ABSTRACT
The discovery of a square magnetic-skyrmion lattice in GdRu2Si2, with the smallest so far found skyrmion size and without a geometrically frustrated lattice, has attracted significant attention. In this work, we present a comprehensive study of surface and bulk electronic structures of GdRu2Si2 by utilizing momentum-resolved photoemission (ARPES) measurements and first-principles calculations. We show how the electronic structure evolves during the antiferromagnetic transition when a peculiar helical order of 4f magnetic moments within the Gd layers sets in. A nice agreement of the ARPES-derived electronic structure with the calculated one has allowed us to characterize the features of the Fermi surface (FS), unveil the nested region along kz at the corner of the 3D FS, and reveal their orbital compositions. Our findings suggest that the Ruderman-Kittel-Kasuya-Yosida interaction plays a decisive role in stabilizing the spiral-like order of Gd 4f moments responsible for the skyrmion physics in GdRu2Si2. Our results provide a deeper understanding of electronic and magnetic properties of this material, which is crucial for predicting and developing novel skyrmion-based systems.
ABSTRACT
This work aims to study the conditions of topological phase transition (TPT) between the topological and trivial states in the antiferromagnetic topological insulator (AFM TI) MnBi[Formula: see text]Te[Formula: see text] and propose some theory about the relationship of this TPT with the possibility of axion-like state realization in this material. Using the density functional approach we have analyzed the changes in the electronic and spin structure of topological surface states (TSSs) and the nearest conduction and valence bands (CB and VB) including the changes in the bulk band gap as well as the Dirac point (DP) gap in TSSs under variation of the spin-orbit coupling strength in the region of the TPT for infinite crystal and slab with a surface both. We have shown that in both cases the TPT occurs with inversion of the contributions of the Bi-[Formula: see text] and Te-[Formula: see text] states of different parity at the gap edges related to change in the gap sign. In the case of surface calculations, the Bi-[Formula: see text] and Te-[Formula: see text] states at the edges of the bulk band gap and their inversion at the TPT point are transformed into the TSSs with an energy gap at the DP. In this case the TPT takes place without closing the band gap, i.e. with a "jump" through zero and the formation of the nonzero gap during such a transition. Our calculations show that the TPT point is also characterized by an inversion of the out-of-plane spin polarization [Formula: see text] at the [Formula: see text] point for lower and upper parts of the Dirac cone and a significant spatial redistribution of the TSSs between the surface and the bulk. We suppose that the nonzero Dirac gap can have some relationship with the formation of the axion-like state, which presumably couples nonmagnetic spin-orbit and magnetic contributions at the boundary between the topological and trivial phases for a system with parameters close to the TPT conditions. A practically realized system is proposed - the AFM TI with a stoichiometry close to that of MnBi[Formula: see text]Te[Formula: see text]Se[Formula: see text] with partial (about 50%) substitution of Te atoms for Se atoms in MnBi[Formula: see text]Te[Formula: see text] which can be an experimental platform for the implementation and experimental analysis of the TPT and the corresponding possibility of the axion-like state realization in Condensed Matter. Besides, such system could serve as a good platform for studying the dynamic axion effect, where the axion field fluctuations are maximised when a small external field is applied to the system which state is close to the TPT.
ABSTRACT
The orientation of the 4f moments offers an additional degree of freedom for engineering the spin-related properties in spintronic nanostructures of lanthanides. Yet, precise monitoring of the direction of magnetic moments remains a challenge. Here, on the example of the antiferromagnets HoRh2Si2 and DyRh2Si2, we investigate the temperature-dependent canting of the 4f moments near the surface. We demonstrate that this canting can be understood in the framework of crystal electric field theory and the exchange magnetic interaction. Using photoelectron spectroscopy, we disclose subtle but certain temperature-dependent changes in the line shape of the 4f multiplet. These changes are directly linked to the canting of the 4f moments, which is different for the individual lanthanide layers near the surface. Our results illustrate the opportunity to monitor the orientation of the 4f-moments with high precision, which is essential for development of novel lanthanide-based nanostructures, interfaces, supramolecular complexes, and single-molecule magnets for various applications.
