RESUMO
Craniocerebral injury with seawater immersion is a special kind of compound injury, with low temperature, high permeability, high alkali, high salt content, and bacterial infection being the main causes. The injury is also characterized with complex damage mechanisms, difficulty to treat, and poor prognosis. At present, the damage mechanisms of craniocerebral injury with seawater immersion are mainly studied by establishing the experimental animal models at the levels of tissue, cell, organelle, molecule, etc. However, the craniocerebral injury with seawater immersion is more complex than the simple onshore craniocerebral injury, therefore, a stable disease model is not easy to construct. Most researches on the specific injury mechanisms are relatively single and one-sided, with many different views in existence, and the damage mechanisms of craniocerebral injury with seawater immersion have hitherto not been clear. The authors reviewed the research progress in the damage mechanisms of craniocerebral injury with seawater immersion, in order to promote the in-depth study of the mechanism of craniocerebral injury with seawater immersion and provide reference for its clinical treatment.
RESUMO
Traumatic brain injury (TBI) has been recognized as a risk factor for developing dementia. Currently, around 69 million people worldwide suffer from TBI each year, while the overall incidence of TBI among Chinese residents is on a rapid rise. Such a large population of TBI patients may lead to a future surge in the number of dementia patients, bringing heavy burdens on families and societies. However, it seems to be suggested by numerous studies that not all TBI patients are associated with an increased risk of dementia. Dementia can result in disability as well as interfere with caregivers ′ normal lives. Therefore, it will be significant to clarify the relationship between TBI and dementia as well as explain the process of onset and development of post-TBI dementia. In this study, the authors summarize post-TBI dementia from aspects of influencing factors and pathogenic mechanisms, so as to provide relevant references for related studies, therapy, and prophylaxis of post-TBI dementia.
RESUMO
The condition of patients with severe traumatic brain injury (sTBI) complicated by corona virus 2019 disease (COVID-19) is complex. sTBI can significantly increase the probability of COVID-19 developing into severe or critical stage, while COVID-19 can also increase the surgical risk of sTBI and the severity of postoperative lung lesions. There are many contradictions in the treatment process, which brings difficulties to the clinical treatment of such patients. Up to now, there are few clinical studies and therapeutic norms relevant to sTBI complicated by COVID-19. In order to standardize the clinical treatment of such patients, Critical Care Medicine Branch of China International Exchange and Promotive Association for Medical and Healthcare and Editorial Board of Chinese Journal of Trauma organized relevant experts to formulate the Chinese expert consensus on clinical treatment of adult patients with severe traumatic brain injury complicated by corona virus infection 2019 ( version 2023) based on the joint prevention and control mechanism scheme of the State Council and domestic and foreign literatures on sTBI and COVID-19 in the past 3 years of the international epidemic. Fifteen recommendations focused on emergency treatment, emergency surgery and comprehensive management were put forward to provide a guidance for the diagnosis and treatment of sTBI complicated by COVID-19.
RESUMO
Traumatic cerebrospinal fluid leakage commonly presents in traumatic brain injury patients, and it may lead to complications such as meningitis, ventriculitis, brain abscess, subdural hematoma or tension pneumocephalus. When misdiagnosed or inappropriately treated, traumatic cerebrospinal fluid leakage may result in severe complications and may be life-threatening. Some traumatic cerebrospinal fluid leakage has concealed manifestations and is prone to misdiagnosis. Due to different sites and mechanisms of trauma and degree of cerebrospinal fluid leak, treatments for traumatic cerebrospinal fluid leakage varies greatly. Hence, the Craniocerebral Trauma Professional Group of Neurosurgery Branch of Chinese Medical Association and the Neurological Injury Professional Group of Trauma Branch of Chinese Medical Association organized relevant experts to formulate the " Chinese expert consensus on the diagnosis and treatment of traumatic cerebrospinal fluid leakage in adults ( version 2023)" based on existing clinical evidence and experience. The consensus consisted of 16 recommendations, covering the leakage diagnosis, localization, treatments, and intracranial infection prevention, so as to standardize the diagnosis and treatment of traumatic cerebrospinal fluid leakage and improve the overall prognosis of the patients.
