ObjectiveThis study aims to explore the effect of Feiyanning granules on ferroptosis in lung cancer cells and its regulatory function within the nuclear transcription factor E₂-related factor 2 （Nrf2）/mouse solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） signaling pathway. MethodsThe cell counting kit-8 （CCK-8） method was used to detect the effect of Feiyanning granule on the proliferation of A549 lung cancer cells. A549 lung cancer cells were categorized into a blank group， a ferroptosis inhibitor-1 （Fer-1） group （10 μmol·L^-1）， a Feiyanning granules （600 mg·L^-1） group， and a Feiyanning granules + Fer-1 group. After 48 hours of intervention， the activity and morphology of the cells were observed. The CCK-8 method was employed to measure cell viability. Biochemical assays were carried out to measure the levels of reactive oxygen species （ROS）， malondialdehyde （MDA）， glutathione （GSH）， and ferrous ions （Fe²⁺） in A549 cells. Western blot was utilized to evaluate the expression levels of Kelch-like ECH-associated protein 1 （Keap1）， Nrf2， SLC7A11， and GPX4 proteins. A549 lung cancer cells were categorized into a blank group and a Feiyanning Granule group （600 mg·L^-1）， and mitochondrial morphology was examined via transmission electron microscopy （TEM）. ResultsAfter the intervention of Feiyaning granules， the proliferation of A549 cells was significantly inhibited in a concentration-dependent manner compared with that in the blank group （P<0.01）. Compared with the blank group， the Feiyanning granules group exerted an significantly inhibitory effect on the viability of lung cancer cells （P<0.01）. Compared with that in the Feiyanning granules group， the cell viability in the Feiyanning granules +Fer-1 group was obviously restored （P<0.05）. Compared with the blank group， the Feiyanning Granule group showed a significant increase in the levels of ROS， MDA， and Fe²⁺ （P<0.01）， a significant decrease in the GSH level （P<0.01）， and facilitated ferroptosis. Compared with the blank group， the Feiyanning granules group showed significantly decreased expression of Nrf2， SLC7A11， and GPX4 proteins and enhanced expression of Keap1 （P<0.01）. Compared with those in the Feiyanning Granule group， the protein levels of Nrf2， SLC7A11， and GPX4 increased significantly （P<0.01）， and the expression of Keap1 decreased significantly in the Feiyanning granules + Fer-1 group （P<0.01）. Compared with the blank group， the Feiyaning granules group exhibited reduced mitochondrial size and increased matrix electron density. ConclusionFeiyanning granules can induce ferroptosis in lung cancer cells， and its underlying mechanism might be associated with the inhibition of the Nrf2/SLC7A11/GPX4 signaling pathway.

OBJECTIVE To investigate the effects of subanesthetic dose of esketamine on postoperative anxiety and recovery in patients undergoing laparoscopic cholecystectomy. METHODS A total of 200 patients scheduled for laparoscopic cholecystectomy at Suzhou Ninth Hospital Affiliated to Soochow University from January 2023 to December 2024 were randomly assigned to control group （n＝100） and observation group （n＝100）. One minute before the initiation of anesthesia， patients in the control group received intravenous injections of Propofol emulsion injection， Sufentanil citrate injection， and Succinylcholine chloride injection. On this basis， patients in the observation group received an intravenous injection of Esketamine hydrochloride injection. The anxiety status of patients in both groups was compared， along with their general intraoperative conditions （including sufentanil dosage， duration of pneumoperitoneum， operative time， anesthesia time， and extubation time）， postoperative recovery， incidence of adverse reactions， and the need for dezocine rescue analgesia. Heart rate and mean arterial pressure， entropy index （state entropy and response entropy）， inflammatory marker levels [interleukin-6 （IL-6） and C-reactive protein （CRP）]， numerical rating scale （NRS） for pain intensity were compared between the two groups at different time points. RESULTS No significant differences were found between the two groups in pneumoperitoneum duration， operative time， anesthesia time，extubation time， incidence of postoperative dry mouth， entropy index or length of stay in the post-anesthesia care unit （P＞0.05）. Compared with the control group， the observation group showed significantly lower postoperative STAI-S scores， reduced intraoperative sufentanil consumption， decreased incidence of postoperative nausea， vomiting， and shivering， the need for dezocine rescue analgesia， as well as lower plasma IL-6 and CRP levels at 24 h after surgery， and NRS （P＜0.05）. The heart rate and mean arterial pressure of patients in the observation group at the start of surgery， end of surgery， and during extubation were all significantly higher than those in the control group （P＜0.05）. CONCLUSIONS Subanesthetic dose of esketamine can effectively alleviate postoperative anxiety， reduce intraoperative opioid consumption， suppress postoperative inflammatory response， relieve postoperative pain， and promote recovery in patients undergoing laparoscopic cholecystectomy.

