This study aimed to investigate the correlation between changes in intestinal toxicity and compositional alterations of Euphorbiae Ebracteolatae Radix(commonly known as Langdu) before and after milk processing, and to explore the detoxification mechanism of milk processing. Mice were intragastrically administered the 95% ethanol extract of raw Euphorbiae Ebracteolatae Radix, milk-decocted(milk-processed), and water-decocted(water-processed) Euphorbiae Ebracteolatae Radix. Fecal morphology, fecal water content, and the release levels of inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in different intestinal segments were used as indicators to evaluate the effects of different processing methods on the cathartic effect and intestinal inflammatory toxicity of Euphorbiae Ebracteolatae Radix. LC-MS/MS was employed to analyze the small-molecule components in the raw product, the 95% ethanol extract of the milk-processed product, and the milky waste(precipitate) formed during milk processing, to assess the impact of milk processing on the chemical composition of Euphorbiae Ebracteolatae Radix. The results showed that compared with the blank group, both the raw and water-processed Euphorbiae Ebracteolatae Radix significantly increased the fecal morphology score, fecal water content, and the release levels of TNF-α and IL-1β in various intestinal segments(P<0.05). Compared with the raw group, all indicators in the milk-processed group significantly decreased(P<0.05), while no significant differences were observed in the water-processed group, indicating that milk, as an adjuvant in processing, plays a key role in reducing the intestinal toxicity of Euphorbiae Ebracteolatae Radix. Mass spectrometry results revealed that 29 components were identified in the raw product, including 28 terpenoids and 1 acetophenone. The content of these components decreased to varying extents after milk processing. A total of 28 components derived from Euphorbiae Ebracteolatae Radix were identified in the milky precipitate, of which 27 were terpenoids, suggesting that milk processing promotes the transfer of toxic components from Euphorbiae Ebracteolatae Radix into milk. To further investigate the effect of milk adjuvant processing on the toxic terpenoid components of Euphorbiae Ebracteolatae Radix, transmission electron microscopy(TEM) was used to observe the morphology of self-assembled casein micelles(the main protein in milk) in the milky precipitate. The micelles formed in casein-terpenoid solutions were characterized using particle size analysis, fluorescence spectroscopy, ultraviolet spectroscopy, and Fourier-transform infrared(FTIR) spectroscopy. TEM observations confirmed the presence of casein micelles in the milky precipitate. Characterization results showed that with increasing concentrations of toxic terpenoids, the average particle size of casein micelles increased, fluorescence intensity of the solution decreased, the maximum absorption wavelength in the UV spectrum shifted, and significant changes occurred in the infrared spectrum, indicating that interactions occurred between casein micelles and toxic terpenoid components. These findings indicate that the cathartic effect of Euphorbiae Ebracteolatae Radix becomes milder and its intestinal inflammatory toxicity is reduced after milk processing. The detoxification mechanism is that terpenoid components in Euphorbiae Ebracteolatae Radix reassemble with casein in milk to form micelles, promoting the transfer of some terpenoids into the milky precipitate.
Animals ; Mice ; Milk/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Male ; Tumor Necrosis Factor-alpha/immunology* ; Intestines/drug effects* ; Interleukin-1beta/immunology* ; Tandem Mass Spectrometry ; Female

Progressive pulmonary fibrosis (PPF) is a progressive and lethal condition with few effective treatment options. Improvements in quality of life for patients with PPF remain limited even while receiving treatment with approved antifibrotic drugs. Traditional Chinese medicine (TCM) has the potential to improve cough, dyspnea and fatigue symptoms of patients with PPF. TCM treatments are typically diverse and individualized, requiring urgent development of efficient and precise design strategies to identify effective treatment options. We designed an innovative Bayesian adaptive two-stage trial, hoping to provide new ideas for the rapid evaluation of the effectiveness of TCM in PPF. An open-label, two-stage, adaptive Bayesian randomized controlled trial will be conducted in China. Based on Bayesian methods, the trial will employ response-adaptive randomization to allocate patients to study groups based on data collected over the course of the trial. The adaptive Bayesian trial design will employ a Bayesian hierarchical model with "stopping" and "continuation" criteria once a predetermined posterior probability of superiority or futility and a decision threshold are reached. The trial can be implemented more efficiently by sharing the master protocol and organizational management mechanisms of the sub-trial we have implemented. The primary patient-reported outcome is a change in the Leicester Cough Questionnaire score, reflecting an improvement in cough-specific quality of life. The adaptive Bayesian trial design may be a promising method to facilitate the rapid clinical evaluation of TCM effectiveness for PPF, and will provide an example for how to evaluate TCM effectiveness in rare and refractory diseases. However, due to the complexity of the trial implementation, sufficient simulation analysis by professional statistical analysts is required to construct a Bayesian response-adaptive randomization procedure for timely response. Moreover, detailed standard operating procedures need to be developed to ensure the feasibility of the trial implementation. Please cite this article as: Zhang C, Nie YS, Zhang CT, Yang HJ, Zhang HR, Xiao W, Cui GF, Li J, Li SJ, Huang QS, Yan SY. An adaptive Bayesian randomized controlled trial of traditional Chinese medicine in progressive pulmonary fibrosis: Rationale and study design. J Integr Med. 2025; 23(2): 138-145.
