45 results about "ACUTE INFLAMMATIONS" patented technology

The invention provides a method for constructing an animal chronic gouty arthritis model, which comprises the following steps: a hyperuricemia model establishment stage: feeding a tested animal with a special feed containing oteracil potassium and yeast; establishing a chronic gouty arthritis model: repeatedly injecting urate into the tested animal; meanwhile, oteracil potassium is used for intragastric administration of the tested animal. On the basis of feeding with oteracil potassium combined with a special yeast feed, oteracil potassium solution is injected, blood uric acid level fluctuation is induced on the basis of blood uric acid increase, and urate crystals are injected repeatedly, so that the disease cause and pathological process of chronic gouty arthritis are simulated to the greatest extent; a chronic gouty arthritis animal model is successfully established by injecting urate crystals into joints of experimental animals repeatedly for a long time, inducing repeated attack of local acute inflammation of the joints and simulating pathological characteristics of chronic gouty arthritis.

The invention belongs to the technical field of medicinal chemistry, and discloses a modular preparation method and application of a protein degradation agent targeting soluble epoxide hydrolase (sEH). The derivative has a structural general formula as shown in a formula (I), wherein X and Y substituent groups can be randomly combined. The compound can effectively degrade sEH level in cells and living bodies, and shows a remarkable protective effect on acute liver inflammation of mice in the living bodies. Particularly, the compound shows excellent degradation activity (EC50 = 2.9 nM) in 1d, can quickly relieve acute inflammation induced by LPS, and can be used for research and development of drugs for acute inflammation related diseases.

The invention belongs to the technical field of medicine, and discloses application of SHLP2 in preparation of medicine for relieving and treating acute and chronic inflammatory pain, and the amino acid sequence of SHLP2 polypeptide is MGVKFFTLSTRFFPSVQRAVPLWTNS. After the SHLP2 polypeptide is treated in an intrathecal (5 [mu] g / 10 [mu] g / 20 [mu] g) injection mode, the SHLP2 polypeptide shows a good treatment effect in an acute inflammation pain model induced by formalin and capsaicin and a chronic inflammation pain model induced by carrageenan and a complete Freund's adjuvant. The SHLP2 is utilized to target a mitochondrial genome, the effect of relieving acute and chronic inflammatory pain is achieved in a central sheath injection mode, and a target different from a traditional analgesic drug can be searched for treatment of the acute and chronic inflammatory pain.

This invention discloses a *Lactobacillus plantarum* YBE2 and its applications. The *Lactobacillus plantarum* provided by this invention, which produces a high amount of extracellular polysaccharides primarily composed of rhamnose, can simultaneously degrade different types of bile salts, including specifically hydrolyzing glycocholic acid. It also exhibits cholesterol-lowering and acute inflammation-relieving effects. Furthermore, *Lactobacillus plantarum* YBE2 can reduce fat deposition in the abdomen of caged broilers, increase intramuscular fat, promote fatty acid deposition in muscles, and reduce plasma total bile acids, triglycerides, and low-density lipoprotein cholesterol. This significantly improves lipid metabolism and muscle quality in poultry, and can be widely applied in caged broiler farming to promote healthy poultry farming and improve farming efficiency.

The invention relates to the field of biological medicine, in particular to polypeptide for inhibiting TBK1 and inflammation and application. The invention provides a series of polypeptides. A cell-penetrating peptide sequence TAT capable of penetrating a cell membrane and a connecting sequence (GSG) are added to the N end of the amino acid sequence of the polypeptides. The sequence can target TBK1 and influence the interaction of TBK1-STING-IRF3 so as to influence the activation of a pathway and achieve the purpose of inhibiting inflammation. The TBK1 targeting peptide LK shows remarkable anti-inflammatory activity in various established mouse inflammation or autoimmune disease models, including a lipopolysaccharide (LPS) induced systemic and acute inflammation model, a dextran sodium sulfate (DSS) induced ulcerative colitis model and a Trex1 defect AGS model. In addition, the polypeptide LK shows even a strong synergistic effect with a PD-1 antibody in cancer immunotherapy in various in vivo tumor models.

A method for treating acute conditions (e.g., acute conditions including acute inflammation), such as cytokine release syndrome, sepsis, and acute kidney injury, using a complex based on a lipid-binding protein.

