Репозиторий Университета

© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley  &  Sons Ltd. Aims: Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade. Materials and Methods: Systematic searches for articles published from January 1, 2004 to August 1, 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form. Results: The final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low- to middle-income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta-analysis. Conclusions: Therapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes.

© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley  &  Sons Ltd. Aim: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies. Materials and Methods: This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance. Results: Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was −1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, −0.45% per unit increase in HbA1c; HbA1c ≥9%, −0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92–1.09%; P <.001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P <.001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P <.001]). Conclusions: Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions.

© Copyright 2018, Mary Ann Liebert, Inc., publishers 2018. Aim: To compare a program based on intermittent hypoxia-hyperoxia training (IHHT) consisting of breathing hypoxic-hyperoxic gas mixtures while resting to a standard exercise-based rehabilitation program with respect to cardiorespiratory fitness (CRF) in older, comorbid cardiac outpatients. Materials and Methods: Thirty-two cardiac patients with comorbidities were randomly allocated to IHHT and control (CTRL) groups. IHHT completed a 5-week program of exposure to hypoxia-hyperoxia while resting, CTRL completed an 8-week tailored exercise program, and participants in the CTRL were also exposed to sham hypoxia exposure. CRF and relevant hematological biomarkers were measured at baseline and after treatment in both groups. Results: After intervention, CRF in the IHHT group was not significantly different (n = 15, 19.9 ± 6.1 mlO2 minutes-1 kg-1) compared with the CTRL group (n = 14, 20.6 ± 4.9 mlO2 minutes-1 kg-1). CRF in IHHT increased significantly from baseline (6.05 ± 1.6 mlO2 minutes-1 kg-1), while no difference was found in CTRL. Systolic and diastolic blood pressures were not significantly different between groups after treatment. Hemoglobin content was not significantly different between groups. Erythrocytes and reticulocytes did not change pre/post interventions in both experimental groups. Conclusions: IHHT is safe in patients with cardiac conditions and common comorbidities and it might be a suitable option for older patients who cannot exercise. A 5-week IHHT is as effective as an 8-week exercise program in improving CRF, without hematological changes. Further studies are needed to clarify the nonhematological adaptations to short, repeated exposure to normobaric hypoxia-hyperoxia.

© 2017 Elsevier B.V. Microneedles is the technique of drug delivery enhancement, which was primarily designed for facilitating percutaneous drug delivery. Started from the development of simple solid microneedles, providing microporation of stratum corneum and therefore enhancement of topical drug delivery, for two decades the technique has progressed in various modifications such as hollow, coated, dissolving and hydrogel forming microneedles. In their turn, the modifications have resulted in new mechanisms of drug delivery enhancement and followed by the expansion of applicability range in terms of targeted tissues and organs. Thus, in addition to percutaneous drug delivery, microneedles have been considered as an efficient technique facilitating ocular, oral mucosal, gastrointestinal, ungual and vaginal drug administration. It is anticipated that the technique of microneedle-assisted drug delivery will soon become relevant for majority of organs and tissues.

© 2018 Veremeyko, Yung, Dukhinova, Kuznetsova, Pomytkin, Lyundup, Strekalova, Barteneva and Ponomarev. Although it has been demonstrated that cAMP pathway affect both adaptive and innate cell functions, the role of this pathway in the regulation of T-cell-mediated central nervous system (CNS) autoimmune inflammation, such as in experimental autoimmune encephalomyelitis (EAE), remains unclear. It is also unclear how cAMP pathway affects the function of CD4 T cells in vivo at the site of inflammation. We found that adenylyl cyclase activator Forskolin besides inhibition of functions autoimmune CD4 T cells also upregulated microRNA (miR)-124 in the CNS during EAE, which is associated with M2 phenotype of microglia/macrophages. Our study further established that in addition to direct influence of cAMP pathway on CD4 T cells, stimulation of this pathway promoted macrophage polarization toward M2 leading to indirect inhibition of function of T cells in the CNS. We demonstrated that Forskolin together with IL-4 or with Forskolin together with IL-4 and IFNγ effectively stimulated M2 phenotype of macrophages indicating high potency of this pathway in reprogramming of macrophage polarization in Th2-and even in Th1/Th2-mixed inflammatory conditions such as EAE. Mechanistically, Forskolin and/or IL-4 activated ERK pathway in macrophages resulting in the upregulation of M2-associated molecules miR-124, arginase (Arg)1, and Mannose receptor C-type 1 (Mrc1), which was reversed by ERK inhibitors. Administration of Forskolin after the onset of EAE substantially upregulated M2 markers Arg1, Mrc1, Fizz1, and Ym1 and inhibited M1 markers nitric oxide synthetase 2 and CD86 in the CNS during EAE resulting in decrease in macrophage/microglia activation, lymphocyte and CD4 T cell infiltration, and the recovery from the disease. Forskolin inhibited proliferation and IFNγ production by CD4 T cells in the CNS but had rather weak direct effect on proliferation of autoimmune T cells in the periphery and in vitro, suggesting prevalence of indirect effect of Forskolin on differentiation and functions of autoimmune CD4 T cells in vivo. Thus, our data indicate that Forskolin has potency to skew balance toward M2 affecting ERK pathway in macrophages and indirectly inhibit pathogenic CD4 T cells in the CNS leading to the suppression of autoimmune inflammation. These data may have also implications for future therapeutic approaches to inhibit autoimmune Th1 cells at the site of tissue inflammation.