Female ; Humans ; Male ; Bayes Theorem ; Disease Progression ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional/methods* ; Pulmonary Fibrosis/therapy* ; Quality of Life ; Randomized Controlled Trials as Topic ; Research Design ; Adaptive Clinical Trials as Topic

Objective To explore the postmortem diffusion rule of Aconitum alkaloids and their metabo-lites in poisoned rabbits,and to provide a reference for identifying the antemortem poisoning or post-mortem poisoning of Aconitum alkaloids.Methods Twenty-four rabbits were sacrificed by tracheal clamps.After 1 hour,the rabbits were administered with aconitine LD50 in decocting aconite root powder by intragastric administration.Then,they were placed supine and stored at 25℃.The biological samples from 3 randomly selected rabbits were collected including heart blood,peripheral blood,urine,heart,liver,spleen,lung and kidney tissues at 0 h,4 h,8 h,12 h,24 h,48 h,72 h and 96 h after intragastric administration,respectively.Aconitum alkaloids and their metabolites in the biological samples were ana-lyzed by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Results At 4 h after intragastric administration,Aconitum alkaloids and their metabolites could be detected in heart blood,peripheral blood and major organs,and the contents of them changed dynamically with the preservation time.The contents of Aconitum alkaloids and their metabolites were higher in the spleen,liver and lung,especially in the spleen which was closer to the stomach.The average mass fraction of benzoylmesaconine metabolized in rabbit spleen was the highest at 48 h after intragastric administration.In contrast,the contents of Aconitum alkaloids and their metabolites in kidney were all lower.Aconi-tum alkaloids and their metabolites were not detected in urine.Conclusion Aconitum alkaloids and their metabolites have postmortem diffusion in poisoned rabbits,diffusing from high-content organs(stomach)to other major organs and tissues as well as the heart blood.The main mechanism is the dispersion along the concentration gradient,while urine is not affected by postmortem diffusion,which can be used as the basis for the identification of antemortem and postmortem Aconitum alkaloids poisoning.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Skin, as the body's largest organ, acts as the primary defense mechanism against infection and injury. The maintenance of skin health heavily relies on the regulation of epidermal stem cells, crucial for ensuring epidermal homeostasis, hair regeneration, and the repair of epidermal injuries. Recent studies have placed a growing emphasis on G protein-coupled receptor (GPCR) in the context of understanding epidermal stem cells, uncovering its significant role in determining their fate. The activation of GPCR triggers the subsequent dissociation of the βγ subunits from the α subunit of G protein, leading to the modulation of various downstream signaling pathways, such as the WNT-BMP signaling crosstalk and the Gαs-PKA signaling pathway. These pathways collectively influence the fate of epidermal stem cells. Consequently, targeted GPCR therapy has emerged as a promising strategy for improving skin health by orchestrating the fate of epidermal stem cells, unveiling potential therapeutic targets that demand further investigation.
Humans ; Stem Cells/cytology* ; Receptors, G-Protein-Coupled/physiology* ; Animals ; Epidermal Cells/physiology* ; Signal Transduction ; Epidermis/physiology* ; Skin/cytology*

Background: and Purpose To examine the clinical and safety outcomes after endovascular treatment (EVT) for acute basilar artery occlusion (BAO) with different anesthetic modalities. Methods: This was a retrospective analysis using data from the Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION) registry. Patients were divided into two groups defined by anesthetic modality performed during EVT: general anesthesia (GA) or non-general anesthesia (non-GA). The association between anesthetic management and clinical outcomes was evaluated in a propensity score matched (PSM) cohort and an inverse probability of treatment weighting (IPTW) cohort to adjust for imbalances between the two groups. Results: Our analytic sample included 1,672 patients from 48 centers. The anesthetic modality was GA in 769 (46.0%) and non-GA in 903 (54.0%) patients. In our primary analysis with the PSM-based cohort, non-GA was comparable to GA concerning the primary outcome (adjusted common odds ratio [acOR], 1.01; 95% confidence interval [CI], 0.82 to 1.25; P=0.91). Mortality at 90 days was 38.4% in the GA group and 35.8% in the non-GA group (adjusted risk ratio, 0.95; 95% CI, 0.83 to 1.08; P=0.44). In our secondary analysis with the IPTW-based cohort, the anesthetic modality was significantly associated with the distribution of modified Rankin Scale at 90 days (acOR: 1.45 [95% CI: 1.20 to 1.75]). Conclusion In this nationally-representative observational study, acute ischemic stroke patients due to BAO undergoing EVT without GA had similar clinical and safety outcomes compared with patients treated with GA. These findings provide the basis for large-scale randomized controlled trials to test whether anesthetic management provides meaningful clinical effects for patients undergoing EVT.