This invention relates to the field of intelligent medical technology, and more particularly to a method for early warning of intestinal fibrosis in Crohn's disease based on a large model. The method includes: acquiring intestinal MRI image sequences of Crohn's disease patients; inputting the intestinal MRI image sequences into a pre-trained large model for intestinal structure analysis to locate the initial intestinal fibrosis region; determining whether the degree of intestinal luminal stenosis in Crohn's disease patients meets the standard based on the intestinal stenosis progression index, and adjusting the feature contrast threshold of the large model based on the difference; determining whether the acute inflammation masking effect of Crohn's disease patients is adequate based on intestinal wall edema characterization parameters, and adjusting the T2-weighted imaging modal weights of the large model based on the relative difference; and determining whether the patency of the fibrotic permeation channel in Crohn's disease patients is adequate based on the fibrotic permeation resistivity, and adjusting the boundary loss weights of the large model based on the ratio. This invention improves the accuracy of early warning of intestinal fibrosis in Crohn's disease.

The invention discloses a dual-regulation pharmaceutical composition for sepsis treatment, a preparation method and application, and belongs to the technical field of biological medicine, and the pharmaceutical composition comprises doxorubicin liposome, all-trans retinoic acid phospholipid complex nanoparticles and antibiotics. Preferably, the doxorubicin liposome is prepared from the sialic acid modified doxorubicin liposome, the sialic acid modified all-trans retinoic acid phospholipid compound nanoparticles and meropenem. Dynamic monitoring of myeloid-derived suppressor cells MDSCs and sialic acid binding immunoglobulin type lectin-E (SiglecE) positively expressed myeloid-derived suppressor cells, namely SiglecE + MDSCs cell subsets, in the middle and later periods of sepsis is used as an evaluation index of the immunosuppression state, and dual regulation and control of sepsis acute inflammation and immunosuppression are achieved. The method has remarkable advantages in the aspects of increasing the survival rate, precisely targeting immunosuppression, improving the drug delivery efficiency and the like, and a brand new solution is provided for clinical treatment of sepsis.

The invention discloses an effective part for chemoradiotherapy-induced oral mucositis in traditional Chinese medicinal material white flower and a preparation process of the effective part. The effective part is identified as a flavonoid component through standard substance spectrogram comparison. Tests prove that the production process of the effective part is practical and feasible, and the total flavonoids in the finally obtained extracting solution are greater than or equal to 50%. Besides, pharmacodynamic studies show that the effective part has a remarkable bacteriostasis effect on staphylococcus aureus, escherichia coli and candida albicans, the bacteriostasis rate is larger than or equal to 80%, the effective part has a remarkable treatment effect on rat oral mucosa acute inflammation caused by chemoradiotherapy, and the application prospect of the effective part in the adaptation disease is shown.

The invention provides an application of children Danqing Shuanglian granules in preparation of drugs for treating acute inflammation. The acute inflammation comprises acute upper respiratory tract infection, bronchitis, amygdalitis and pneumonia caused by virus infection (H1N1, H3N2, FluB and HRSV) or abnormal immunoreaction. Raw materials of the granules comprise nauclea officinalis, artemisia apiacea, scutellaria baicalensis and other traditional Chinese medicinal materials and anti-inflammatory regulatory peptide. The preparation process comprises the following steps: extracting volatile oil by steam distillation, extracting effective components by combining microwave assistance and ultrasonic enhancement, carrying out beta-cyclodextrin inclusion on polypeptide to enhance the stability, and finally granulating to obtain granules with the water content of less than or equal to 6%. Experiments show that the inhibition rate of the drug to HRSV under the maximum non-toxic concentration reaches 81.8% + / -2.0%, and the therapeutic index is SIgt; 2, the latency period of ammonia water induced mouse cough can be remarkably prolonged, the cough frequency is reduced, the antiviral, anti-inflammatory and antitussive effects are achieved, and a safe and effective traditional Chinese medicine choice is provided for clinical treatment of viral acute inflammation.

