60°,75°,and 90° of abduction,including scapular rotation angle and displacement distance.RESULTS AND CONCLUSION:(1)During shoulder abduction,the scapula of both groups showed upward rotation,but the upward rotation of the rotator cuff tear group was greater than that of the control group,and the difference was significant when the abduction was 30°-90°(P＜0.01).At the same time,the scapula internal rotation of both groups gradually increased,but the rotator cuff tear group was significantly greater than the control group when the abduction was 45°-90°(P＜0.01).In addition,the anteroposterior tilt of the scapula of the two groups was significantly different when the abduction was 15°-90°(P＜0.01).The scapula posterior tilt of the control group gradually increased during abduction,while the scapula of the rotator cuff tear group tilted forward except for a slight posterior tilt at 15°-30° abduction.(2)In terms of displacement,the upward displacement of the rotator cuff tear group was less than that of the control group during abduction,and the difference was significant at 15°-90°(P＜0.05),but there was no significant difference in lateral and anterior-posterior displacement between the two groups(P＞0.05).(3)Rotator cuff tear can cause scapular dyskinesis,characterized by increased upward rotation,internal rotation,and abnormal forward tilt during shoulder abduction.Identifying and addressing scapular dyskinesis is crucial for treating rotator cuff tear.

Objective To analyze the prevalence characteristics and influencing factors of metabolic syndrome (MS) in people aged 35-75 years in Hubei Province. Methods The follow-up data from 2016 to 2022 in the early screening and comprehensive intervention project for high-risk cardiovascular population in Hubei Province were collected. SAS 9.4 software was used to conduct 2-test and multivariate logistic regression to analyze the prevalence of MS and its influencing factors. Results Among the 89 199 subjects, 24 757 were affected by MS, with a prevalence rate of 27.75% and a standardized rate of 23.55%. Among the various components of MS, the prevalence of abnormal blood pressure was the highest, at 70.88%, and the standardized rate was 59.32%. Secondly, abnormal blood glucose was 36.26%, and the standardized rate was 30.04%. Central obesity was 33.12%, and the standardized rate was 30.28%. Hypertriglyceridemia was 32.90%, and the standardized prevalence rate was 32.70%. The rate of low HDL-C syndrome was 10.25%, and the standardized rate was 11.67%. The results of multivariate logistic regression analysis showed that the risk of MS increased with age, and the risk of MS in urban residents was lower than that in rural residents (OR=0.835, 95%CI: 0.77-0.886). Administrative and professional workers had a higher risk of MS than farmers (OR=1.313, 95%CI:1.194-1.445). Overweight, obesity, central obesity, history of self-reported hypertension, history of self-reported diabetes, and history of self-reported dyslipidemia were associated with a higher risk of MS, and the differences were statistically significant (P < 0.001). Conclusion The prevalence of MS is high in people aged 35-75 years in Hubei Province. On the basis of comprehensive intervention, focus monitoring should be strengthened to control the risk factors of MS and reduce the risk of cardiovascular and cerebrovascular diseases.

Aberrant activation of glycolysis represents a key metabolic mechanism underlying the initiation and progression of nasal inflammation. Allergic rhinitis, chronic rhinosinusitis, and vasomotor rhinitis exhibit distinct etiologies, yet all are characterized by inflammatory responses, impaired epithelial barrier function, and neurovascular dysregulation, in which glycolytic metabolic reprogramming acts as a central hub connecting immunometabolism and inflammatory regulation.Recent evidence indicates that glycolysis-dependent activation of immune cells provides the essential energy basis for inflammatory onset. In dendritic cells, eosinophils, mast cells, and Th2 cells, the expression of key glycolytic enzymes including HK2, PKM2, and LDHA is upregulated, thereby promoting cellular activation and proinflammatory cytokine release via the mTOR-HIF-1α signaling axis. Notably, the metabolic reprogramming of eosinophils prolongs their survival and enhances the release of cytotoxic granules, while in mast cells, enhanced glycolysis facilitates IgE-mediated degranulation and histamine release. Furthermore, glycolysis also influences the Th17/Treg balance, with enhanced glycolytic flux promoting Th17 differentiation and contributing to the heterogeneous inflammatory