RESUMO
Posttraumatic stress disorder (PTSD), the most common mental illness after patients suffer physically or emotionally from traumatic events, can cause persistently strong, painful and terrible avoidance symptoms, emotional and cognitive changes, causing psychologically strong stimulation and heavy burden to patients and even leading to some extreme behavioral reactions. Traumatic brain injury (TBI) is an important factor in the occurrence of PTSD, both of which shares many similar pathological overlaps, and may coexist and interact with each other. The hippocampus and amygdala play a central role in the pathogenesis of PTSD, but the specific cellular and molecular and neural circuit mechanisms are still unclear. About two-thirds of the patients still meet the diagnostic criteria for PTSD after psychotherapy. However, the current treatment methods are complicated and not unified, and patients treated with medications may have adverse drug reactions, poor treatment outcomes and recurrence. Therefore, it is of great significance to further clarify the occurrence and development of PTSD in TBI patients. The authors reviewed the research progress of the pathogenesis and treatment of PTSD in TBI patients, so as to provide reference for the related research and treatment of PTSD in TBI patients.
RESUMO
Traumatic rib fractures are the most common injury in thoracic trauma. Previously,the patients with traumatic rib fractures were mostly treated non-surgically,of which 50%,especially those combined with flail chest presented chronic pain or chest wall deformities and over 30% had long-term disabilities,being unable to retain a full-time job. In the past two decades,thanks to the development of internal fixation material technology,the surgical treatment of rib fractures has achieved good outcomes. However,there are still some problems in clinical treatment,including inconsistency in surgical treatment and quality control in medical services. The current consensuses on the management of regional traumatic rib fractures published at home and abroad mainly focus on the guidance of the overall treatment decisions and plans,and relevant clinical guidelines abroad lacks progress in surgical treatment of rib fractures in recent years. Therefore,the Chinese Society of Traumatology affiliated to Chinese Medical Association and Chinese College of Trauma Surgeons affiliated to Chinese Medical Doctor Association,in conjunction with national multidisciplinary experts,formulate the Chinese Consensus for Surgical Treatment of Traumatic Rib Fractures(2021)following the principle of evidence-based medicine,scientific nature and practicality. This expert consensus puts forward some clear,applicable,and graded recommendations from aspects of preoperative imaging evaluation,surgical indications,timing of surgery,surgical methods,rib fracture sites for surgical fixation,internal fixation methods and material selections,treatment of combined injuries in rib fractures,in order to provide references for surgical treatment of traumatic rib fractures.
RESUMO
Ship surgery is one of the core competence elements for naval warfare treatment. It includes not only surgical forces in hospital ships, but also the surgical units temporarily deployed on large ships. The authors review the history of the development of ship surgery in China, analyze the present problems faced by ship surgery, and propose future development direction of ship surgery, in an attempt to promote orderly, standardized and rapid development in the field of ship surgery in China.
RESUMO
Traumatic optic nerve injury is common in patients with traumatic brain injury,mainly in young adults.The optic nerve has no regenerative function,leaving problems of visual field defect and loss of vision and causing high disability rate among patients with traumatic brain injury.The current clinical treatments of traumatic optic nerve injury are hormonotherapy and decompression of optic nerve canal,lacking definite clinical efficacy and treatment norm.In recent years,a series of brand new treatments,such as neuroprotective drugs,neurotrophic factor therapy,nerve transplantation,stem cell therapy and gene therapy,have offered new perspectives for solving the problem of high disability rate of traumatic optic nerve injury clinically.This article attempts to summarize the status quo and latest progress in clinical treatment of traumatic optic nerve injury based on relevant literature in recent years,which can serve as reference for clinicians in choosing the optimal therapeutic regimen.
RESUMO
Traumatic brain injury (TBI) is a leading cause of death and disability in young adults,leaving patients with multiple sequelae and dysfunction,including cognition,sensation,motor dysfunction and chronic pain.Rehabilitative treatment of functional disorders can help improve the quality of life for TBI patients and help them return to work.Currently,medication and exercise rehabilitation are often adopted,yet with certain limitations.Non-invasive brain stimulation (NBS) mainly includes transcranial magnetic stimulation,transcranial direct current stimulation,low-energy laser therapy,and transcranial Doppler ultrasound.Currently,many studies have been exploring the application of NBS in TBI treatment.NBS is expected to play an important role in improving cognition,sensation,motor function and alleviating chronic pain,providing a new approach for the rehabilitation of TBI patients.This article reviews the common dysfunction after TBI and NBS application in TBI treatment in order to provide reference for its further application.