The present application relates to treatment of nasal cavity inflammation and mucus hypersecretion. One aspect of the present invention is a method of treatment of rhinitis and rhinosinusitis, wherein the treatment reduces nasal stuffiness, nasal congestion, and phlegm secretion. Reduction of phlegm secretion from the nasal cavity into the pharynx can also reduce cough frequency from infectious and allergic rhinitis. In the preferred embodiment, FEMA 4557, is an example of a molecule, topically applied to the nasal mucosa, that can be used to treat rhinitis. FEMA 4557 is a potent non-irritating suppressor of acute inflammation in the nasal cavity and sinuses, a property not previously described for other topical cooling agents. Thus, FEMA 4557 and related analogs may have therapeutic utility for treating nasal inflammation and mucus hypersecretion.

A platform of drug delivery based on self-lysis of ECN, a constructing method, and use of the platform are provided. The platform of drug delivery comprises ECN, a Pvhb-GST-PhiX174E circuit genetically introduced into ECN, and a drug encapsulation material. When the platform is used as an anti-cancer drug carrier, the platform delivers a high concentration of chemotherapeutic drugs to a tumor site. Additionally, through the Pvhb-GST-PhiX174E circuit, ECN is induced to lyse in response to tumor microenvironment signals, leading to cell death in the tumor region and enhancing ECN's biosafety in vivo. Furthermore, ECN within the platform of drug delivery based on self-lysis of ECN serves as an immune adjuvant, stimulates the immune cell activity in the tumor site, triggers acute inflammation, and strengthens the anti-tumor effect, thereby achieving multi-modal anti-tumor therapy through live-cell, chemotherapy, and immunotherapy.

The invention belongs to the technical field of drug development, and particularly relates to stigmasterol hydrogen sulfide derivatives and application thereof in anti-inflammation, anti-oxidation and anti-fibrosis. The molecular formula of the stigmasterol hydrogen sulfide derivative is C42H56O4S3. The stigmasterol hydrogen sulfide derivative disclosed by the invention can be used as an anti-inflammatory, anti-oxidation and anti-fibrosis drug, and shows an ear swelling inhibition effect equivalent to that of a positive drug diclofenac in acute inflammation; the pain threshold is obviously improved when the compound is used as an analgesic drug. The compound has good safety, and CCK-8 experiments show that the compound has no significant influence on the survival rate of macrophages under the treatment concentration (2-16 [mu] M), and has low cytotoxicity.

The invention belongs to the technical field of biology, and discloses application of a composition of neoagaro-oligosaccharide and astaxanthin in preparation of a transdermal drug for treating osteoarthritis and a composite gel preparation. The composition provided by the invention comprises neoagaro-oligosaccharide, astaxanthin, carbomer and alginate in a mass ratio of (1-10): (1-10): (0.01-0.5): (0.1-1), and can realize efficient enrichment of neoagaro-oligosaccharide and astaxanthin in an articular cavity through a substance diffusion path of skin penetration, deep tissue diffusion, joint capsule permeation and articular cavity enrichment, so that the content of neoagaro-oligosaccharide and astaxanthin in the articular cavity is improved, and the content of astaxanthin in the articular cavity is reduced. The new agar oligosaccharide and the astaxanthin have an excellent synergistic effect, so that the acute inflammation symptom of gouty osteoarthritis can be efficiently relieved, the progress of the disease course is blocked, the pathological change of joint tissue is repaired, and the new agar oligosaccharide and the astaxanthin have an excellent application prospect in preparation of the transdermal medicine for treating osteoarthritis.

The invention discloses an establishment method and application of a rat acute inflammation model for simulating clinical inflammation, and relates to the technical field of biology. According to the invention, lipopolysaccharide is taken as a modeling drug, continuous intraperitoneal injection is carried out on a rat at the dosage of 20-40 [mu] g / kg, 30-50 [mu] g / kg and 40-60 [mu] g / kg for three days, and expression and release of interleukin-6 are promoted by activating a Toll-like receptor 4 signal channel, so that the acute inflammation model of the rat is established. The established rat acute inflammation model can cause significant increase of inflammatory biomarkers such as interleukin-6, C-reactive protein and alpha1 acid glycoprotein on the basis of not causing rat liver and kidney injury, and is more similar to clinical acute inflammation states; and a new experimental animal model is provided for exploring the influence of acute inflammation on pharmacokinetics of drugs.

