ObjectiveTo investigate the clinical features and outcomes of recompensation in patients with autoimmune hepatitis （AIH）-related decompensated cirrhosis， to identify independent predictive factors， and to construct a nomogram prediction model for the probability of recompensation. MethodsA retrospective cohort study was conducted among the adult patients with AIH-related decompensated cirrhosis who were admitted to The Fifth Medical Center of PLA General Hospital from January 2015 to August 2023 （n=211）. The primary endpoint was achievement of recompensation， and the secondary endpoint was liver-related death or liver transplantation. According to the outcome of the patients at the end of the follow-up， the patients were divided into the recompensation group （n=16） and the persistent decompensation group（n=150）.The independent-samples t test was used for comparison of normally distributed continuous data with homogeneity of variance， and the Mann-Whitney U rank sum test was used for comparison of non-normally distributed continuous data with heterogeneity of variance； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups； the Kaplan-Meier method was used for survival analysis； the Cox proportional-hazards regression model was used to identify independent predictive factors， and a nomogram model was constructed and validated. ResultsA total of 211 patients were enrolled， with a median age of 55.0 years and a median follow-up time of 44.0 months， and female patients accounted for 87.2%. Among the 211 patients， 61 （with a cumulative proportion of 35.5%） achieved recompensation. Compared with the persistent decompensation group， the recompensation group had significantly higher white blood cell count， platelet count （PLT）， total bilirubin （TBil）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， total bile acid， prothrombin time， international normalized ratio （INR）， SMA positive rate， Model for End-Stage Liver Disease （MELD） score， Child-Pugh score， and rate of use of glucocorticoids （all P0.05）， as well as significantly lower age at baseline， number of complications， and death/liver transplantation rate （all P0.05）. At 3 and 12 months after treatment， the recompensation group had continuous improvements in AST， TBil， INR， IgG， MELD score， and Child-Pugh score， which were significantly lower than the values in the persistent decompensation group （all P0.05）， alongside with continuous increases in PLT and albumin， which were significantly higher than the values in the persistent decompensation group （P0.05）. The multivariate Cox regression analysis showed that baseline ALT （hazard ratio ［HR］=1.067， 95% confidence interval ［CI］： 1.010 — 1.127， P=0.021）， IgG （HR=0.463，95%CI：0.258 — 0.833， P=0.010）， SMA positivity （HR=3.122，95%CI：1.768 — 5.515， P0.001）， and glucocorticoid therapy （HR=20.651，95%CI：8.744 — 48.770， P0.001） were independent predictive factors for recompensation， and the nomogram model based on these predictive factors showed excellent predictive performance （C-index=0.87，95%CI：0.84 — 0.90）. ConclusionAchieving recompensation significantly improves clinical outcomes in patients with AIH-related decompensated cirrhosis. Baseline SMA positivity， a high level of ALT， a low level of IgG， and corticosteroid therapy are independent predictive factors for recompensation. The predictive model constructed based on these factors can provide a basis for decision-making in individualized clinical management.

OBJECTIVES: To investigate the therapeutic mechanism of Danzhi Jiangtang Capsule (DZJTC) for repairing renal vascular endothelial injury in rats with diabetic nephropathy (DN). METHODS: Fifty male SD rat models of DN, established by left nephrectomy, high-sugar and high-fat diet and streptozotocin injection, were randomized into DN model group, low-, medium-, and high-dose DZJTC treatment groups, and DAPT (a γ-secretase inhibitor) treatment group, with 10 rats with normal feeding as the control group. DZJTC was administered by daily gavage at 0.315, 0.63, or 1.26 g/kg, and DAPT (20 mg/kg, dissolved in 50% CMC-Na solution) was given by gavage every other day for 4 weeks; normal saline was given in the control and model groups. After treatment, the levels of creatinine (CRE), blood urea nitrogen (BUN), and microalbuminuria (mALB) were detected with ELISA, and renal pathologies were observed by transmission electron microscopy. Renal expressions of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were measured by immunohistochemistry, and the protein expressions of CD31 and Notch signaling pathway components were detected using Western blotting. RESULTS: The rat models of DN showed significantly increased CRE, BUN, and mALB levels, obvious renal pathologies under electron microscopy, increased renal VEGF, ET-1 and CD31 expressions, and upregulated Notch1, NICD, and MAML1 protein levels. Treatment with DZJTC at the 3 doses and DAPT significantly reduced CRE, BUN, and mALB levels, improved renal pathology, decreased VEGF, ET-1 and CD31 expressions, and lowered Notch1, NICD and MAML1 levels, and the effects were the most pronounced with high-dose DZJTC. CONCLUSIONS DZJTC ameliorates hyperproliferation and dysfunction of renal vascular endothelium in DN rats possibly by regulating renal VEGF and ET-1 levels via inhibiting NICD- and MAML1-mediated Notch signaling pathway.