RESUMO
Objective To discuss the effects and the possible mechanismof curcumin on pulmonary functions and expression of TGF-β1 and NF-κB in paraquat-induced pulmonary fibrosis of rats.Methods SPF Wistar rats were randomly (random number) divided into three groups:paraquat-poisoned group (PQ group,with PQ 50 mg/kg by gavage),Curcumin-treatment group (PC group after 30,with curcumin (200 mg/kg) by intraperitoneal injection),and Blank group (B group,with same volume of sterile saline at the same time).After 14 d,the lung function of rats was observed,and the expression of TGF-β1 and NF-κB protein were detected by immunohistochemistry.Results The survival rates of mice significant difference in the PC and PQ groups with (70.83% vs.41.67%,P <0.05).Compared with the B group,lung function index (Te,PIF,PEF,EF50,TV,F) of PQ group significantly decreased (P < 0.05,P < 0.01).Compared with the PQ group,lung function index (Te,PEF,TV,F) of PC group significantly increased (P < 0.05 or P < 0.01).There are some expression of lung tissues of rats with TGF-β1,NF-κB in B group.Compared with B group,PQ group significantly enhanced (P <0.01or P <0.05).Compared with the PQ,PC group significantly decreased (P < 0.01 or P < 0.05).Conclusions Curcumin can relieve paraquat-induced pulmonary fibrosis by inhibiting the over expression of TGF-β1,NF-κB in lung tissue of rats.
RESUMO
Objective To observe the effects of curcumin on pulmonary fibrosis and functions on paraquat (PQ)-challenged rats, and investigate the possible mechanism. Methods 108 SPF Wistar rats were divided into three groups according to random number sheet: normal saline (NS) control group, PQ model group and curcumin-treatment group. The rats in each group were subdivided into three subgroups according to different time points (3, 7, 14 days), with 12 rats in each subgroup. PQ-challenged models were reproduced by intragastrical administration of PQ solution 50 mg/kg, and those in NS control group were given the equal volume of NS. After 30 minutes, the rats in curcumin-treatment group were given 200 mg/kg of curcumin by intraperitoneal injection, and those in NS control group and PQ model group were given the equal volume of NS. At 3, 7, 14 days, the tidal volume (VT) was examined, and the blood was drawn from femoral artery for blood gas analysis. Then the rats were sacrificed and the lung tissues were harvested, the hydroxyproline (Hyp) content was measured by alkaline hydrolysis; the expression of transforming growth factor-β1 (TGF-β1) was determined by immuno-histochemistry; the distribution and the change of the pulmonary collagen fiber were observed after Masson staining. Results After exposure to PQ, the VT and arterial partial pressure of oxygen (PaO2) were decreased gradually, and the levels of Hyp and TGF-β1 were increased gradually, reaching the trough or the peak at 14 days, which were significantly lower or higher than those in NS control group [14-day VT (mL):1.52±0.33 vs. 2.81±0.47, 14-day PaO2(kPa): 5.87±0.95 vs. 14.15±1.02, 14-day Hyp (μg/mg): 3.12±0.06 vs. 1.14±0.05, 14-day TGF-β1 (integral A value): 29.72±4.27 vs. 4.15±0.52, all P < 0.01]. After intervene of curcumin, the parameters were significantly improved as compared with those of PQ model group [14-day VT (mL): 2.34±0.19 vs. 1.52±0.33, 14-day PaO2(kPa): 10.23±1.01 vs. 5.87±0.95, 14-day Hyp (μg/mg): 2.31±0.04 vs. 3.12±0.06, 14-day TGF-β1 (integral A value): 15.46±2.89 vs. 29.72±4.27, all P < 0.01]. It was shown by Masson staining that in PQ model group, with the PQ-poisoned time prolonging, diffused pulmonary fibrosis and a large number of collagen deposition were observed gradually, and the most serious collagen deposition was observed at 14 days; after intervene of curcumin, pulmonary fibrosis was alleviated significantly at different time points as compared with the PQ model group. Conclusion Curcumin can enhance the pulmonary function by reducing the deposition of collagen fiber and inhabiting pulmonary fibrosis of PQ-poisoned rats.