In screening cooling agents for their actions in the oral cavity, the molecule FEMA 4557, registered for use in chewing gum and hard candy, produced a long-lasting, stinging, and painful cold, like ice chips on the throat. To further study its properties, FEMA 4557 was formulated as a topical gel and shown to relieve skin discomfort without causing any skin injury or irritation. FEMA 4557 relieved inflammation from flea bites and a bumble bee sting and relieved the inflammation of dermatological disorders such as skin allergy, urticaria, and thermal injury. The duration of the anti-inflammatory action was for several hours after a single application. The pharmacological potency of FEMA 4557 did not correlate to the EC50 potency at the TRPM8 receptor. Surprisingly, when FEMA 4557 was delivered to the inflamed nasal mucosa with a compressor-nebulizer, it relieved nasal stuffiness and inhibited phlegm secretion in subjects with rhinitis, as measured by patient-outcome responses and an objective gravimetric method, respectively. FEMA 4557 was also effective for treating rhinitis when administered in nose drops or in a rinse. The effective therapeutic amount of FEMA 4557 was about 1 to 5 mg per retained dose. The conclusion is that FEMA 4557 is a potent non-irritating suppressor of acute inflammation in the nasal cavity and sinuses, a property not previously described for other topical cooling agents. Thus, FEMA 4557 and related analogs may have therapeutic utility for treating nasal inflammation and mucus hypersecretion.

Methods for treating acute conditions (e.g., acute conditions comprising acute inflammation), such as cytokine release syndrome, sepsis and acute kidney injury using lipid binding protein-based complexes.

The invention relates to a 5-aminohexahydro-6,7,8-trihydroxy-3H-oxazo-lo[3,4-a]pyridin-3-one (i.e. 2,3,4-trihydroxy-5N,6O-oxomethylidene-nojirimycin-1-amine) glycol-ipid mimetic derivative of formula (I) acting as antagonists or agonist of the TLR4 for the treatment and / or prevention of an immune disease such as e.g. acute inflammation, chronic disease allergy, the Metabolic Syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), immune mediated hepatitis, an autoimmune disease, graft rejection pathology, inflammatory bowel disease, atherosclerosis and airway hyperactivity, such as e.g. asthma and allergic rhinitis. An exemplary compound is e.g. example 1, compound (1).

The invention discloses a reagent composition for constructing an acute inflammation model and a construction method. In the invention, local slow release of TNF-alpha is realized through the temperature-sensitive hydrogel, the limitation of traditional systemic administration is broken through, the gradient diffusion characteristic of inflammatory factors in a focus area is restored, and model distortion caused by excessive activation of systemic immune response is avoided. The stepped delivery of the lipopolysaccharide, the prostaglandin E2 analogue and the IL-1beta histamine aerosol effectively covers key pathological links such as vascular permeability change, neutrophil infiltration, oxidative stress and the like through multi-channel synergistic amplification of an inflammation cascade effect. Dynamic balance maintenance of the active oxygen scavenger significantly improves the stability of the model, ensures that the inflammation process is controllable and reversible, provides a reliable window period for drug testing, and real-time fluorescence monitoring and end-point multi-index joint inspection form a closed-loop verification system, so that dynamic migration characteristics of inflammation can be captured, the end damage degree can be quantified, and the accuracy of drug detection is improved. And a complete data link from a process to a result is provided for mechanism research.

The application discloses a three-layer time sequence regulation type inflammation targeting composite repair system for repairing endometrial injury and a preparation method and application thereof. The system is a three-layer composite structure, which comprises, from outside to inside, (1) an outer ROS response hydrogel layer loaded with anti-inflammatory drugs, which can respond to early high expression of active oxygen to rapidly degrade the drugs, so that acute inflammation is inhibited; (2) a middle layer of targeted delivery and metabolic repair, which is a M1 macrophage membrane pseudo-loaded drug liposome (NMN@M-Lipo), which is exposed after the degradation of the outer hydrogel, actively targets the inflammation lesion through the M1 membrane, and slowly releases nicotinamide mononucleotide (NMN) to restore cell energy metabolism; and (3) an inner layer of cell recruitment and regeneration, which is a decellularized matrix scaffold loaded with SDF-1 alpha, which continuously releases SDF-1 alpha to recruit endogenous stem cells in the later repair stage, and promotes functional regeneration of the endometrium. The application utilizes the time sequence microenvironment changes of endometrial repair, and realizes the cascade regulation of 'anti-inflammation first, metabolic repair second, and regeneration promotion third'. Animal experiments show that the system can significantly restore the reproductive function of the injured endometrium and improve the number of offspring.