As a distinctive resource of Chinese civilization， traditional Chinese medicine （TCM） technology transfer faces significant opportunities under the background of digital and intelligent transformation， while also being constrained by unique challenges such as the complexity of its theoretical system， lengthy industrial chains， and multidimensional policy restrictions， resulting in a "high-value-high-threshold" paradox. At present， TCM technology transfer is deeply trapped in a "threefold reluctance" dilemma， i.e.， unwillingness to transfer， inability to transfer， and lack of capacity to transfer. Specifically， the disconnection between scientific research evaluation systems and market demand leads to low conversion rates of research achievements， unclear ownership and compliance risks suppress innovation incentives， and the absence of professional services intensifies supply-demand mismatches. This article systematically analyzes the specific characteristics of TCM technology transfer and proposes a breakthrough pathway centered on full-chain digital and intelligent transformation. By integrating technologies such as intelligent sorting systems， blockchain-based traceability， and AI diagnostic models， the TCM ecosystem spanning "cultivation-production-service" can be reconstructed. In terms of standardization， promoting the progression from "experience-based data conversion" to "data standardization" and further to "intelligent standardization" is advocated to resolve quality control challenges. For example， a "three-no-one-full" certification system can strengthen quality trust. Policy coordination should focus on optimizing mechanisms for the transformation of scientific and technological achievements， while exploring intellectual property securitization and risk-sharing models to stimulate research momentum. In terms of internationalization， reliance on the Belt and Road Initiative platform to promote the export of geo-authentic medicinal material brands and standards is recommended to build a dual-driven model of "technology plus culture". Looking ahead， through the construction of national-level databases， the cultivation of interdisciplinary talent， and the mutual recognition of international standards， a new paradigm of "scientific intelligent manufacturing" can be formed， providing systematic solutions for the modernization of TCM and global health governance.

Parkinson's disease （PD） is a neurodegenerative disorder primarily characterized by motor dysfunction. Traditionally， its main clinical features include resting tremor， muscular rigidity， bradykinesia， and postural balance disorders. However， an increasing number of studies have shown that its non-motor symptoms （NMS） exert an even greater impact on patients' quality of life than motor symptoms， severely affecting daily functioning and increasing the burden on families and society. Among these， depression is one of the most common and most debilitating NMS， with statistics indicating that the incidence of depression among PD patients reaches as high as 40%-50%. The pathological mechanisms are complex， involving the interplay between degenerative changes in dopaminergic neurons and disruptions in emotional regulatory circuits， which poses a substantial challenge to clinical treatment. Traditional Chinese medicine （TCM）， characterized by holistic regulation and multi-target intervention， has demonstrated significant advantages in the treatment of PD and depression， offering new insights for managing PD-depression comorbidity. This study integrates research extracted from multiple databases， including PubMed， Web of Science， Google Scholar， and China National Knowledge Infrastructure （CNKI）， that investigates the potential mechanisms of PD and depression as well as TCM-based treatments for these conditions. The aim is to elucidate the shared pathological mechanisms underlying PD and depression and to explore the therapeutic potential of TCM in effectively combating PD-depression comorbidity through these shared mechanisms， thereby providing valuable insights for the development of targeted therapies.