Animals ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Diabetic Nephropathies/drug therapy* ; Receptor, Notch1/metabolism* ; Kidney/blood supply* ; Diabetes Mellitus, Experimental ; Down-Regulation ; Endothelium, Vascular/metabolism* ; Nuclear Proteins/metabolism*

Objective To explore the perfusion distribution of vertebral arteries(VA)in healthy adults,and to observe the impact of VA diameter on perfusion distribution based on territorial arterial spin labeling(t-ASL)technique.Methods A total of 228 healthy adult volunteers were prospectively recruited.t-ASL imaging was utilized to analyze VA perfusion patterns in supratentorial region.Bilateral VA diameters,absolute inter-side VA diameter differences,as well as perfusion volumes(PV)supplied by each VA to supratentorial,cerebellar and their combined were recorded.Pearson correlation analysis was performed to analyze the correlations of VA diameters with PVsupratentorial,PVcerebellar and PVsupratentorial+cerebellar.Results Five patterns of distinct perfusion distribution were identified in supratentorial region,leading to participant stratification into 5 groups.Significant differences of absolute inter-side VA diameter differences was found among groups(P＜0.001).The mean bilateral VA diameter,PVsupratentorial,PVcerebellar and PVsupratentorial+cerebellar was(1.94±0.49)mm,(91.77±49.34)cm3,(74.72±27.68)cm3 and(166.49±59.53)cm3,respectively.VA diameter showed low-moderate positive correlations with PVsupratentorial,PVcerebellar and PVsupratentorial+cerebellar(r=0.483,0.179,0.484,all P＜0.001).Conclusion Perfusion imaging of t-ASL could visualize various perfusion distribution forms of VA in supratentorial region.Diameter of VA had certain impact on both spatial distribution characteristics and quantitative perfusion volumes.

Objective To construct a graded nursing program for exercise rehabilitation of children with hematopoietic stem cell transplantation(HSCT)and carry out a preliminary application,aiming to provide a basis for healthcare personnel to guide the exercise rehabilitation of children with HSCT.Methods Literature analysis and Delphi expert correspondence were used to construct a graded nursing program of exercise rehabilitation for children with HSCT.Through the convenience sampling method,children with HSCT in the hematology department of a tertiary-level children's hospital in Suzhou City were selected as the study subjects from June-December 2023,of which 26 children with HSCT from September-December 2023 served as an experimental group,and 23 children with HSCT from June-August 2023 as a control group.The experimental group was applied with the graded nursing program of exercise rehabilitation,and the control group was applied with the conventional nursing care.The comparison of cardiorespiratory fitness and adverse events between the 2 groups after 8 weeks of exercise intervention was conducted,and the adherence to the exercise intervention programme in the experimental group was recorded.Results The final constructed graded care program of exercise rehabilitation for children with HSCT included 6 primary indicators,20 secondary indicators,and 44 tertiary indicators.Finally,21 children in the experimental group and 23 children in the control group were included in the study.After the intervention,the 6 min walking distance of the experimental group increased compared with that of the control group,and the difference was statistically significant(P＜0.001).85.71％of children in the experimental group had good exercise compliance,and there was no adverse events in both groups.Conclusion The constructed graded nursing program of exercise rehabilitation for children with HSCT is scientific,reasonable,safe and feasible,which can improve the cardiorespiratory capacity of children with HSCT and provide the basis for their exercise rehabilitation.