The application discloses a high-temperature-resistant self-delivery circular RNA and a synthesis method and application thereof in preparation of anti-inflammatory drugs, and relates to the technical field of biological medicines.The nucleotide sequence of the high-temperature-resistant self-delivery circular RNA is shown as SEQ ID NO.1.Through nucleic acid extraction and high-throughput sequencing analysis on the decoction of Radix Curcumae, combined with a reverse splicing site identification method, a specific circular RNA is screened and named as circW77.Further research shows that the circW77 can stably exist in a 100 DEG C environment and can significantly inhibit the expression of inflammation-related factors, thereby playing an anti-inflammatory role.Through verification of an in-vitro cell inflammation model, it is found that the circW77 can enter cells without the aid of a carrier and can effectively reduce the transcription and secretion of proinflammatory factors;in-vivo research shows that the circW77 can relieve acute inflammation and non-alcoholic fatty liver inflammation.

A catastrophe-theoretic approach is provided for predicting an occurrence of an acute inflammatory condition or event (e.g., SIRS or sepsis) for a human patient based on a time series of monitored vital signs values measured from a patient, and in some instances, for providing advanced notice to clinicians or caregivers when such an acute inflammatory event is forecasted or modifying treatment for the patient, according to the predicted likelihood. In particular, an acute inflammatory condition management system is provided for determining a likelihood of near-term future significant acute inflammation in human patients. Embodiments of the disclosure described herein may provide a forecasted risk for future significant acute inflammation within a time horizon comprising a future time interval. In one embodiment, the future time interval is from 30 min to approximately 8 hours into the future, and may be dependent on the frequency of vital signs measurements.

The invention provides application of plant lactobacillus in prevention and / or treatment of acute inflammation caused by LPS, and relates to the technical field of microorganisms, for mice with acute inflammation caused by LPS, plant lactobacillus DY6 can inhibit immune system transition activation and lymphocyte abnormal proliferation by adjusting blood routine indexes and visceral organ indexes; the anti-inflammatory effect is achieved by down-regulating inflammatory factors and neutrophil infiltration markers and inhibiting a TLR4 signal channel; redox balance is adjusted, intestinal flora unbalance is improved, and the effect of preventing and / or treating acute inflammation caused by LPS is achieved.

The invention belongs to the technical field of externally applied anti-inflammation compositions, and particularly relates to an anti-inflammation and detumescence externally applied composition and application thereof.The anti-inflammation and detumescence externally applied composition is prepared from mirabilite particles and borneol powder according to the mass ratio of 1000: (2-6), and 8%-10% of crystal water is removed from the mirabilite particles, and the particle size of the mirabilite particles is 5-30 meshes; the external composition disclosed by the invention has excellent anti-inflammatory and detumescence effects on acute inflammation, and meanwhile, toxins are eliminated and poisoning symptoms are relieved; the external medicine composition is good in medicine effect and high in safety, the external medicine composition can take effect after being used for half an hour, a medicine package becomes wet after being used for 6-8 hours, and symptoms are obviously relieved; the invention provides a method for promoting recovery for local pathological states of acute inflammation, and the effect is remarkable; the invention solves the problem that no medicine or method with good effect and wide anti-inflammatory effect exists in the market at present, and provides an important treatment means and a new way for research on treatment medicines for various acute inflammations such as new coronavirus infection and acute pancreatitis.

The application provides a fast-acting flunixin meglumine injection and a preparation method thereof, and belongs to the technical field of veterinary medicine, and contains the following components: flunixin meglumine 5-10 (w / v) %, alpha-pyrrolidone 10-30 (w / v) %, hydrophilic solvent 0.5-1 (w / v) %, antioxidant 0.1-0.3 (w / v) % and the balance of water for injection. The application takes flunixin meglumine as the main drug, matches alpha-pyrrolidone as a solvent and a targeting guide distribution component, uses a hydrophilic solvent to assist dissolution and promote absorption, and uses an antioxidant to inhibit the oxidative degradation of the main drug, so that the dissolution and absorption rate of the main drug and the target tissue distribution efficiency can be effectively improved, the storage stability can be ensured, the bacterial endotoxin and the injection site redness rate meet the requirements, the acute inflammation and pain of livestock and poultry can be quickly and efficiently relieved, and the demand for instant intervention in large-scale breeding can be met.