ABSTRACT
This Expert Council focuses on the meta-analysis of studies on the risk of atrial fibrillation (AF) in patients taking omega-3 polyunsaturated fatty acids (PUFA) and of data on the omega-3 PUFA treatment in patients with cardiovascular and kidney diseases.The major statements of the Expert Council: the meta-analysis of AF risk in patients taking omega-3 PUFA showed an increased risk of this arrhythmia. However, it should be taken into account that the risk of complications was low, and there was no significant increase in the risk of AF when omega-3 PUFA was used at a dose of ≤1âg and a standard dose of the only omega-3 PUFA drug registered in the Russian Federation, considering all AF episodes in the ASCEND study.At the present time, according to Russian and international clinical guidelines, the use of omega-3 PUFA can be considered in the following cases: ⢠for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction as a supplement to the basic therapy (2B class of recommendations according to the 2020 Russian Society of Cardiology guidelines (RSC) and the 2022 AHAâ/âACCâ/âHFSA guidelines); ⢠for patients with hypertriglyceridemia (>1.5 mmol/l) as a part of combination therapy (IIb class of recommendations and B level of evidence according to the 2021 European guidelines on cardiovascular disease prevention, etc.); ⢠for adult patients with stage 3-4 chronic kidney disease (CKD), long-chain omega-3 PUFA 2 g/day is recommended for reducing the level of triglycerides (2C class of recommendations). Data on the use of omega-3 PUFA for other indications are heterogenous, which can be partially explained by using different form and doses of the drugs.
Subject(s)
Atrial Fibrillation , Cardiovascular System , Fatty Acids, Omega-3 , Renal Insufficiency, Chronic , Adult , Humans , Stroke Volume , Ventricular Function, Left , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Russia/epidemiologyABSTRACT
The sphere of application of biomarkers is expanding every year and already comprises their using as indicator of presence or absence of disease, response to therapy, efficiency of medications or pre-clinical model of diagnostic parameter and even participant of process of search of mechanism of effect of medications. Hence, it is impossible to overestimate significance of studying of biomarkers. The article is dedicated to systematization and structuring of present information concerning biomarkers, starting from primary screening and completing with validation of chosen molecule or characteristic.
Subject(s)
Biomarkers, Pharmacological/blood , Biomarkers/blood , Early Diagnosis , Humans , Mass ScreeningABSTRACT
The aim of the study is to evaluate a preventive effectiveness of food products with elevated content of biologically active substances by community-acquired pneumonia with unknown causative agent. The authors studied two groups of youngsters (18 years old) during period of adaptation to conditions of organized group: with normal nutritional status [with body mass index (BMI) = 19.5-22.9 kg/m2] and decreased one (with BMI = 18.5-19.4 kg/m2). Tumor necrosis factor (TNFα) and interleukin 1α (IL-1ß) levels in blood serum were criteria of degree of inflammatory process. Functional activity of phagocytes was also evaluated with the use of nitroblue tetrasol test (NTT-test). To prevent pneumonia natural concentrated food product made of vegetable raw materials (3.0 g per day) by cryogen technology was added in diet of persons with normal nutritional status during two periods (15 days) with an interval (30 days). But persons with decreased nutritional status got the product made of protein-vegetable raw materials during 15 days only and additionally product made of protein-vegetable raw materials by cryogen technology one time per day (35.0 g) during 15 days. The persons with normal nutritional status were divided in three group: persons (480 men) in the first group got the product only, persons (100 men) of the second group underwent vaccination with polysaccharide polyvalent «Pneumo-23¼ vaccine only, persons (316 men) of the third group underwent vaccination in combination with the product intake. The persons (231 men) with decreased nutritional status composed one group and got the food product only. Control group consisted of 263 men with normal nutritional status. The authors evaluated incidence rates during three months of observation and duration of in-patient treatment. The results were compared with data obtained in baseline period (the same time periods during three years before the study). The authors received data on the decrease of a reserve ability of phagocytes; it provided evidence about an initial deficiency of immune protection factors in persons with decreased nutritional status. In adaptation period, this phenomenon was observed in persons with normal nutritional status too. The including of protein-vegetable product in diet promoted the increase of bactericidal function of neutrophils and body weight among youngsters with decreased nutritional status; but including of vegetable product kept bactericidal function of neutrophils on normal level. In adaptation period, TNFα levels increased in both groups by 21.0 and 35.1%, respectively; IL-1ß level did not significantly change in group with normal nutritional status, but increased 2.25 fold in persons with decreased nutritional status. The levels of studied cytokins decreased to baseline values in 30 days after the product intake. To this time, TNFα increased 1.8 fold and IL-1ß increased 2.86 times in control group. A preventive effectiveness of the especially created products in nidus with unknown causative agent was confirmed by the decrease of incidence rate (82.4-78.4%) in persons with normal and lower nutritional status that coincided with effectiveness of a vaccinal prevention only. The food product with antioxidant properties potentiated a vaccinal prevention. The positive effect consisted in lack of fatal outcomes and outbreaks of the disease; mean bed-day decreased on 3.5 days; predominance of mild form of the disease in clinical picture in comparison with same parameters during basic period of observation.