Thyroid-associated ophthalmopathy(TAO)is an autoimmune inflammatory disease involving multiple orbital tissues with a variety of clinical manifestations, which has serious effects on the life quality of patients.Interventions of TAO mainly include medical treatment to stabilize thyroid function, reduce inflammation and regulate immune function, as well as surgical treatment to relieve ocular symptoms. Botulinum toxin type A can paralyze muscles by blocking nerve impulse conduction at the neuromuscular junction, which is of certain therapeutic value for restrictive strabismus due to extraocular muscle involvement and upper eyelid retraction due to involvements of levator palpebrae superioris and Müller's muscle in TAO patients, especially when they have surgical contraindications, lack surgical opportunity, or refuse surgery. This paper reviews the application of botulinum toxin type A in the treatment of TAO, focusing on its pharmacological mechanism, dosage, effectiveness, and possible complications when treating restrictive strabismus and upper eyelid retraction, and discussing potential therapeutic values of botulinum toxin type A for intraocular pressure elevation, glabellar frown lines and dry eye caused by extraocular muscle compression in TAO patients, in order to provide a reference for clinical intervention.

Objective To investigate the effects of propofol and sevoflurane on neurological recovery of traumatic brain injury (TBI) patients in the early postoperative stage.Methods We retrospectively analyzed the clinical data of TBI patients who underwent craniotomy or decompressive craniectomy. Generalized additive mixed model (GAMM) was used to analyze effects of propofol and sevoflurane on Glasgow Coma Scale (GCS) on postoperative days 1, 3, and 7. Multivariate regression analysis was used to analyze effects of the two anesthetics on Glasgow Outcome Scale (GOS) at discharge.Results A total of 340 TBI patients were enrolled in this study. There were 110 TBI patients who underwent craniotomy including 75 in the propofol group and 35 in the sevoflurane group, and 134 patients who underwent decompressive craniectomy including 63 in the propofol group and 71 in the sevoflurane group. It showed no significant difference in GCS at admission between the propofol and the sevoflurane groups among craniotomy patients (β = 0.75, 95%CI: -0.55 to 2.05, P = 0.260). However, elevation in GCS from baseline was 1.73 points (95%CI: -2.81 to -0.66, P = 0.002) less in the sevoflurane group than that in the propofol group on postoperative day 1, 2.03 points (95%CI: -3.14 to -0.91, P < 0.001) less on day 3, and 1.31 points (95%CI: -2.43 to -0.19, P = 0.022) less on day 7. The risk of unfavorable GOS (GOS 1, 2, and 3) at discharge was higher in the sevoflurane group (OR = 4.93, 95%CI: 1.05 to 23.03, P = 0.043). No significant difference was observed among two-group decompressive craniectomy patients in GCS and GOS.Conclusions Compared to propofol, sevoflurane was associated with worse neurological recovery during the hospital stay in TBI patients undergoing craniotomy. This difference was not detected in TBI patients undergoing decompressive craniectomy.