Objective:To investigate the association of serum/body fluid heparin-binding protein (HBP) and blood lactate levels with disease severity and their impact on prognosis in intensive care unit (ICU) patients with sepsis.Methods:Clinical data from 100 sepsis patients admitted to Ma'anshan Shiqiye Hospital ICU (January 2023-September 2024) were retrospectively analyzed. According to Sepsis-3.0 criteria, patients were divided into: uncomplicated sepsis (general group, n=28), sepsis with organ failure/hypotension (severe group, n=61), and septic shock (shock group, n=11). Comparisons included serum/body fluid HBP, lactate, APACHE Ⅱ scores, and mortality across severity groups and laboratory parameters between survivors and non-survivors. Logistic regression was used to identify prognostic predictors. Non-normally distributed data were presented as M(Q1,Q3), comparison between groups were completed by Kruskal-Wallis H test and Mann-Whitney U tests. Spearman correlation was used to analyze relationships between biomarkers and APACHE Ⅱ scores. Categorical data were presented as n(%), and comparison between groups were completed by χ2 test or Fisher's exact tests. ROC curves was used to evaluate predictive value. Results:Shock group demonstrated significantly higher serum HBP [13.3 (12.6-16.4) μg/L], infection-site HBP [230.3 (226.3-241.1) μg/L], lactate [5.4 (4.9-5.6) mmol/L], and APACHE Ⅱ[22.0 (21.0-24.0)] than severe group [9.6 (8.9-10.5) μg/L; 208.9 (200.5-216.1) μg/L; 2.7 (2.6-2.8) mmol/L; 18.0 (17.0-19.0)] and general group [7.4 (6.3-8.1) μg/L; 190.6 (180.5-202.1) μg/L; 1.5 (1.4-1.7) mmol/L; 13.0 (12.0-14.0)] (all P<0.001). There was statistically significant difference in the mortality rate during hospita lization among three groups of patients ( χ2=30.49, P<0.001). Mortality was higher in shock group than severe group than general group [72.7% (8/11) vs. 11.5% (7/61) vs. 3.6% (1/28), all P<0.001]. Non-survivors exhibited elevated lactate [4.8 (2.7-5.5) vs. 2.6 (1.7-2.8) mmol/L, Z=-4.13, P=0.001], serum HBP [12.2 (9.2-13.3) vs. 9.3 (7.8-10.4) μg/L, Z=-3.12, P=0.002], and infection-site HBP [226.8 (209.9-237.6) vs. 203.6 (194.0-212.8) μg/L, Z=-4.32, P<0.001] vs. survivors. Serum HBP ( r=0.74), infection-site HBP ( r=0.64), and lactate ( r=0.86) were all positively correlated with APACHE Ⅱ (all P<0.001). After adjusting for age and APACHE Ⅱ, elevated serum HBP ( OR=3.743, 95% CI:1.834-7.640), infection-site HBP ( OR=3.540, 95% CI:1.932-6.486), and lactate ( OR=5.155, 95% CI:1.868-14.229) independently predicted mortality (all P<0.001). Combined biomarker detection showed superior predictive value (AUC=0.909) versus individual markers (serum HBP:0.747, infection-site HBP:0.842, lactate:0.827, all P<0.001). Conclusion:Elevated blood lactate and serum/infection-site HBP levels correlate with sepsis severity and independently predict mortality. The biomarker combination provides optimal prognostic stratification.