ABSTRACT
There are revealed the features in the registration of newly diagnosed morbidity in cases in the organized team out of number of persons constantly living in the conditions of Baltic Sea (Kaliningrad region), as well as in those coming from other parts of the Russian Federation. This stipulates the elaboration of measures for prevention of disadaptational shifts in the organism related with adaptational processes as well as the process of acclimatization.
Subject(s)
Acclimatization/physiology , Adaptation, Physiological/physiology , Climate , Weather , Adolescent , Environment , Humans , Russia , Young AdultABSTRACT
Mouse single-cell embryos exhibit robust Regulatory Volume Decrease (RVD). In what manner the very early mammalian embryo following zygote stage is appreciably altered by the anisotonic extracellular solution is, as yet, totally unclear. Little attention was paid to this direction since there was no way to determine the blastomere volume. This work has served to quantitatively investigate the osmotic response of bicellular mouse embryos employing Laser Scanning Microtomography (LSM) followed with three-dimensional reconstruction (3 DR). We have shown that bicellular mouse embryos in hypotonic Dulbecco's experience RVD. Embryonic cells subjected to hyposmolar exhibit rapid osmotic swelling followed by gradual shrinking back toward their original volume. The van't Hoff law defines swelling phase with the effective hydraulic conductivity of 0.3 micron x min(-1) x atm(-1). Water release during RVD in bicellular mouse embryos is abolished by Cytochalasin B (Cyto B) and the volume recovery is insensitive to ouabain treatment.
Subject(s)
Blastomeres/physiology , Embryo, Mammalian/physiopathology , Sodium-Potassium-Exchanging ATPase/physiology , Animals , Blastomeres/drug effects , Blastomeres/enzymology , Cell Membrane Permeability , Cell Size , Cytochalasin B/pharmacology , Embryo, Mammalian/drug effects , Embryo, Mammalian/enzymology , Hypotonic Solutions , Imaging, Three-Dimensional , Mice , Microscopy, Confocal , Osmotic Pressure , Ouabain/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Water/metabolismABSTRACT
A case of dirofilariosis is reported. The disease is believed to be caused by the contact with the cat that the patient brought in from Uzbekistan. The authors emphasize the importance of analysis of the medical history of the patients presenting with the pathology being considered, their medical examination, and correct interpretation of X-ray images of the paranasal sinuses taking into account the possibility of distribution of rare helminth species beyond their usual ranges.