profiles observed across different rhinitis subtypes.As a central metabolite, lactate contributes to the formation of a metabolism-inflammation vicious cycle through multiple mechanisms. Lactate acidifies the local microenvironment to activate TRPV1 channels and facilitate neuropeptide release, mediates immune cell chemotaxis through GPR81, and regulates gene expression via histone lactylation, thereby sustaining proinflammatory gene transcription. These lactate-mediated processes collectively amplify local inflammation and contribute to the persistence of nasal symptoms.Glycolytic reprogramming in epithelial cells is modulated by the EGF/EGFR pathway, and its dysregulation may result in disrupted tight junctions, abnormal goblet cell hyperplasia, and subsequent tissue remodeling. Substance P and calcitonin gene-related peptide released from sensory neurons, in conjunction with metabolic products, synergistically maintain persistent inflammatory stimulation by activating mast cells, forming a neuro-immune-metabolic regulatory network that drives disease chronicity.From a therapeutic perspective, glycolytic inhibitors such as 2-deoxyglucose, FX11, and 3-bromopyruvate exert anti-inflammatory effects by targeting key enzymes including HK2 and LDHA, each with distinct mechanisms: 2-DG competitively inhibits hexokinase, FX11 selectively targets LDHA to reduce lactate production, and 3-BrPA modulates multiple glycolytic enzymes. Moreover, traditional Chinese medicine formulas, monomeric active components, and small-molecule compounds have shown promising potential in alleviating nasal inflammation by regulating the mTOR-HIF-1α axis, exerting antioxidant effects, and modulating endoplasmic reticulum stress pathways. The multi-target characteristics of these natural products offer advantages in addressing the complex pathophysiology of nasal inflammatory diseases.Despite these advances, several challenges remain. The non-selective inhibition of glycolysis may interfere with epithelial repair and mucosal regeneration, leading to delayed wound healing. Technical limitations in dynamic metabolic monitoring and sampling precision hinder the accurate assessment of local nasal metabolism. Furthermore, current animal models, which predominantly rely on acute stimulation protocols, inadequately recapitulate the chronic tissue remodeling processes characteristic of human rhinitis.This review systematically summarizes glycolysis as a common metabolic node shared by different rhinitis subtypes, offering a novel theoretical basis for the development of precision therapeutic strategies targeting metabolic reprogramming.

ObjectiveTo investigate the epidemiological and clinical characteristics of human bocavirus (HBoV) in hospitalized children with acute lower respiratory tract infection (ALRTI) at a single-center children’s hospital in Shanghai, thereby providing evidence for the diagnosis, treatment, and prevention of HBoV infection. MethodsA retrospective study was conducted on 19 537 hospitalized children with ALRTI at Shanghai Children’s Hospital from January 2021 to December 2023. Multiplex polymerase chain reaction (PCR) combined with capillary electrophoresis was used to detect HBoV and 12 other common respiratory viruses /atypical pathogens. The positive detection rate, demographic characteristics (sex, age), temporal distribution (year, season) of HBoV, as well as the clinical characteristics of severe and non-severe pneumonia were analyzed. ResultsThe overall HBoV-positive rate was 2.57% (503/19 537), with 59.44% (299/503) being single infections and 40.56% (204/503) being co-infections. The positive detection rate was significantly higher in boys than that in girls (2.78% vs 2.33%, χ²=3.88, P=0.049). The highest infection rate was observed in toddlers, followed by infants (χ²=379.57, P<0.001). The positive rate peaked in 2021 and reached its lowest point in 2023 (χ²=45.49, P<0.001), with epidemics mainly prevalent in summer and autumn. The main clinical symptoms were cough (90.06%, 453/503), fever (75.94%, 382/503), and wheezing (39.96%, 201/503). Children with severe pneumonia showed a higher incidence of wheezing compared with the non-severe group (P<0.001), while underlying diseases and co-infections had no significant association with disease severity (P>0.05). ConclusionHBoV was an important pathogen of ALRTI in children, predominantly affecting infants and toddlers, with higher susceptibility in boys and seasonal peaks in autumn and summer. The main clinical manifestations included cough, fever, and wheezing, with wheezing being more prevalent in children with severe pneumonia.