Objective:To compare the efficacy and safety of crisaborole ointment 2% versus pimecrolimus cream 1% in the treatment of mild to moderate atopic dermatitis in children aged 2 years or older.Methods:A multicenter, randomized, open-label, controlled clinical trial was conducted. A total of 120 pediatric patients aged 2 - 17 years with mild to moderate atopic dermatitis were enrolled from departments of dermatology of 8 hospitals in China between March 2022 and February 2023. The participants were randomly assigned in a 1∶1 ratio to the crisaborole group and the pimecrolimus group, and received the treatment with crisaborole ointment 2% and pimecrolimus cream 1% respectively, twice a day for 4 weeks. Visits were scheduled at baseline/on day 1, as well as on days 8, 15, and 29. The primary efficacy outcome was the percentage of patients achieving the Investigator's Static Global Assessment (ISGA) success (defined as clear [0] or almost clear [1] on the ISGA scale, combined with ≥ 2‐grade improvement from baseline) on day 29. The secondary efficacy outcomes included changes in the Eczema Area and Severity Index (EASI) total scores from baseline to day 29, percentages of patients achieving ISGA improvement (defined as clear [0] or almost clear [1] on the ISGA scale), as well as changes in the Peak Pruritus Numerical Rating Scale (NRS) scores, Dermatology Life Quality Index (DLQI) /Infants' Dermatology Life Quality Index (IDLQI) /Children's Dermatology Life Quality Index (CDLQI) scores, and in the Dermatitis Family Impact (DFI) scores. Drug safety was evaluated according to the incidence of adverse events. Categorical data were compared using the chi-square test. Since measurement data did not follow a normal distribution, the rank sum test was used for comparisons of measurement data between groups.Results:A total of 106 children with mild to moderate atopic dermatitis were included in the per-protocol analysis set, with 52 in the crisaborole group (26 males and 26 females) and 54 in the pimecrolimus group (27 males and 27 females). There were no significant differences in age, disease duration, ISGA and EASI scores at baseline between the two groups (all P > 0.05). On day 29, 22 patients (42.31%) in the crisaborole group and 25 (46.30%) in the pimecrolimus group achieved ISGA success, with no significant difference between the two groups ( χ2 = 0.17, P = 0.68) ; 35 patients (67.31%) in the crisaborole group and 45 (83.33%) in the pimecrolimus group achieved ISGA improvement, also with no significant difference between the two groups ( χ2 = 3.68, P = 0.06) ; additionally, there were no significant differences in the EASI, pruritus NRS, DLQI/IDLQI/CDLQI, or DFI scores between the two groups (all P > 0.05). Adverse reactions to the two topical agents were mainly local reactions such as mild to moderate pain, itching, or worsening of itching, and no obvious systemic adverse reactions occurred. The incidence of drug-related adverse reactions was 46.15% (24 cases) in the crisaborole group and 37.04% (20 cases) in the pimecrolimus group, with no significant difference between the two groups ( χ2 = 0.91, P = 0.34) . Conclusion:The efficacy of crisaborole ointment 2% was comparable to that of pimecrolimus cream 1% in the treatment of mild to moderate atopic dermatitis in children aged ≥ 2 years, and it yielded early and rapid improvement in the quality of life of patients and their families, with good safety and tolerability profiles.

Objective:To explore the application effect of comfort-based light sedation strategy nursing model in early rehabilitation exercises for critically ill patients after gastrointestinal surgery, aiming to provide a reference for the recovery of patients after gastrointestinal surgery.Methods:A randomized controlled trial was conducted using purposive sampling to select 110 critically ill patients who underwent gastrointestinal surgery from July 2022 to December 2023 in the Department of Critical Care Medicine of Shantou Central Hospital. Patients were randomly assigned into the control group and the observation group, with 55 cases in each group. The control group received routine sedation care, while the observation group adopted a comfort-based light sedation strategy nursing model. The NRS (Digital Rating Scale for Pain), RASS (Rationalizing Self-Assessment Scale), SAS (Self-Rating Anxiety Scale), analgesic and sedative drug usage, postoperative bowel sounds, flatus, and defecation onset time, ICU length of stay, delirium incidence, postoperative 24-hour MRC muscle strength score, and discharge Modified Barthel Index (MBI) scores were compared between the two groups at 