Subject(s)
Dirofilaria repens/isolation & purification , Dirofilariasis , Epidermal Cyst , Orbital Diseases , Punctures/methods , Animals , Anti-Bacterial Agents/therapeutic use , Cats , Dirofilariasis/complications , Dirofilariasis/diagnosis , Dirofilariasis/parasitology , Dirofilariasis/physiopathology , Dirofilariasis/therapy , Epidermal Cyst/etiology , Epidermal Cyst/physiopathology , Epidermal Cyst/therapy , Female , Humans , Middle Aged , Orbit/pathology , Orbital Diseases/etiology , Orbital Diseases/physiopathology , Orbital Diseases/therapy , Paranasal Sinuses/pathology , Periostitis/drug therapy , Periostitis/etiology , Periostitis/physiopathology , Rare Diseases/complications , Rare Diseases/diagnosis , Rare Diseases/parasitology , Rare Diseases/physiopathology , Rare Diseases/therapy , Treatment OutcomeABSTRACT
The paper outlines materials on how to improve a method for indication of water viral pollution in different water objects of the environment, by applying a MFM filtration module based on tangentially radial-mode water microfiltration and viral concentration on the positively charged membranes, by using the secondary stage of concentration. Experimental and full-scale studies have demonstrated that this method for virus isolation has a high effectiveness and is based on the employment of the materials made in Russia. This determines its rapid introduction into the system for the sanitary-virological monitoring of practical laboratories of various departments, which will favor the higher efficiency of epidemiological surveillance as an integral part of nonspecific prophylactic measures of virus infections of water etiology.
Subject(s)
Sanitation/instrumentation , Virus Diseases/prevention & control , Viruses/isolation & purification , Water Microbiology/standards , Water Pollutants/analysis , Water Purification/instrumentation , Water/analysis , Environmental Monitoring/methods , Equipment Design , Humans , Reproducibility of Results , Virus Diseases/virologyABSTRACT
The efficiency of estimating the carcinogenic activity of chemical substances was compared for five short-term tests and structure-activity relationships (SAR) analysis. The sample included 84 substances with known biological testing results obtained by the Ames test, bacterial SOS chromotest (SOS), chromosome aberration (CA) cytogenetic test, sister chromatid exchange (SHE) test, and gene mutation (GM) test with mammalian cells in vitro and by carcinogenicity assays in rodents in vivo. Structural descriptors were selected using an original database, which included the structural formulas of substances with known carcinogenic activity in rodents. Original software was created to generate and select the descriptors that statistically coincided with carcinogenic activity. The descriptors that were associated exclusively with carcinogenic substances from the database and the tests that produced positive results exclusively with carcinogens were used to evaluate the carcinogenic activity of the substances. A combination of three short-term tests (Ames, SOS, and CA tests) and the SAR model proved to identify carcinogenicity for more than 60% of carcinogens.
Subject(s)
Carcinogens/analysis , Databases, Factual , Models, Biological , Animals , Carcinogenicity Tests , Carcinogens/chemistry , Humans , Structure-Activity RelationshipABSTRACT
A new approach to the description of quantitative structure-activity relationships (QSAR analysis) based on compound descriptors has been used. The effect of the structural characteristics of nitric compounds on their carcinogenicity has been studied. It has been found that the carcinogenicity of nitric compounds is determined by the presence of furyl and/or azole heterocycles not condensed with benzene rings in their molecular structures. The carcinogenicity of the nitric compounds in which the benzene ring is the basic structure is determined by the presence of other substituents (halogens, amines, and methyl groups) and their positions relative to the nitro group.