RESUMO
Objective To observe the effects of curcumin on the lung collagen area and the expression of TNF-α,IL-6 and NE in paraquat-poisoning rats at different intervals,and discuss the possible mechanism of curcumin antagonizing paraquat poisoning.Methods A total of 108 SPF Wistar rats were divided into three groups (random number):blank group (B group) for control,paraquat poisonin group (PQ group) and curcumin-treatment group (PC group).The rats of PQ group and PC group were given paraquat (50 mg/kg) by gavage,and the rats of B group were given equal volume of sterile saline solution at the same time.Thirty minutes later,the rats of PC group were given curcumin (200 mg/kg) by intraperitoneal injection,and rats of B group and PC group were given equal volume of sterile saline solution instead.At 3 d,7 d and 14 d after modeling,the distribution and pathological changes of lung tissue and collagen fiber were observed by HE and Masson staining.The concentration of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were detected by enzyme-immunoassay.The lung neutrophil elastase (NE)expression was observed by immuno-histochemical method.Result Compared with B group,PQ group had pulmonary alveolitis in different degrees at different intervals,and the most serious pulmonary alveolitis was observed at 7 d after modeling.Diffused pulmonary fibrosis of the lung tissue and a large area of collagen fiber deposition were observed especially at 14 d after modeling,as well as the expression of NE was observed obviously,especially at 14 d after modeling.The concentration of TNF-α,IL-6 in serum were significantly increased (P < 0.05,P < 0.01).Compared with PQ group,the pulmonary alveolitis and fibrosis obviously in PC group with obvious reduction in the expression of NE and significant descrease in the concentrations of TNF-o and IL-6 (P < 0.05).Conclusion Inhabiting inflammatory factors to alleviate the seriousness of alveolar inflammation and pulmonary fibrosis might be one of the mechanism of treatment with curcumin for paraquat poisoning rats.
RESUMO
BACKGROUND:Core decompression and autogenous bone grafts are widely used in treatment of early avascular necrosis of femoral head. According to the report, the success rate of this therapy has obvious difference;the reasons may be related to inaccurate puncture location and secondary damnification of repeated puncture. OBJECTIVE:To reconstruct three-dimensional model of femoral head necrosis by Mimics software for reappearance of lesions in the necrotic area to realize measurement of necrotic area of the femoral head and estimation of its volume. METHODS:We restructured images by using multi-slice spiral CT Syngommvvp VE23A workstation, Inspace software and NeuroDSA software. Hip CT data in DICOM format were imported into Mimics 13.0 software systems. Necrotic area of the femoral head was reconstructed with Mimics SimuIation software to truly reproduce the integrated form, scope and stereochemical structure of the necrotic area so as to achieve the measurement of the necrotic area of the femoral head and the volume estimation. We designed the best core decompression channel, simulated core decompression surgery, so that the patients could refer to the best simulated decompression path in the operation of core decompression. RESULTS AND CONCLUSION:(1) Among 36 patients (48 hips) with avascular necrosis of femoral head, there were phase I in 8 hips, accounting for 17%, phase II in 28 hips, accounting for 58%, and phase III in 12 hips, accounting for 25%. (2) The volume of necrotic area was (1 475.48±647.342) mm3 in the phase I, (4 571.77±2 344.55) mm3 in the phase II, and (4 836.46±2 969.33) mm3 in the phase III. (3) We simulated the core decompression based on the radius of the sphere of the necrotic area as parameter in the Mimics Simulation software module, and then completely cleared the necrotic area. (4) Surgery can more clearly understand information and stereochemical structure of the necrotic area with Mimics software to simulate the core decompression. It is the theoretical basis of operation.