Animal experimentation constitutes a critical link between basic research and clinical application, making its research quality and translational efficiency paramount. Although considerable progress has been made in standardizing operational procedures and ethical guidelines, the standardization of outcome evaluation systems has significantly lagged, creating a key bottleneck that constrains the quality of biomedical research and evidence synthesis. This deficiency is manifested by pronounced heterogeneity in outcome selection across similar studies, incomplete methodological reporting, and disparate criteria for result interpretation, which severely impairs the comparability of findings and the evidence integration. To cope with this challenge, this paper systematically introduces a mature methodological tool from clinical research–the core outcome set (COS)–and explores its construction strategies and application potential in the field of animal experimentation. Given the extensive diversity of animal experiments, a pragmatic strategy of "focusing on key areas, implementing phased pilots, and promoting gradual expansion" should be adopted. This approach prioritizes the development of domain-specific COS for disease areas characterized by high research volume, urgent translational needs, and well-established animal models. A multi-source integration pathway for COS development is detailed, comprising systematic literature searches, methodological appraisals, and expert consensus, with the feasibility of leveraging artificial intelligence (AI) to enhance efficiency also being examined. The development and promotion of such COS are not intended to restrict scientific exploration; rather, they aim to establish a new, tiered evaluation paradigm consisting of "core outcomes" (mandatory), "recommended outcomes" (encouraged), and "exploratory outcomes" (optional). This framework is expected not only to enhance research quality through standardization and to adhere to the "3R" principles but also to accelerate the accumulation of high-quality evidence. This, in turn, provides a solid foundation for higher-level evidence synthesis, ultimately facilitating the effective translation of basic research findings into clinical practice and providing an essential methodological framework for scientific advancement in relevant disciplines.

ObjectiveTo investigate the mechanism of salt processing of Psoraleae Fructus （PF） through modern analytical techniques and biotechnology， focusing on its effects related to hepatotoxicity and anti-osteoporosis activity. MethodsThe zebrafish model was utilized to evaluate the impact of PF and salt-processed Psoraleae Fructus （SPF） on the hepatotoxicity （using 134.17 ， 178.89， 268.34 mg·L^-1 as low， medium， and high dose groups of PF， 135.04， 180.06， 270.08 mg·L^-1 as low， medium， and high dose groups of SPF， respectively） and anti-osteoporotic activity （using 33.54 ， 67.08 and 134.17 mg·L^-1 as low， medium， and high dose groups of PF， 33.76， 67.52， 135.04 mg·L^-1 as low， medium， and high dose groups of SPF， respectively）， which was using alizarin red skull staining of zebrafish as an indicator of different batches of PF. The specific dosage of a batch of PF was taken as an example. Then ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry（UPLC-Q-TOF-MS） analysis was employed to identify the chemical composition of PF before and after salt processing， and PCA， OPLS-DA， and independent sample t-test were used to elucidating the compositional changes associated with the effects of salt processing on hepatotoxicity and anti-osteoporosis activity. ResultsUnder specific conditions， PF induced notable hepatotoxicity in zebrafish while simultaneously demonstrating protective effect against prednisolone-induced osteoporosis. In comparison to PF， SPF showed alleviated hepatotoxicity while retaining significant anti-osteoporosis activity. UPLC-Q-TOF-MS analysis revealed that after salt processing， the overall chemical composition of PF showed a downward trend， with 69 components showing a decrease in content， represented by psoralen， and 13 components showing an increase， represented by 4′-O-methyl psoralen B. Further multivariate statistical analysis revealed 11 key differential components before and after salt processing of PF， including psoralen and bakuchiol. ConclusionSalt processing effectively diminishes hepatotoxicity without impairing therapeutic efficacy against osteoporosis of PF， which may be related to the compositional changes before and after salt processing of PF and provides key evidence to reveal the scientific significance of salt processing of PF.