Aberrant activation of glycolysis represents a key metabolic mechanism underlying the initiation and progression of nasal inflammation. Allergic rhinitis, chronic rhinosinusitis, and vasomotor rhinitis exhibit distinct etiologies, yet all are characterized by inflammatory responses, impaired epithelial barrier function, and neurovascular dysregulation, in which glycolytic metabolic reprogramming acts as a central hub connecting immunometabolism and inflammatory regulation.Recent evidence indicates that glycolysis-dependent activation of immune cells provides the essential energy basis for inflammatory onset. In dendritic cells, eosinophils, mast cells, and Th2 cells, the expression of key glycolytic enzymes including HK2, PKM2, and LDHA is upregulated, thereby promoting cellular activation and proinflammatory cytokine release via the mTOR-HIF-1α signaling axis. Notably, the metabolic reprogramming of eosinophils prolongs their survival and enhances the release of cytotoxic granules, while in mast cells, enhanced glycolysis facilitates IgE-mediated degranulation and histamine release. Furthermore, glycolysis also influences the Th17/Treg balance, with enhanced glycolytic flux promoting Th17 differentiation and contributing to the heterogeneous inflammatory profiles observed across different rhinitis subtypes.As a central metabolite, lactate contributes to the formation of a metabolism-inflammation vicious cycle through multiple mechanisms. Lactate acidifies the local microenvironment to activate TRPV1 channels and facilitate neuropeptide release, mediates immune cell chemotaxis through GPR81, and regulates gene expression via histone lactylation, thereby sustaining proinflammatory gene transcription. These lactate-mediated processes collectively amplify local inflammation and contribute to the persistence of nasal symptoms.Glycolytic reprogramming in epithelial cells is modulated by the EGF/EGFR pathway, and its dysregulation may result in disrupted tight junctions, abnormal goblet cell hyperplasia, and subsequent tissue remodeling. Substance P and calcitonin gene-related peptide released from sensory neurons, in conjunction with metabolic products, synergistically maintain persistent inflammatory stimulation by activating mast cells, forming a neuro-immune-metabolic regulatory network that drives disease chronicity.From a therapeutic perspective, glycolytic inhibitors such as 2-deoxyglucose, FX11, and 3-bromopyruvate exert anti-inflammatory effects by targeting key enzymes including HK2 and LDHA, each with distinct mechanisms: 2-DG competitively inhibits hexokinase, FX11 selectively targets LDHA to reduce lactate production, and 3-BrPA modulates multiple glycolytic enzymes. Moreover, traditional Chinese medicine formulas, monomeric active components, and small-molecule compounds have shown promising potential in alleviating nasal inflammation by regulating the mTOR-HIF-1α axis, exerting antioxidant effects, and modulating endoplasmic reticulum stress pathways. The multi-target characteristics of these natural products offer advantages in addressing the complex pathophysiology of nasal inflammatory diseases.Despite these advances, several challenges remain. The non-selective inhibition of glycolysis may interfere with epithelial repair and mucosal regeneration, leading to delayed wound healing. Technical limitations in dynamic metabolic monitoring and sampling precision hinder the accurate assessment of local nasal metabolism. Furthermore, current animal models, which predominantly rely on acute stimulation protocols, inadequately recapitulate the chronic tissue remodeling processes characteristic of human rhinitis.This review systematically summarizes glycolysis as a common metabolic node shared by different rhinitis subtypes, offering a novel theoretical basis for the development of precision therapeutic strategies targeting metabolic reprogramming.

ObjectiveTo investigate the role of interleukin （IL）-17A in acute inhalational pneumonia induced by the highly drug-resistant and hypervirulent Staphylococcus aureus strain USA300-R in mice. MethodsAn acute inhalational pneumonia model was established in mice using an aerosolized pulmonary delivery technique. RNA sequencing （RNA-seq） and enzyme-linked immunosorbent assay （ELISA） were employed to examine the expression dynamics of Il17a mRNA and IL-17A protein， respectively， in the lungs of infected mice. Il17a knockout （Il17a^-/-） mice were generated using CRISPR/Cas9 gene editing technology. The survival rate， body weight， bacterial load in lung tissue， and histopathological changes were compared between Il17a^-/- and wild-type （WT） mice following inhalational infection with USA300-R. Results12 hours after USA300-R infection， compared to pre-infection， the expression level of Il17a mRNA in lung tissue and the level of IL-17A protein in bronchoalveolar lavage fluid （BALF） increased by approximately 50-fold （P<0.01） and 6-fold （P<0.001）， respectively. Compared to WT mice， Il17a^-/- mice exhibited approximately 10-fold higher bacterial loads in lung tissue at both 12 and 24 hours post-infection （P<0.001， P<0.05）. However， they showed significantly attenuated lung histopathological injury， reduced alveolar wall thickening， markedly decreased neutrophil infiltration， and an approximately 50% improvement in survival rate （P<0.05）. ConclusionIn acute Staphylococcus aureus USA300-R inhalational pneumonia， IL-17A contributes to bacterial clearance by recruiting neutrophils； however， excessive neutrophil infiltration exacerbates pulmonary inflammation and injury， reduces survival rates， and represents a potential therapeutic target.