RESUMO
BACKGROUND:As the high proliferation and low apoptosis of the bone marrow in polycythemia vera patients, hematopoietic stem cels transplanted into NOD/SCID mice can differentiate into erythroid cels, but whether hematopoietic stem cels transplantation could improve the hematopoietic function of aplastic anemia mice is not yet reported. OBJECTIVE:To investigate whether transplantation of bone marrow mononuclear cels with JAK2V617F mutation from polycythemia vera patients can influence hematopoietic reconstruction in aplastic anemia mice. METHODS:Severe aplastic anemia mouse models were established by using recombinant human interferon-γplus busulfan, and then, these mouse models were randomly divided into experimental group (n=10) and control group (n=10). Bone marrow mononuclear cels isolated from polycythemia vera patients with positive JAK2V617F mutation were transplanted into the mice in the experimental group via tail vein at 5 days after drug withdrawal.The same volume of normal saline was administered to the control group. Routine peripheral blood test, morphology of bone marrow cels, bone marrow biopsy, and percentage of CD45+ cels in the peripheral blood and marrow were determined at 14 days after transplantation. RESULTS AND CONCLUSION: At 14 days after transplantation, pancytopenia occurred in the experimental group, bone marrow smears showed scattered lymphocytes and hematopoietic progenitors, and bone marrow biopsy presented that hematopoietic tissues were reduced and a smal amount of granulocyte cels and erythroblasts could be seen, but megakaryocytes were rare. In contrast to the control group, there was no improvement in the hematopoietic function of mice in the experimental group. CD45+ cels were detectable in the peripheral blood and bone marrow in the experimental group, but not in the control group; and a higher percentage of CD45+ cels was measured in the bone marrow than in the peripheral blood of experimental group mice. Experimental findings indicate that bone marrow mononuclear cels from polycythemia vera patients with positive JAK2V617F mutation can be engrafted into aplastic anemia mice, but cannot improve the hematopoietic function of mice.
RESUMO
Objective To determine the incidence of lung infection and associated factors in patients with traumatic brain injury for the sake of improving the clinical outcomes.Methods A retrospective analysis was made on records of 325 patients who hospitalized between January 2014 and June 2014.There were 198 male and 127 female patients,aged 11-78 years [(38.4 ±8.3) years].A total of 172 patients were injured in traffic accidents,80 in high falls,56 in blow accidents,and 17 in others.Lung infection status was documented and related risk factors were analyzed.Results Thirty-two patients (9.8%) had lung infection.Pseudomonas aeruginosa amounting to 12 strains was the most common pathogenic bacteria.Univariate analysis showed mechanical ventilation,airway open,and aspiration were significantly related to lung infection.Logistic regression identified aspiration (OR =2.891,P < 0.05) and mechanical ventilation (OR =1.323,P < 0.05) as the independent risk factors for lung infection.Conclusions Lung infection is a serious complication of traumatic brain injury,affected largely by aspiration and mechanical ventilation.Active preventions,reductions of risk factors,and early treatments should be done to get the best efficacy.
RESUMO
BACKGROUND:It is important to establish an ideal mouse model of severe aplastic anemia for investigating the mechanism and finding new therapies for aplastic anemia. OBJECTIVE:To establish a severe aplastic anemia mouse model by using recombinant human interferon-γand busulfan. METHODS:Sixty healthy Kunming female mice were randomly divided into two groups:model group (n=50) and control group (n=10). The model group was given recombinant human interferon-γat a dose of 1×104 U/d by intraperitoneal injection and busulfan at a dose of 18 mg/(kg·d) through stomach feeding for 7 days. The same volume of physiological saline was given to control group. Multi-parameters, including general condition, body weight, blood cellcount, morphology and biopsy of bone marrow were analyzed in two groups. RESULTS AND CONCLUSION:At day 7 after treatment, the weight, white blood cellcount, hemoglobin, blood platelet, reticulocyte count in model group were significantly lower than control group (P<0.05). Bone marrow smears and biopsy of model group showed marked reduction of bone marrow proliferation and increases of percentages of non-hematopoietic cellclusters and adipose tissue. The oil drop and fat vacuole were apparently seen in the model group. Severe aplastic anemia mouse model can be established by using recombinant human interferon-γand busulfan successful y, which is economic, stable and easy to operate.