ObjectiveTo investigate the efficacy and safety of Babaodan Capsule （BBD） in the treatment of patients with chronic hepatitis B virus （HBV） infection with damp-heat in the liver and gallbladder comorbid with gallbladder polyps. MethodsA randomized， double-blinded， placebo-controlled single-center trial was conducted among 120 patients with chronic HBV infection who were admitted to Beijing YouAn Hospital， Capital Medical University， from August 2020 to April 2023， and they were divided into treatment group （BBD） and control group （placebo）， with 60 patients in each group. The course of treatment was 24 weeks， and follow-up assessments were conducted every 4 weeks. The primary outcome measures were the number and maximum diameter of gallbladder polyps （assessed by ultrasound）， and the secondary outcome measures included traditional Chinese medicine （TCM） syndrome score， blood lipid levels， and liver function parameters. The independent-samples t test or the Wilcoxon rank-sum test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups； the Wilcoxon rank-sum test was used for comparison of ranked data between two groups； the generalized estimating equation was used to analyze repeated measures data. ResultsAfter 8 weeks of treatment， the treatment group had a significantly smaller diameter of polyps and a significantly lower number of polyps than the control group （Z=-1.76 and -1.80， both P<0.05）， and after 24 weeks of treatment， the treatment group had a significantly higher polyp reduction rate than the control group （30.51% vs 10.91%， P<0.05）. The subgroup analysis showed that patients receiving combined antiviral therapy， male patients， patients with a diameter of polyps of <5 mm， and patients with multiple polyps tended to achieve significantly greater benefits. At week 8 of treatment， the treatment group had a significantly better TCM syndrome score than the control group （Z=-2.35， P<0.05）； after treatment， compared with the control group， the treatment group had a significantly greater increase in high-density lipoprotein （Z=-1.85， P<0.05） and significantly lower levels of alanine aminotransferase （Z=-2.06， P <0.05）， aspartate aminotransferase （Z=-2.13， P<0.05）， total bilirubin （Z=-2.12， P<0.05）， and direct bilirubin （Z=-3.09， P<0.05）. No serious adverse events were reported in either group. ConclusionBBD can effectively reduce the size of gallbladder polyps， improve TCM syndrome score， and reduce the level of bilirubin in patients with chronic HBV infection with damp-heat in the liver and gallbladder， with a favorable safety profile， and it may be more suitable for patients receiving combined antiviral therapy and specific subgroups （male patients， patients with a diameter of polyps of <5 mm， and patients with multiple polyps.

BACKGROUND:At present,there are few reports on the postoperative efficacy of arthroscopic coracoid tunnel-free suspension fixation and coracoid single tunnel fixation in the treatment of acromioclavicular joint dislocation at home and abroad.The specific clinical efficacy of the two procedures and whether there are other risks need to be explored. OBJECTIVE:To compare the short-term postoperative clinical efficacy of arthroscopic TightRope band plate fixation with single tunnel fixation of the coracoid process and tunnel-free suspension fixation of the coracoid process in the treatment of acute type Ⅲ-Ⅴ acromioclavicular joint dislocation. METHODS:A retrospective analysis was performed in 45 patients with acromioclavicular joint dislocation who met the inclusion criteria admitted to the Sixth Affiliated Hospital of Xinjiang Medical University from June 2019 to September 2022,and were divided into coracoid single tunnel fixation group(20 cases)and coracoid tunnel-free suspension fixation group(25 cases)according to the surgical treatment plan.Operation time,incision length,blood loss,Constant-Murley score,visual analogue scale score,the American Shoulder and Elbow Surgeons(ASES)score and intraoperative and postoperative complications of the shoulder joint before operation,3 months after surgery and the last follow-up were compared between the two groups. RESULTS AND CONCLUSION:All patients successfully completed the operation,and there was no important nerve or blood vessel damage during the operation.The operation time of the coracoid tunnel-free suspension fixation group was significantly shorter than that of the coracoid tunnel-free suspension fixation group(P<0.05).There was no significant difference in intraoperative blood loss and incision length between the two groups(P>0.05).All patients were followed up for 12 to 24 months,with an average of(15.29±2.73)months.In the coracoid single tunnel fixation group,at 3 months after operation and the final follow-up,the visual analogue scale score was significantly lower than the preoperative score(P<0.05);Constant-Murley score and ASES score were significantly increased compared with the preoperative values(P<0.05).In the coracoid tunnel-free suspension fixation group,at 3 months after operation and the final follow-up,the visual analogue scale score was significantly lower than the preoperative score(P<0.05);the Constant-Murley score and the ASES score were both significantly higher than the preoperative scores(P<0.05).At 3 months after operation,the Constant-Murley score of the coracoid tunnel-free suspension fixation group was higher than that of the coracoid single tunnel fixation group(P<0.05),while there was no significant difference in visual analogue scale and ASES scores between the two groups(P>0.05).There was also no significant difference in the visual analogue scale,Constant-Murley,and ASES scores between the two groups at the corresponding time points before surgery and at the final follow-up(P>0.05).Intraoperative and postoperative complications:In the coracoid single tunnel fixation group,there was one case of coracoid cortical rupture and fracture during the tunnel drilling during the operation,and one case of a loss of reduction at 3 months after operation,which was repositioned and fixed with hook plate transposition of the coracoacromial ligament.All patients had good acromioclavicular joint function recovery and no re-dislocation at the final follow-up.All patients in the coracoid tunnel-free suspension fixation group did not suffer from coracoid fractures,loss of reduction and other complications during surgery,postoperatively and at the last follow-up.To conclude,these two arthroscopic treatments for acute type Ⅲ-Ⅴ acromioclavicular joint dislocation have the advantages of less trauma,reliable reduction and fixation,and good recovery of shoulder joint function after operation.However,compared with the coracoid single tunnel technique,the coracoid tunnel-free suspension fixation requires shorter time,faster recovery of shoulder joint function in the short term,and avoids the establishment of bone tunnels on the coracoid process,which reduces the probability of iatrogenic fracture of the coracoid process during operation and provides a higher degree of safety.