8 hours, 24 hours, 48 hours, 72 hours, and 96 hours postoperatively.Results:During the study, 5 cases dropped out from both the observation and control groups, leaving 50 cases each complete. The control group consisted of 32 males and 18 females, with an average age of (66.94 ± 14.39) years; the observation group consisted of 34 males and 16 females, with an average age of (68.01 ± 14.76) years. At 8, 24, 48, 72, 96 hours postoperatively, the NRS scores for the observation group were (3.11 ± 0.58), (3.14 ± 0.53), (3.09 ± 0.56), (2.97 ± 0.50), and (2.48 ± 0.45), respectively, were all lower than those of the control group (3.55 ± 0.61), (3.46 ± 0.59), (3.42 ± 0.62), (3.38 ± 0.54), (2.87 ± 0.53), with statistically significant differences ( t values were 2.80 - 3.97, all P<0.05). The RASS scores at postoperative 8, 24, 48, 72, 96 hours were (- 1.42 ± 0.43), (- 1.41 ± 0.42), (- 1.39 ± 0.44), (- 1.36 ± 0.41), (- 1.32 ± 0.40) respectively, compared to the control group (- 1.85 ± 0.47), (- 1.78 ± 0.44), (- 1.81 ± 0.50), (- 1.80 ± 0.48), (- 1.68 ± 0.45), with statistically significant differences ( t values were 4.23 - 4.93, all P<0.05). The SAS scores at postoperative 48, 72, 96 hours were (49.68 ± 4.55), (48.69 ± 4.41), (46.71 ± 4.33) respectively, compared to the control group (53.75 ± 4.76), (53.13 ± 4.69), (52.84 ± 4.51), with statistically significant differences ( t = 4.37, 4.89, 6.93, all P<0.05); the propofol dosage in the observation group (3 228.52 ± 587.78) mg and the dexmedetomidine dosage (1 205.58 ± 311.46) μg were all lower than those of the control group (4 056.77 ± 638.04) mg and (1 650.77 ± 432.69) μg, with statistically significant differences ( t = 6.75, 5.92, both P<0.05). The start time of bowel sounds in the observation group was (18.63 ± 5.96) hours, the start time of flatus was (1.42 ± 0.57) days, and the start time of defecation was (2.02 ± 1.25) days. The ICU hospitalization duration of the observation group (5.54 ± 1.51) days was shorter than that of the control group (7.36 ± 1.89) days, with differences being statistically significant ( t values were 2.71 - 5.32, all P<0.05). The postoperative delirium incidence rate of the observation group was 8.00% (4/50) lower than that of the control group 24.00% (12/50), with differences being statistically significant ( χ2 = 4.76, P<0.05). The postoperative 24-hour MRC muscle strength score (5.34 ± 0.58) and the discharge MBI score (77.56 ± 11.34) in the observation group were both significantly higher than those of the control group (4.79 ± 0.65) and (68.25 ± 10.47), respectively ( t = 4.46, 4.27, both P<0.05). Conclusions:The comfort-oriented light sedation strategy nursing model can improve the postoperative sedation and analgesia effects for ICU gastrointestinal surgery patients, promote gastrointestinal function recovery, shorten ICU hospital stay, reduce delirium incidence, and accelerate patient postoperative recovery.

Objectives To construct frailty risk prediction models based on logistic regression anal-ysis,decision tree and random forest algorithm in elderly patients with heart failure(HF),and to compare the predictive performance of three models.Methods A total of 426 elderly HF patients hospitalized in the Affiliated Hospital of Nantong University from September 2022 to October 2023 were selected using convenience sampling.Based on the results of frailty assessment,194 of them were classified into the frail group and the other 232 into the non-frail group.The 426 patients were divided into training(299 casses)and testing sets(127 cases)in a 7∶3 ratio.Three prediction models were then constructed in the training set,while the test set was used to validate the results.Area under curve and confusion matrix were used to measure performance of the mod-els.The optimal model was then selected by evaluating the performance on the testing set.Results The area under curve value of the logistic regression model,decision tree model and random forest model in the testing set was 0.898,0.825 and 0.903,with a classification accuracy of 84.25％,77.95％and 83.46％,a sensitivity of 82.76％,68.97％and 82.76％,a specificity of 85.51％,85.51％and 84.06％,a positive predictive value of 82.76％,80.00％and 81.36％,and a negative predictive value of 85.51％,76.62％and 85.29％,respectively.The factors that ultimately affecting frailty in elderly HF patients were age,left atrial diameter,depression,albumin,physical activity level and social support.Conclusion Among the three prediction models,the logistic regression model demonstrates best predictive performance for frailty risk in elderly HF patients than the decision tree and random forest models.