© 2017 Elsevier Masson SAS A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11–18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.

© 2017 FRUCT. Some results of Data Mining of scientific publication activity in Scopus database and Text Big Data analytics using API access to Google about Information transformation are presented. The whole ecosystem of Internet of Health and its place within Internet of Things are described. System analysis is given about: Big Data market in Health Care, ways of Medical Information Systems development, and the direction of hospitals transition to new condition based on three 'whales' (hybrid Cloud computing, supercomputer and data center). The Internet of Things ecosystem foregrounds some important aspects related to gerontology, genetics, biorhythmology, and gravitational biology. Sociological understanding of people's role in formation of the new high IT dependence reality allows to determine the main vectors of farsighted forecast. The technological evolution can be described as subsequent stages: distribution of IT - automation - Digital transformation and Internet of Things - Big Data analytics - Artificial Intelligence solutions - people connection to Augmented Reality - Context-as-A-Service - NBIC- and GRAIN-technologies - Humanity Plus. The essence of concept 'patient' is changing. Patient transforms into an e-patient (all records about patient have been digitized) and then into Internet-patient with monitoring of health parameters within the Internet of Things surrounding people. Getting Augmented Reality patient is becoming a Digital patient. Augmented Reality methods are already being developed to treat patients. Medicine as part of social structure becomes more diffuse, covering common space of Internet of Things. Medical culture acquires a new value for society. Five measures for successful transformation of Health Care in Russia are recommended in the article.

© 2018 Aisanov et al. The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A–D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation.

© 2017 Elsevier B.V. The need for investigating alcohol abuse by means of objective tools is worldwide accepted. Among the currently available biomarkers of chronic alcohol abuse, carbohydrate-deficient transferrin (CDT) is one of the most used indicator, mainly because of its high specificity. However, some CDT analytical and interpretation aspects are still under discussion, as witnessed by numerous research papers and reviews. The present article presents a critical review of the literature on CDT appeared in the period from 2007 to 2017 (included). The article is organized in the following sections: (1) introduction, (2) pre-analytical aspects (3) analytical aspects (4) diagnostic aspects (5) concluding remarks. As many as 139 papers appeared in the international literature and retrieved by the search engines PubMed, Web of Science and Scopus are quoted.

© 2017 American Chemical Society. Erythropoietin Fc (EPO-Fc) fusion proteins are potential drug candidates that have been designed for the treatment of anemia in humans by stimulating erythrocyte production. Such compounds can be considered performance-enhancing agents that may be used by athletes in endurance sports. This study describes the primary structure of commercially available EPO-Fc based on comprehensive liquid chromatography coupled with mass spectrometry (LC-MS) analysis. A bottom-up approach and the intact molecular weight (MW) measurement of deglycosylated protein and its IdeS proteolytic fractions was used to determine the amino acid sequence of EPO-Fc. Using multiple proteases, peptides covering unknown fusion breakpoints (spacer peptides) were identified. We demonstrated that "spacer peptides" can be used in the determination of EPO-Fc fusion proteins in biological samples using common LC-tandem MS methods.