OBJECTIVE: To assess the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) for treatment of type 2 diabetes in a randomized, double-blind, placebo-controlled multicenter clinical trial. METHODS: A total of 200 patients were randomized to receive SZ-A (n=100) or placebo (n=100) for 16 weeks. The data analysis system for electronic data capture clinical trial central randomization system was used for randomization and dispensing of drugs. The primary outcome was the change in glycosylated hemoglobin (HbA1c) level. The secondary outcome included the proportions of cases with HbA1c <7.0% and HbA1c <6.5%, fasting blood glucose (FBG), postprandial blood glucose (PBG), area under curve for the PBG (AUC_0-2h), body weight, and body mass index (BMI). Adverse events (AEs), severe adverse events (SAEs), treatment-related adverse events (TAEs), gastrointestinal disorders (GDs), blood pressure, routine blood tests, and liver and kidney function were monitored. RESULTS: Compared with baseline, the change of HbA1c at week 16 was -0.80% (95% CI: -0.98% to -0.62%) and -0.09% (95% CI: -0.27% to 0.09%) in SZ-A group and placebo group, respectively. The proportion of patients with HbA1c <7% and <6.5% was higher in the SZ-A group than in the placebo group (46.8% vs. 21.6% and 29.9% vs. 10.8%). The observed values and changes in FBG, 1 h-PBG, 2 h-PBG, and AUC_0-2h differed significantly between groups (P<0.001), but differences were not significant in body weight and BMI (P>0.05). The incidence rates of AEs, TAEs, and GDs differed significantly between groups (P=0.010, P=0.005, and P=0.006, respectively), whereas the incidence rates of SAEs showed no significant differences between groups (P=1.000). CONCLUSION SZ-A are effective and safe for treatment of type 2 diabetes. The protocol was registered in http://www.chictr.org.cn/showproj.aspx?proj=60117 (ChiCTR2000038550).
Alkaloids ; Blood Glucose ; Diabetes Mellitus, Type 2/drug therapy* ; Double-Blind Method ; Glycated Hemoglobin A ; Humans ; Hypoglycemic Agents/therapeutic use* ; Morus ; Tablets/therapeutic use* ; Treatment Outcome

Objective: To explore the effects of enteral immunonutrition support therapy on nutritional metabolism, immune function, and inflammatory response in adult burn patients at nutritional risk as assessed by the modified 2^nd nutrition risk screening (NRS) 2002. Methods: A prospective randomized controlled study was conducted. From December 2019 to January 2022, 500 adult patients who were admitted to the Affiliated Huaihai Hospital of Xuzhou Medical University and had nutritional risk assessed by the modified 2^nd NRS 2002 were recruited into the study. According to burn severity, the patients were divided into common burn patients (n=450) and severe burn patients (n=50). According to the random number table, the patients with common burn were divided into common burn diet nutrition group and common burn diet enteral immunonutrition group, with 225 patients in each group, and the patients with severe burn were divided into severe burn diet enteral non-immunonutrition group and severe burn diet enteral immunonutrition group, with 25 patients in each group. The patients in each group were given the corresponding nutritional support therapies on the basis of routine burn treatment. On post injury day (PID) 1, 3, 7, 14, and 21, the total energy intake and total protein intake of the patients in 4 groups were recorded, the plasma prealbumin, albumin, transferrin, serum immunoglobulin A (IgA), IgG, IgM, peripheral blood CD3 positive T cell percentage, CD4 positive T cell count, CD8 positive T cell count, the ratio of CD4 positive T cells to CD8 positive T cells, natural killer cell percentage, plasma interleukin-6 (IL-6), free mitochondrial DNA (mtDNA) copy number, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) of the patients in 4 groups were detected, and the nitrogen balance of the patients in 4 groups on the day was calculated. On PID 7, 14, and 21, the modified 2^nd NRS 2002 scores of the patients in 4 groups were reassessed. The sepsis incidence during treatment and the length of hospital stay of the patients in 4 groups and the length of intensive care unit (ICU) stay of the patients in the 2 severe burn groups were recorded. Data were statistically analyzed with chi-square test, Fisher's exact probability test, Mann-Whitney U test, independent sample t test, analysis of variance for repeated measurement, and Bonferroni correction. Results: A total of 476 patients completed the trial, with 213 patients in common burn diet nutrition group (112 males and 101 females, aged (37±19) years), 218 patients in common burn diet enteral immunonutrition group (115 males and 103 females, aged (42±16) years), 22 patients in severe burn diet enteral non-immunonutrition group (11 males and 11 females, aged (35±8) years), and 23 patients in severe burn diet enteral immunonutrition group (12 males and 11 females, aged (35±8) years). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher total energy intake on PID 1 (t=6.06, P<0.01), significantly lower total energy intake on PID 7 and significantly lower total protein intake on PID 1 (with t values of 6.17 and 4.59, respectively,P<0.01). On PID 21, the total energy intake of patients in severe burn diet enteral immunonutrition group was significantly lower than that in severe burn diet enteral non-immunonutrition group (t=2.70, P<0.01). The total protein intake of patients in severe burn diet enteral immunonutrition group and severe burn diet enteral non-immunonutrition group were similar at each time point post injury (P>0.05). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with t values of 2.05, 2.33, 2.45, and 2.11, respectively, P<0.05), significantly higher level of albumin on PID 7, 14, and 21 (with t values of 2.30, 2.56, and 2.15, respectively, P<0.05), significantly higher level of transferrin on PID 7 and 14 (with t values of 1.99 and 2.27, respectively, P<0.05), significantly higher nitrogen balance on PID 14 and 21 (with t values of 2.51 and 2.07, respectively, P<0.05), and significantly lower modified 2^nd NRS 2002 score on PID 21 (t=1.99, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, the patients in severe burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with t values of 2.50, 2.64, 2.18, and 2.39, respectively, P<0.05), significantly higher level of albumin​on PID 7, 14, and 21 (with t values of 2.27, 2.39, and 2.69, respectively, P<0.05), significantly higher level of transferrin and nitrogen balance but significantly lower modified 2^nd NRS 2002 score on PID 14 and 21 (with t values of 2.30, 2.35, 2.41, 2.16, 2.31, and 2.73, respectively, P<0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly higher level of IgA and IgG on PID 7, 14, and 21 (with t values of 2.19, 2.36, 2.17, 2.49, 1.97, and 2.24, respectively, P<0.05), significantly higher level of IgM on PID 21 (t=2.06, P<0.05), significantly higher percentage of CD3 positive T cells and ratio of CD4 positive T cells to CD8 positive T cells on PID 3, 7, 14, and 21 (with t values of 2.49, 2.25, 2.33, 2.41, 2.39, 2.24, 2.46, and 2.18, respectively, P<0.05), significantly higher CD4 positive T cell count (with t values of 2.15 and 2.27, respectively, P<0.05) but significantly lower CD8 positive T cell count on PID 14 and 21 (with t values of 2.58 and 2.35, P<0.05), and significantly higher percentage of natural killer cells on PID 7, 14, and 21 (with t values of 2.53, 2.21, and 2.36, respectively, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet immunonutrition group had significantly higher level of IgA on PID 7 and 14 (with t values of 2.15 and 2.03, respectively, P<0.05), significantly higher level of IgG on PID 7, 14, and 21 (with t values of 2.09, 2.56, and 2.15, respectively, P<0.05), significantly higher level of IgM on PID 21 (t=2.08, P<0.05), significantly higher percentage of CD3 positive T cells, CD4 positive T cell count, and percentage of natural killer cells on PID 14 and 21 (with t values of 2.52, 2.14, 2.14, 2.39, 2.56, and 2.19, respectively, P<0.05), significantly lower CD8 positive T cell count but significantly higher ratio of CD4 positive T cells to CD8 positive T cells on PID 7, 14, and 21 (with t values of 2.27, 2.81, 2.01, 2.11, 2.69, and 2.05, respectively, P<0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly lower level of IL-6 (with t values of 2.34 and 2.32, respectively, P<0.05) and significantly lower free mtDNA copy number on PID 14 and 21 (with Z values of -2.28 and -2.34,respectively, P<0.05), significantly lower level of sTREM-1 on PID 7, 14, and 21 (with t values of 2.02, 2.94, and 3.72, respectively, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet enteral immunonutrition group had significantly lower level of IL-6 and sTREM-1 on PID 7, 14, and 21 (with t values of 2.15, 2.29, 2.47, 2.43, 2.07, and 2.32, respectively, P<0.05), and significantly lower free mtDNA copy number on PID 14 and 21 (with Z values of -2.49 and -2.21, respectively, P<0.05). During treatment, the sepsis incidences of patients in 2 common burn groups were similar (P>0.05), the sepsis incidences of patients in 2 severe burn groups were similar (P>0.05). The length of ICU stay of patients in severe burn diet enteral immunonutrition group was (11±3) d, which was significantly shorter than (14±3) d in severe burn diet enteral non-immunonutrition group (t=3.12, P<0.01). The length of hospital stay of patients in common burn diet enteral immunonutrition group was significantly shorter than that in common burn diet nutrition group (t=3.11, P<0.01). The length of hospital stay of patients in severe burn diet enteral non-immunonutrition group was similar to that in severe burn diet enteral immunonutrition group (P>0.05). Conclusions: Enteral immunonutrition support therapy for adult burn patients at nutritional risk assessed by the modified 2^nd NRS 2002 can better improve the nutritional status and the immune function of patients, reduce inflammatory response of the body, and shorten the length of hospital stay in common burn patients and the length of ICU stay in severe burn patients.
Adult ; Burns/therapy* ; DNA, Mitochondrial ; Enteral Nutrition ; Female ; Humans ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Interleukin-6 ; Male ; Middle Aged ; Nitrogen ; Prealbumin ; Prospective Studies ; Sepsis ; Transferrins