Objective:To investigate the overall drug resistance, drug resistance trend and distribution of drug resistance mutation sites in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients with antiviral therapy failure in Yunnan Province.Methods:The demographic data and genotype drug resistance of HIV/AIDS population with antiviral therapy failure in Yunnan Province from January 2021 to December 2023 were collected and analyzed by cross-sectional investigation. Statistical analyses were performed using chi-square test.Results:Among 15 159 HIV/AIDS patients, 12 215 cases tested positive by amplification. The circulating recombinant form (CRF) 08_BC was the predominant genetic subtype, accounting for 54.97%(6 714/12 215), followed by CRF01_AE (16.14%(1 972/12 215)) and CRF07_BC (14.48% (1 769/12 215)). When the viral load was ≥200 to <1 000 copies/mL, the incidence of drug resistance was 21.48%(99/461). When it was ≥1 000 to <10 000 copies/mL, the incidence was 51.29%(2 867/5 590). When it was ≥10 000 to <100 000 copies/mL, the incidence was 69.39% (3 979/5 734). When it was ≥100 000 copies/mL, the incidence was 81.86%(352/430). A total of 7 297 drug resistant cases were detected, with a drug resistance rate of 59.74% (7 297/12 215), thus the estimated drug resistance incidence rate among the antiviral treated population in Yunnan Province was 2.00% (7 297/364 238). From 2021 to 2023, the annual drug resistance rates among patients were 60.71%(2 554/4 207), 60.28%(1 671/2 772), and 58.67% (3 072/5 236), respectively, with no statistically significant difference ( χ2=4.47, P=0.107). Among the population with antiviral therapy failure, the drug resistance rates of non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) were 93.70%(6 837/7 297), 44.10%(3 218/7 297) and 5.15%(376/7 297), respectively. The mutation sites with the highest frequencies among the three classes of drugs including NRTI, NNRTI and PI were M184V/I (46.13%(2 123/4 602)), K103N/S (37.14%(2 648/7 129)), L33F (15.50%(82/529)) and M46I/L (15.50%(82/529)), respectively. Analysis of the degree of drug resistance showed that among NNRTI drugs, nevirapine (49.01%(5 987/12 215)) and efavirenz (48.00%(5 863/12 215)) had the highest drug resistance rates, followed by emtricitabine (23.59%(2 882/12 215)) and lamivudine (23.58%(2 881/12 215)) among NRTI drugs. Conclusions:Among HIV/AIDS patients with antiviral therapy failure in Yunnan Province from 2021 to 2023, CRF08_BC is the main genetic subtype. The drug resistance rate of patients increases with the increase of HIV-1 viral load. There is no significant change in the drug resistance rate from 2021 to 2023. NNRTI has the highest drug resistance rate, followed by NRTI, and PI has the lowest. The main mutation sites are M184V/I for NRTI, K103N/S for NNRTI, and M46I/L and L33F for PI. The drug resistance rates of nevirapine, efavirenz, emtricitabine and lamivudine are relatively high.

Objective Taking into account the physical and mental characteristics of patients with COPD,we develop and implement a lung rehabilitation education game software,aiming to explore more effective health education practices for COPD.Methods Drawing on the Health Belief Model theory,the game content was developed by semi-structured interviews,brainstorming sessions,and expert consultations,and it was implemented via a WeChat mini program.Patients with COPD from the respiratory department of a tertiary general hospital of Luzhou city between March and October 2023 were conveniently selected as the study subjects.Among them,40 patients from July to October 2023 were designated as an experimental group,and another 40 from March to June 2023 constituted a control group.The experimental group was provided with routine health education combined with pulmonary rehabilitation games,whereas the control group received standard health education.After the intervention,the researchers compared the COPD knowledge questionnaire scores and pulmonary rehabilitation adherence between the 2 groups,and assessed the satisfaction of both patients and nurses with the software.Results No sample detachment.The score of the COPD knowledge questionnaire in the experimental group was higher than that in the control group,and the difference was statistically significant(Z=5.361,P＜0.001).The proportion of patients in the experimental group with good adherence to pulmonary rehabilitation(85％)was significantly higher than it in the control group(25％),(x2=29.091,P＜0.001).The patients'overall satisfaction rate with the game was 95％,with operational effectiveness receiving the highest satisfaction rating at 97％.Conclusion The pulmonary rehabilitation education game for patients with COPD can improve their knowledge of COPD,enhance their compliance with pulmonary rehabilitation.Patients have high satisfaction with the software.The software enriches the clinical health education methods,which can be used in clinical practice.