Subject(s)
Carcinogens/chemistry , Nitro Compounds/chemistry , Animals , Bayes Theorem , Carcinogenicity Tests , Databases, Factual , Quantitative Structure-Activity Relationship , RatsABSTRACT
Hypotensive, organoprotective, and metabolic effects of angiotensin converting enzyme inhibitor moexipril (7.5-15 mg/day for 16 weeks) with or without combination with hydrochlorothiazide was studied in 34 women (mean age 59.6+/-1.6 years) with postmenopausal metabolic syndrome and hypertension. Thirty four women had dyslipidemia, 22 -- disturbances of carbohydrate metabolism, 18 -- obesity (mean body mass index 31.1+/-0.8 kg/m(2)). Treatment was associated with lowering of office systolic(-20.1%) and diastolic (-17.4%) blood pressure (BP). Target BP (140/90 mm Hg) was achieved in 27 patients. There also occurred significant lowering of mean 24 hour, diurnal, and nocturnal systolic and diastolic BP (p<0.05), significant changes of values of systolic and diastolic BP time indexes, normalization of which was observed both during day and night hours. Significant lowering of total cholesterol (-11.6%, p<0.05), low density lipoprotein cholesterol (-16.3%, p<0.02), and in patients with obesity of triglycerides (-27%, p<0.02) was revealed at the background of treatment with moexipril. In a group as a whole we observed significant lowering of excretion of albumins and b2-microglobulin; most pronounced antiproteinuretic effect was noted in patients with high microproteinuria and obesity. Vasodilating function of vessels improved in all patients with postmenopausal metabolic syndrome, mainly at the account of increment of endothelium dependent vasodilation and normalization of index of vasodilatation.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Blood Pressure/drug effects , Glomerular Filtration Rate/drug effects , Hypertension/drug therapy , Metabolic Syndrome/drug therapy , Postmenopause , Tetrahydroisoquinolines/therapeutic use , Adult , Aged , Delayed-Action Preparations , Diuretics/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Hydrochlorothiazide/therapeutic use , Hypertension/complications , Hypertension/physiopathology , Lipids/blood , Metabolic Syndrome/complications , Metabolic Syndrome/physiopathology , Middle Aged , Syndrome , Treatment Outcome , Vasodilation/drug effectsABSTRACT
Moexipril (7.4-15 mg/day) was given to 34, spirapril (3-6 mg/day) -- to 18 postmenopausal women with hypertension and metabolic syndrome for 16 weeks. Hydrochlorthiazide was added when therapy was not sufficiently effective. Both angiotensin converting enzyme inhibitors had similar hypotensive activity: blood pressure normalized in 71 and 61% of moexipril and spirapril treated women, respectively. Both drugs promoted normalization of metabolism of lipid (lowering of levels of cholesterol, atherogenic lipoproteins and triglycerides) and carbohydrates (lowering of hyperinsulinemia). Patients with postmenopausal metabolic syndrome had elevation of leptin level up to 27.5+/-5.5 pg/ml. Moexipril and spirapril caused lowering of elevated levels of leptin. These drugs did not affect levels of sex hormones. They exerted vasoprotective (normalization of endothelium dependent and independent vasodilatation) and nephroprotective (attenuation and normalization of microalbuminuria) effects. Thus spirapril and moexipril are effective in treatment of hypertension in patients with postmenopausal metabolic syndrome.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Enalapril/analogs & derivatives , Metabolic Syndrome/drug therapy , Postmenopause , Tetrahydroisoquinolines/therapeutic use , Blood Pressure/drug effects , Drug Therapy, Combination , Enalapril/therapeutic use , Female , Follow-Up Studies , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/physiopathology , Lipids/blood , Metabolic Syndrome/blood , Metabolic Syndrome/complications , Middle Aged , Treatment OutcomeSubject(s)
Head and Neck Neoplasms , Lipoma , Aged , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Laryngostenosis/etiology , Lipoma/complications , Lipoma/diagnosis , Lipoma/diagnostic imaging , Lipoma/pathology , Lipoma/surgery , Male , Neck/pathology , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Incidence of chronic renal failure has a worldwide tendency to growth. Hypertension occupies an important place among causes of this upward trend. That is why in patients with hypertension and incipient changes of the kidneys it seems most appropriate to use antihypertensive drugs with renoprotective properties. Early treatment with these drugs enables most effective lowering of risk of renal failure development and thus has a potential to prolong life of a patient. Selective microproteinuria is considered to be a marker of incipient renal impairement. Among groups of antihypertensive agents angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, beta-blockers, and diuretics have proven renoprotective properties.