ObjectiveTo screen and evaluate the antidepressant compounds of Curcumae Rhizoma， and explore its mechanism of regulating the nuclear factor erythroid 2-related factor 2（Nrf2）/glutathione（GSH） peroxidase 4（GPX4）/GSH pathway from an antioxidant perspective. MethodsThe antioxidant activities in vitro of 11 characteristic components from Curcumae Rhizoma， including curcumol， curgerenone， curdione， curzerene， curcumenol， curcumenone， dehydrocurdione， isocurcumenol， furanodienone， furanodiene and zederone， were detected using 1，1-diphenyl-2-picrylhydrazyl（DPPH） and 2，2'-azinobis-（3-ethylbenzothiazoline-6-sulphonic acid） diammonium salt（ABTS） radical scavenging assays. The depression in Drosophila melanogaster was induced by chronic unpredictable mild stress（CUMS）， and W1118 wild-type male D. melanogaster were randomly divided into blank group， model group， curcumol group， curgerenone group， curdione group， curzerene group， curcumenol group，curcumenone group， dehydrocurdione group， isocurcumenol group， furanodienone group， furanodiene group， zederone group and fluoxetine group（10 μmol·L^-1）. The treatment groups received a dose of 0.1 g·L^-1 of 11 characteristic components from Curcumae Rhizoma， while the blank and model groups were administered equivalent volumes of solvent. The sucrose preference test， climbing test and forced swimming test were used to evaluate the behavioral indicators of depression in D. melanogaster. Liquid chromatography-mass spectrometry（LC-MS） was used to detect the levels of 5-hydroxytryptamine（5-HT） and dopamine（DA） in the brain of D. melanogaster， and the entropy weight method was used to comprehensively evaluate neurobehavioral and neurotransmitter indicators， resulting in the identification of the antidepressant active components of Curcumae Rhizoma. In addition， a mouse depression model was established by CUMS， and C57BL/6J mice were randomly divided into blank group， model group， low and high dose groups of curzerene（0.5， 1 mg·kg^-1）， and fluoxetine group（10 mg·kg^-1） to confirm the antidepressant effect of the optimal active ingredient by behavioral analysis. Flow cytometry was used to detect the content of reactive oxygen species（ROS） in the hippocampus of mice from each group. Enzyme-linked immunosorbent assay was used to detect the contents of adenosine triphosphate（ATP）， superoxide dismutase（SOD）， catalase（CAT） and GSH. Transmission electron microscope（TEM） was used to observe the effect of curzerene on the ultrastructure of mitochondria in hippocampal tissue. Western blot was performed to determine the level of Nrf2 protein， and Nrf2 inhibitor（ML385） was used to verify the relationship between the antidepressant effect of curzerene and regulation of Nrf2. Real time fluorescence quantitative polymerase chain reaction（Real-time PCR） was employed to detect the effect of curzerene on the mRNA expression level of GPX. ResultsIn vitro antioxidant experiments showed that curzerene and curgerenone exhibited the most significant ability to scavenge free radicals， and comprehensive evaluation results of entropy weight method indicated that curzerene stood out as the most promising active component. Compared with the blank group， the model group exhibited a significant decrease in sucrose preference coefficient and the number of times entering the open field center（P<0.01）， as well as a significant increase in immobility time in the forced swimming and tail suspension tests（P<0.01）， and the ROS content in hippocampus significantly elevated（P<0.01）， while the ATP content significantly reduced（P<0.01）. In the hippocampal neurons of the model group， mitochondrial cristae were disordered， with vacuolation of the inner membrane and severe damage. Nrf2 protein expression level in the model group was significantly decreased（P<0.05）， and the antioxidant enzymes SOD， CAT and GSH contents were also significantly reduced（P<0.05， P<0.01）， and the gene expression levels of GPX1， GPX4 and GPX7 were significantly decreased（P<0.01）. Compared with the model group， the high-dose group of curzerene showed a significant increase in the sucrose preference coefficient and the number of times entering the open field center（P<0.05）， as well as a significant decrease in immobility time in the forced swimming and