ObjectiveThis paper aims to systematically reveal the effect difference and mechanisms of Zishenwan against chronic prostatitis （CP） before and after salt-processing of Anemarrhenae rhizoma and Phellodendri chinensis cortex based on an integrated strategy of ultra-high performance liquid chromatography-quadrupole-orbitrap mass spectrometry （UPLC-Q-Orbitrap-MS/MS）， network pharmacology， and serum metabolomics. MethodsZishenwan samples before and after salt-processing of Anemarrhenae rhizoma and Phellodendri chinensis cortex were extracted by alcohol-water dual extraction. The chemical components of each sample were detected by UPLC-Q-Orbitrap-MS/MS， and differential components were screened by multivariate statistical analysis. Network pharmacology analysis was performed based on the identified chemical components of Zishenwan to construct a protein-protein interaction （PPI） network of "component， target， and pathway"， and the core components， targets， and pathways of Zishenwan against CP were screened. Forty-two male Sprague-Dawley （SD） rats were randomly divided into a blank group， a model group， a Qianliekang group （1.54 g·kg^-1）， low- and high-dose raw Zishenwan groups （1.8， 5.4 g·kg^-1）， and low- and high-dose salt-processed Zishenwan groups （1.8， 5.4 g·kg^-1）. The CP rat model was established by intraprostatic injection of carrageenan. After one week of recovery， the rats were administered the corresponding drugs for 21 days， while those in the blank group and model group received the same volume of normal saline. After the experiment， serum and tissue samples were collected to evaluate pharmacodynamic indicators including organ indices， histopathology， and inflammatory factors in serum. Subsequently， untargeted serum metabolomics technology was used to analyze metabolite changes and perform pathway enrichment analysis. The network pharmacology was used to construct a network of "differential metabolite， reaction， enzyme， and gene". ResultsA total of 76 components were identified in raw and salt-processed Zishenwan， and 34 differential components were screened by multivariate statistical analysis. Among them， the contents of 14 components， including berberine， berberrubine， and phellodendrine， increased after salt-processing， while the contents of 20 components， such as neomangiferin， decreased. The 28 active components and 185 potential targets were screened out by network pharmacology. The core components included berberine， phellodendrine， magnoflorine， and jatrorrhizine， and the core targets included signal transducer and activator of transcription 3 （STAT3）， protein kinase B1 （Akt1）， and transcription factor AP-1 （JUN）. These targets were significantly enriched in pro-inflammatory signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） and mitogen-activated protein kinase （MAPK）. Compared with the model group， all Zishenwan administration groups showed decreased prostate index， reduced levels of interleukin （IL）-1β， IL-18， and B-cell lymphoma-2 （Bcl-2） in serum （P<0.05， P<0.01）， as well as varying degrees of alleviation in histopathological damage. At the same dose， compared with the raw Zishenwan groups， the salt-processed Zishenwan groups showed lower prostate index， pathological scores， and IL-1β， IL-18， and Bcl-2 levels in serum， but the differences were not statistically significant. Metabolomics reveals that 38 differential metabolites were reversed after salt-processed Zishenwan administration. Both raw and salt-processed Zishenwan regulated pathways such as β-alanine metabolism and tryptophan metabolism. In addition to the common regulated pathways， the salt-processed group specifically regulated pantothenate and coenzyme A biosynthesis， pyrimidine metabolism， and arginine and proline metabolism. The intersecting pathways between network pharmacology and metabolomics were tryptophan metabolism and arginine and proline metabolism， with overlapping targets including monoamine oxidase A （MAOA） and arginase 1 （ARG1）. ConclusionThe increased contents of components such as berberine and phellodendrine in salt-processed Zishenwan may enhance its therapeutic effect on CP by inhibiting the PI3K/Akt and MAPK signaling pathways， along with multi-target regulation of tryptophan， arginine， and pantothenate metabolism pathways to comprehensively regulate inflammatory and immune responses.