The invention discloses an application of (1S, 2S, 4R)-1-methyl-2, 4-bis (prop-1-ene-2-yl)-1-vinylcyclohexane (alias, beta-elemene) in preparation of a medicine, and the medicine is used for treating or preventing diseases related to acute inflammation, such as acute inflammation, acute inflammation, acute inflammation, acute inflammation and acute inflammation. Comprise acute lung injury related to sepsis caused by lipopolysaccharide (LPS), acute edema pancreatitis induced by ceratidine and severe necrotizing pancreatitis induced by L-arginine, but are not limited to the inducers, and specifically, the inducers can be used for inducing acute lung injury related to sepsis caused by lipopolysaccharide (LPS), acute edema pancreatitis induced by ceratidine and severe necrotizing pancreatitis induced by L-arginine. The medicine can inhibit or improve pathological injury and inflammatory response of lung tissue and pancreatic tissue of acute lung injury and acute pancreatitis.

The invention provides bacteriostatic gel for women and a preparation method thereof, and belongs to the technical field of gynecological gel. The gel comprises 97%-99% of a multi-layer structure base material and 1%-3% of a natural plant effective component. The effective components comprise seven natural components such as a fructus cnidii extract, a helichthys italica extract and a radix sophorae flavescentis extract, and the base material comprises multiple layers of hydrogel. In the use process of the bacteriostatic gel for women, the fructus cnidii extract and the radix sophorae flavescentis extract can directly kill pathogenic bacteria of bacterial vaginitis and have an inhibition effect on HPV viruses, and the tea leaf extract and the psidium guajava leaf extract have antioxidant and bacteriostatic characteristics, so that the capacity of removing harmful microorganisms can be further enhanced. And the base material comprising multiple layers of hydrogel not only can enable bacteriostatic and anti-inflammatory components to continuously act on a focus part and improve the treatment effect on vaginitis and vulvitis, but also can reduce direct stimulation of subsequent effective components on sensitive mucous membranes, and is especially suitable for mucous membrane fragile scenes such as gynecologic operations and acute inflammation stages.

The present invention belongs to the field of medical examination, and in particular to a latex immunoturbidimetric assay kit for complement C1q. The kit of the present invention includes reagent 1 and reagent 2, wherein the reagent 1 is composed of tris(hydroxymethyl)aminomethane, sodium chloride, Triton X‑100, bovine serum albumin, a liquid biological preservative and zinc chloride; the reagent 2 is composed of tris(hydroxymethyl)aminomethane, sodium chloride, C1q antibody latex particles, bovine serum albumin and alanine. The present invention also provides a preparation method and a detection method of the above-mentioned kit, which has the advantages of simple detection method, wider linear range, higher precision and accuracy. The test results meet the clinical diagnosis criteria, and the method can be effectively applied to the diagnosis of diseases such as acute inflammation, early infectious diseases, tissue damage, and acute myocardial infarction.

The present invention relates to a method of treating an acute inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a pyrimidinone compound.

The invention relates to the technical field of intelligent medicine, in particular to a Crohn disease intestinal fibrosis condition early warning method based on large model driving, which comprises the following steps: acquiring an intestinal MRI image sequence of a Crohn disease patient; inputting the intestinal MRI image sequence into a pre-trained intestinal structure analysis large model, and positioning the position of an initial intestinal fibrosis region; determining whether the intestinal lumen stenosis degree of the patient with the Crohn disease reaches the standard or not based on the intestinal lumen stenosis progress index, and determining a feature comparison threshold value for adjusting the large model according to the difference value; determining whether the acute inflammation shielding effect of the patient with the Crohn disease is qualified or not based on the intestinal wall edema characterization parameters, and determining and adjusting the T2 weighted imaging modal weight of the large model according to the relative difference; and determining whether the fibrosis seepage channel smoothness of the patient with the Crohn disease is qualified or not based on the fibrosis seepage resistivity, and determining and adjusting the boundary loss weight of the large model according to the ratio. The early warning accuracy of the intestinal fibrosis condition of the Crohn's disease is improved.