© 2017 Informa UK Limited, trading as Taylor  &  Francis Group. A number of concepts exist which reveal an interaction between endogenous and psychogenic factors in stress-induced disorders in patients with schizophrenia. These concepts relate to psychological, pathophysiological, and sociological aspects of the problem. In this study we look at the respective states described within the clinical concept of reactive schizophrenia. Materials: Fifty clinical cases were included: 32 females and 18 males, mean age 38.6 ± 12.5. Thirty-three patients (66%) had a diagnosis of ‘schizophrenia’, 17 patients (34%) were diagnosed with ‘schizotypal personality disorder’ according to DSM-5 criteria. The performed examination included a clinical interview, analysis of the current clinical state, analysis of the medical history. Results: From the perspective of concept of ‘reactive schizophrenia’, the subjects of our study can be split into two groups based on their mechanism of development and psychogenic vs. endogenous contributions. These two groups may be characterized as ‘psychogenic provocation of a schizophreniform disorder’ and ‘endogenous provocation of a psychogenic disorder’ respectively. Conclusions: The results observed made it possible to re-establish the hypothesis of ‘reactive schizophrenia’. The principal feature is the specific interaction between endogenous and psychogenic factors, i.e. the psychogenic provocation of endogenous disorders.

© 2017 Informa UK Limited, trading as Taylor  &  Francis Group. Background: Knowledge of effectiveness and safety of the nonbiologic, nonantihistamine treatments used for chronic urticaria is important as in some cases the principal guideline-recommended drug; omalizumab, has limited effect, side effects or is too expensive or unavailable. Herein, we systematically review the evidence for the use of the nonbiologic treatments in antihistamine-refractory chronic urticaria. Methods: We performed a systematic review of the literature using PubMed and Webofscience and identified studies that reported use of one or more of the nonbiological, nonantihistamine treatment options for chronic urticaria. The studies were evaluated based on study design, number of patients, effect of treatment and safety. Results: We identified 118 studies or case series with 13 different treatments (azathioprine, chloroquine, colchicine, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), methotrexate, montelukast, mycophenolate mofetil, plasmapheresis, sulfasalazine, tranexamic acid and ultraviolet light (UV) A, UVB) totaling 1682 patients. There was a paucity of controlled trials for most of the treatments reviewed albeit the strongest evidence in favor of a beneficial effect in chronic urticaria was, apart from montelukast and cyclosporine, seen for UV therapy and dapsone followed by IVIG. Conclusion: The treatment options reviewed should be seen as potential alternatives in treatment-resistant chronic urticaria where guideline-based selections have failed. However, larger controlled trials are warranted to advance the level of evidence, possibly supporting some treatments’ future recommendation in selected patients.

© 2018 New Reaearch of Tuva. All rights reserved. Tuvinian healing springs, Arzhaans, are examined in this article as an important part of the cultural and religious landscape of the republic. Their importance and the interest in them, displayed by both the local population, primarily Tuvans, and visitors to the region, have been reinforced in the process of contemporary cultural revival. Our study is based on the theoretical and methodological approach of anthropology, which studies the cultural landscape as a space which includes natural objects endowed by man with a certain cultural meaning, changing due to the anthropogenic impact. Methodologically, we rely on the works on the role and place of water sources in cultures, and specifically of arzhaans in Tuva culture. Other sources include the results of the author's field studies in Tuva in 2017-2018 (most importantly, ofs interview with Tuvans). Arzhaans represent a part of the cultural and religious landscape of Tuva, which has its own center, a special shrine - a healing spring. Around this center rise a number of traditional rituals, connecting man with nature, generations of the present with the past, focusing on healing of the body and soul. The cult of arzhaans also performs an identification function, allowing Tuvans to realize their tribal, ethnocultural identity. Scientific studies made by chemists and hydrologists prove the healing properties of arzhaans. This reinforces the faith of the population and visitors in the usefulness of arzhaan tours, which helps advance a suggestion that arzhaans can act as centers of tourist interest.