RESUMO
Objective To evaluate the significance of platelet activation and the expression of inter-leukin (IL)-1β in patients with RA. Methods The activation of platelets and the expression of IL-1β in pla-telets in 50 RA patients(22 high-active, 28 mediate/low active ) and 30 normal controls were determined us-ing flow cytometry. Meanwhile, inflammatory indicators such as erythrocyte sedimentation(ESR), C-reactive protein (CRP) and DAS28 were also recorded. T test and correlation analysis were performed. Results The platelet activation in RA group(19.2±4.8) was higher than the control group(9.0±2.9)(t=10.5, P=0.001). The expression of IL-1β in platelets in RA group(41±11) was higher than control group(21±8)(t=9.01, P =0.000) .The platelet activation in high-active RA group(22 ±4) was higher than mediate/low active RA group(17 ±4)(t =3.96,P =0.001). The expression of IL-1β in platelets in high-active RA group(45 ±10) was higher than mediate/low active RA group (38 ±10)(t =2.329,P =0.024). The expression of IL-1β in platelets in RA group was positively correlated with the level of ESR、CRP and DAS28 (r value and P value were 0.576, 0.578, 0.618 and 0.000, 0.000, 0.000 respectively). Conclusion The platelets of patients with RA are activated and may suggest that IL-1β, which may associate with disease activity. Our research suggest that platelet may play a role in the inflammatory process of RA by secreting IL-1β.
RESUMO
Objective To investigate the hemostatic effect of the radial hemostatic compression device(TR Band hemostatic gasbag)after transradial coronary intervention and discuss the optimal hemostasis time.Methods 266 patients who received transradial coronary angiography and used TR Band hemostatic gasbag for hemostasis were divided into group A,B and C,according to the compression time,the compression time in group A (90 cases)was 8 h,10 h in group B (87cases),12 h in group C (89 cases).The condition of bleeding,changes in blood oxygen saturation,and hand swelling in each group were compared.Results The bleeding rates of group A,B and C were respectively 16.7%,3.4% and 9.0%,the difference was statistically significant.The incidence of hand swelling after operation in group A,B and C were respectively 27.8%,12.6% and 21.3%,the difference was statistically significant.No significant difference was seen in blood oxygen saturation between three groups.Conclusions Application of radial hemostatic compression device after transradial coronary intervention proved good hemostasis effect,compression time for 10 h has the best effect and less adverse effect.
RESUMO
Objective To compare the clinical efficacy and safety of two different conditioning regimens in nonmyeloablative autologous peripheral blood stem cell transplantation (NAST) for the treatment of systemic lupus erythematosus (SLE).Methods Different conditioning regimens were used in two groups:cytarabin combined cyclophosphamide in group 1 and ATG combined cyclophosphamide in group 2.Different recovery time of leucocytes,neutrophils and platelets in the two groups were compared.Statistical analysis were carried out by paired t-test.Results The mean time for peripheral leucocytes reaching 1.0×109/L,neutrophils getting up to 0.5×109/L,platelet raising to 100×l09/L and hemoglobin rising to 120 g/L in group 1 were [(7.2±1.3),(8.0±1.5),(10.5±1.4),(22.1±2.3)days] and [(10.4±2.1),(12.0±1.9),(19.3±2.1),(28.1± 2.4)] days in group 2.The difference was statistically significant (P<0.01).CD4+ cell count and the ratio of CD4+/CD8+ of pre- and pro-NAST was changed.No significant differences were observed in the two groups.Conclusion For the sake of safety and hematopoietic reconstitution,we recommend cytarabin combined cyclophosphamide as the preferred conditioning regimen.
RESUMO
Objective To investigate the long-term efficacy of nonmyeloablative autologous peripheral blood stem cell transplantation(NAST) to cure refractory autoimmune disease(AD).MethodLong-term follow up of four cases of AD patients with NAST were summarized.The pretreatment regimen was intravenous injection of cytarabin (200 mg· kg-1· d-1 ) and cyclophosphamide (40 mg· kg-1· d-1).The therapeutic effect was evaluated by the change of symptoms and signs and long term complications.Changes of immune function were detected by flow-cytometry.ResultsFive cases of patients had been successfully engrafted.The average time for peripheral leucocytes count to reach 4.0×109/L was 12 days.It needed 10 days for platelets to return to 100×109/L and 22 days for hemoglobin to 120 g/L.Apparent remission of symptoms and signs was observed after transplantation.Lymphocyte subtypes analysis pre- and post- NAST showed that count of CD4+ and the ratio of CD4 +/CD8 + was returned to normal.One patient gave birth to a healthy baby four years after transplantation.Three female patients returned tonormal life. Conclusions Compared with classical myeloablative stem cell transplantation,NAST has a rapid hematopoietic recovery and good long-term therapeutic effect in AD.The quality of life in AD patients treated with NAST is higher than those treated with myeloablative hematopoietic stem cell transplantation.