Subject(s)
Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Hypertension/complications , Hypertension/drug therapy , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/prevention & control , Kidney/drug effects , Proteinuria/etiology , Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Adult , Aged , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Coronary Disease/complications , Diabetes Mellitus, Type 2/complications , Diuretics/pharmacology , Diuretics/therapeutic use , Double-Blind Method , Humans , Middle Aged , Multicenter Studies as Topic , Placebos , Randomized Controlled Trials as TopicABSTRACT
Recent data from RHIC for high- pT hadrons raised again the long-standing problem of quantitatively understanding the Cronin effect, i.e., nuclear enhancement of high- pT hadrons. All existing models for the Cronin effect rely on a fit to the data to be explained. We develop a phenomenological description based on the light-cone QCD-dipole approach which allows one to explain data without fitting to them and to provide predictions for pA collisions at RHIC and LHC. We point out that the underlying mechanism drastically changes with energy, from incoherent production of high- pT hadrons on different nucleons at low energies, to an entirely coherent process at very high energies.
ABSTRACT
Based on WHO MONICA methods and diagnostic criteria, it is shown that first-ever stroke incidence and mortality in Siberia (a total number of residents included in the analysis varied from 450,000 to about 800,000) that are among the highest in the world. In Novosibirsk, for the period from 1982 through 1991 there was a trend towards decreasing stroke incidence and mortality rates, but for the period from 1992 through 1997 there was a trend towards increasing there rates in both men and women. Age-standardized (US white population was used as a standard) stroke incidence rates increased from west to east and from south to north across Siberia, with a corresponding increase in the proportion of hemorrhagic strokes. In 1987-1988, age-adjusted stroke incidence rate in Novosibirsk was 212 per 100,000 residents per year, in Krasnoyarsk--325, in Tynda--329, in Anadyr--348. Stroke-case fatality rates ranged from 28% in Tynda to 41% in Anadyr. A multivariate regression analysis revealed that hypertension, left ventricular hypertrophy, ischemic heart disease. mitral valve disease, current cigarette smoking, excessing body mass index, winter season, and low ambient temperature are all significant and independent risk factors for the occurrence of ischemic stroke in Novosibirsk. A significant association between stroke occurrence and air pressure/geomagnetic activity change was found. Possible reasons for such unfavorable trends in stroke incidence in Siberia are discussed, and an optimal approach for improving organization of cerebrovascular disease care is suggested.
Subject(s)
Stroke/epidemiology , Aged , Aged, 80 and over , Catchment Area, Health , Female , Humans , Male , Middle Aged , Siberia/epidemiologySubject(s)
Galvanic Skin Response/physiology , Adolescent , Adult , Aged , Electrocardiography , Electroencephalography , Electrooculography , Electrophysiology , Humans , Middle Aged , Signal Processing, Computer-Assisted , Skin Temperature/physiology , Sleep/physiology , Vasomotor System/physiology , Wakefulness/physiologyABSTRACT
BACKGROUND AND PURPOSE: Population-based data on transient ischemic attack (TIA) incidence are scarce. This study defines incidence rates of first-ever TIA in Novosibirsk, Russia, during 1987-1997 and compares the incidence of first TIA with that of first stroke. METHODS: This is a prospective registry population-based study of all new cases of TIA and stroke in an overall population of 455 765 residents of Novosibirsk. All new TIA and stroke incident cases (whether inpatient or outpatient) that occurred during 1987-1988 and 1996-1997 study periods were recorded and analyzed. A 95% CI was estimated for all age- and sex-specific strata. RESULTS: During the 2 study periods, a total of 211 patients with first TIA were registered in the population studied. The crude annual TIA incidence rate per 100 000 residents was 16 (95% CI, 8 to 33) in 1987-1988 and 29 (95% CI, 9 to 87) in 1996-1997; these rates standardized to the European population were 17 (95% CI, 8 to 34) and 27 (95% CI, 9 to 79), respectively. Eighty-three percent of TIAs occurred in the carotid arteries (rate, 48/100 000), 10% occurred in the vertebrobasilar territory (rate, 6/100 000), and 7% of cases had a TIA of uncertain distribution (rate, 2/100 000). CONCLUSIONS: Unlike stroke incidence rate, the incidence rate of TIA in Novosibirsk is similar to that in other populations and constitutes approximately 10% of stroke incidence. For the last decade (1987-1997), there was a tendency, although statistically insignificant, toward increasing incidence rate of TIA in the population studied.