tail suspension tests（P<0.05， P<0.01）. The ROS content in the hippocampus of the high-dose group of curzerene was significantly reduced（P<0.01）， while the ATP content was significantly increased（P<0.05）. The neuronal mitochondrial damage in the hippocampus of the high-dose group of curzerene was alleviated， and the expression level of Nrf2 protein was significantly increased（P<0.05）. The Nrf2 inhibitor ML385 reversed the improvement of curzerene on depressive behaviors in CUMS mice. The GSH content in the hippocampal neurons of the high-dose group of curzerene was significantly increased（P<0.01）， while there were no significant differences in SOD and CAT contents. The expression level of GPX4 gene in the hippocampal neurons of the high-dose group of curzerene was significantly increased（P<0.05）， while there were no significant differences in other GPX genes. ConclusionCurzerene is the best component with antidepressant activity in Curcumae Rhizoma. It may improve mitochondrial dysfunction to exert its antidepressant effect by regulating Nrf2 and its downstream GPX4/GSH pathway rather than CAT or SOD pathways.

ObjectiveTo elucidate the critical role of rehabilitation medical records (including electronic records) in rehabilitation medicine's clinical practice and management, comprehensively analyzed the structure, core content and data standards of rehabilitation medical records, to develop a standardized medical record data architecture and core dataset suitable for rehabilitation medicine and to explore the application of rehabilitation data in performance evaluation and payment. MethodsBased on the regulatory documents Basic Specifications for Medical Record Writing and Basic Specifications for Electronic Medical Records (Trial) issued by National Health Commission of China, and referencing the World Health Organization (WHO) Family of International Classifications (WHO-FICs) classifications, International Classification of Diseases (ICD-10/ICD-11), International Classification of Functioning, Disability and Health (ICF), and International Classification of Health Interventions (ICHI Beta-3), this study constructed the data architecture, core content and data standards for rehabilitation medical records. Furthermore, it explored the application of rehabilitation record summary sheets (home page) data in rehabilitation medical statistics and payment methods, including Diagnosis-related Groups (DRG), Diagnosis-Intervention Packet (DIP) and Case Mix Index. ResultsThis study proposed a systematic standard framework for rehabilitation medical records, covering key components such as patient demographics, rehabilitation diagnosis, functional assessment, rehabilitation treatment prescriptions, progress evaluations and discharge summaries. The research analyzed the systematic application methods and data standards of ICD-10/ICD-11, ICF and ICHI Beta-3 in the fields of medical record terminology, coding and assessment. Constructing a standardized data structure and data standards for rehabilitation medical records can significantly improve the quality of data reporting based on the medical record summary sheet, thereby enhancing the quality control of rehabilitation services, effectively supporting the optimization of rehabilitation medical insurance payment mechanisms, and contributing to the establishment of rehabilitation medical performance evaluation and payment based on DRG and DIP. ConclusionStructured rehabilitation records and data standardization are crucial tools for quality control in rehabilitation. Systematically applying the three reference classifications of the WHO-FICs, and aligning with national medical record and electronic health record specifications, facilitate the development of a standardized rehabilitation record architecture and core dataset. Standardizing rehabilitation care pathways based on the ICF methodology, and developing ICF- and ICD-11-based rehabilitation assessment tools, auxiliary diagnostic and therapeutic systems, and supporting terminology and coding systems, can effectively enhance the quality of rehabilitation records and enable interoperability and sharing of rehabilitation data with other medical data, ultimately improving the quality and safety of rehabilitation services.