ObjectiveTo analyze the clinicopathological features of patients with comorbidities of chronic hepatitis B （CHB） and steatotic liver disease （SLD）， to investigate the impact of hyperglycemia on the risk of liver fibrosis and end-stage liver diseases （ESLD）， and to provide a basis for the clinical management of such population. MethodsA total of 668 adult patients with CHB-SLD confirmed by liver biopsy in The Fifth Medical Center of Chinese PLA General Hospital from January 2011 to December 2019 were enrolled， and a retrospective cohort was established with the time of liver biopsy as the baseline and the onset of ESLD as the endpoint. All patients were followed up to March 31， 2024. Propensity score matching （PSM） was performed at a ratio of 1∶4 to balance baseline features between groups， resulting in 82 patients in the hyperglycemia group and 281 in the non-hyperglycemia group. The two groups were compared in terms of metabolic profiles， laboratory markers， and histopathological features. The Mann-Whitney U test was used for comparison of non-normally distributed quantitative data between two groups. The chi-square test or Fisher exact test was used for comparison of categorical data between two groups. A multivariate Logistic regression analysis was used to investigate the influencing factors for advanced fibrosis （AF）， and the Kaplan-Meier survival analysis and the Cox proportional-hazards regression model were used to determine the influencing factors for the development of ESLD. ResultsCompared with the non-hyperglycemia group， the hyperglycemia group had a significantly higher number of factors for metabolic disorders， a significantly higher degree of hepatic steatosis， and a significantly higher detection rate of AF （all P<0.05）. The multivariate Logistic regression analysis showed that hyperglycemia was a risk factor for AF （odds ratio = 1.753， 95% confidence interval ［CI］： 1.017　—　3.023， P=0.043）. The survival analysis showed that hyperglycemia increased the risk of ESLD （χ²=4.340， P=0.037）. The multivariate Cox regression analysis confirmed that hyperglycemia was a significant metabolic risk factor for ESLD in patients with AF （adjusted hazard ratio=3.208， 95%CI： 1.201　—　8.568， P=0.020）. ConclusionHyperglycemia can increase the risk of AF and ESLD in CHB-SLD patients. Clinical monitoring and active management should be strengthened for patients who have already developed AF and hyperglycemia.

Background Long working hours, as a common risk factor for occupational stress, is closely related to the occurrence of depressive symptoms. Understanding how long working hours affect occupational stress and depressive symptoms will inform occupational health interventions. Objective To quantify the impact of long working hours exposure on occupational stress and depressive symptoms among Internet industry employees, translate black-box outputs into actionable insights, and demonstrate the value of interpretable machine learning for early-warning occupational-health surveillance. Methods A dataset was derived from a cross-sectional survey involving 2866 internet industry employees in China. This survey was part of the project Risk Assessment Of Long Working Hour Exposure And Its Adverse Health Effects, conducted by the National Institute for Occupational Health and Poisoning Control, Chinese Center for Disease Control and Prevention, from 2021 to 2023. Working hours, occupational stress and depressive symptoms were quantified with a set of structured questionnaires including the Core Occupational Stress Scale and the Patient Health Questionnaire. Pairwise associations were screened by Mantel tests and variance-inflation factors. Key predictors identified through feature selection were fed into six machine-learning risk-prediction models. Visual interpretation was provided by feature importance, Shapley additive explanations (SHAP) and local interpretable model-agnostic explanations (LIME), while directed causal effects and intervention impacts of prolonged working hours exposure on occupational stress and depressive symptoms were dissected with causal explanation of features techniques. Results The positive rates of occupational stress and depressive symptoms among internet employees were 12.9% and 77.8% respectively. Twelve core features for occupational stress and nine for depressive symptoms were retained after selection. After these features were supplied to six predictive algorithms and evaluated on five metrics, the Light Gradient Boosting Machine (LGBM) achieved the highest accuracy—0.89 for occupational stress and 0.79 for depressive symptoms on the hold-out test set. The feature-importance rankings converged on fatigue accumulation and life satisfaction as dominant drivers for both outcomes, whereas weekly working hours and daily overtime emerged as the principal exposure-related predictors. The SHAP summary plots revealed that longer weekly hours and daily overtime systematically elevated the probability of occupational stress. The causal feature explanation further quantified that ascending one category in weekly working hours increased the probability of occupational stress by 7.04%. Conclusion Exposure to long working hours is associated with both occupational stress and depressive symptoms among internet industry employees. Interpretable machine-learning frameworks translate these associations into transparent, defensible drivers, enabling precise identification of the pivotal factors and their interplay. This evidence base equips occupational-health practitioners with actionable insights for designing targeted prevention and intervention strategies.