© IV Karpenko et al. A modern military physician can perform their duties at a high professional level only when they are au fait with a complex of military medical disciplines, such as military field surgery, military hygiene, organisation and tactics of medical service and some others, along with general medical knowledge. Back in his time, our great fellow countryman N.I. Pirogov described war as a “traumatic epidemic”. Hence the importance of knowledge of military field surgery for a military physician, which is difficult to overestimate. This article presents the historical picture of the introduction of issues of military field surgery, first in hospital schools, then at the Saint Petersburg Medical and Surgical Academy (MSA), and then, during Soviet times, at the S.M. Kirov Military Medical Academy (the Military Medical Academy of the Workers’ and Peasants’ of the Red Army). It is shown that particular issues of military surgery were sporadically taught in hospital schools since the 18th century. Usually, it would happen on the brink of or during military conflicts, and the students attending would be graduates of hospital schools going to the front. First, particular issues of military surgery can be found in the programme of the Department of Theoretical Surgery of the Saint Petersburg MSA introduced by Professor P.A. Dubovitsky in 1844. The next stage was the establishment in the academy in 1869 of the first independent course of military field surgery which was addressed to military physicians who were annually seconded to the academy for improvement in military field surgery. Since 1879, this course was also studied by students of the Saint Petersburg MSA. The opening in the Academy in 1936 of the first independent Department of Military Field Surgery in the USSR, headed by the well-known scientist and surgeon V.A. Oppel, can be considered the completion of the development of the teaching of this academic discipline.

© NA Kuznetsov. This article reviews the main approaches to the interpretation of the term “risk”, which has acquired the status of a general scientific and widely interpreted concept. The unresolved issues of surgical risk terminology make it extremely difficult to solve the problem of perioperative prognosis at the narrow professional (medical) level. The author considers the problem of objec-tifying operational risk at an interdisciplinary level. In his opinion, understanding risk as a specific form of the subject’s active relation to the surrounding reality is the most justified at the present time. The essential particular features of such activities are the lack of confidence and the subject’s uncertainty in achieving the stated goal since a doctor’s professional activity takes place under conditions of risk, uncertainty and in contradictory situations. The author of the article suggests using the definition of “risk” proposed by A.P. Algin, according to which risk should be understood “as an activity connected with overcoming uncertainty and the situation of inevitable choice, in the process of which it is possible to quantitatively and qualitatively assess the probability of achieving the expected result, failure and deviation from the goal.” This definition prevents the use of antiscientific and scholastic views of this phenomenon. With reference to medical science (in particular, to surgery), this approach to risk allowed the author to formulate an individual quantitative prognosis and to distinguish five types of perioperative prognosis.

© EV Arsentyev,. The article deals with the main turning points in the life and work of N.A. Semashko, the first People’s Commissar of Health of the RSFSR, from 1920 to 1925. The authors of the article proceed from the fact that the historical and biographical data available about Semashko are interpreted according to ideologically tinted stereotypes that were formed in the Soviet historiographic school. Based on various sources (mainly documents from the State Archives of the Russian Federation and Semashko’s family archive), as well as critical analysis of data from literature, an attempt was made to give an ideologically neutral assessment of the participation of Semashko in the organization of the sanatorium and resort sector in the RSFSR and the assistance provided to Soviet Russia from foreign public organizations. New facts were discovered about Semashko’s life, which in particular made it possible to clarify his role in helping medical personnel in Crimea during political repressions there (after the Bolsheviks established power on the peninsula). The authors of the article point out that despite the difficulties that existed at that time, in many respects, it was only due to Semashko’s authority and organizational abilities that the famous Soviet All-Russia health resort was established in Crimea. While work was carried out on the archives, data were found on the supply of humanitarian aid to the People’s Commissar of Health by US public organizations, sympathizing with Soviet Russia in the first half of the 1920s. It is concluded that the formation of Semashko’s scientific biography, which assumes an objective assessment, in particular, concerning his contribution to the organization of medical care, will make it possible in general to move on to an objective analysis of the features of the Soviet health care system and the transformation of the Soviet model (the Semashko model) into the modern Russian model of health care.

© SD Batoev. The current continuing outflow of valuable production forces and intellectual resources from Transbaikal has a negative impact on the socio-economic development of this border area. A retrospective analysis of the health care system provided to the Russian population living in remote areas demonstrates that not all formative stages of the health care system in Transbaikal were completed without problems. The Russian Empire implemented a state policy on the demographic and socio-cultural integration of Transbaikal for the purpose of rational economic development, effective consolidation of the territory and provision of border security. The pre-revolutionary government, facing significant financial shortages and an unfavorable socio-economic and political situation from the mid 18th century, carried out continuous work to create the foundations for the Transbaikal public health system. However, social issues were not a priority with regard to all population groups living on the outskirts of the Russian Empire, therefore many projects and decisions were implemented with significant delays or in a reduced format. In addition, it is necessary to take into account an objective point restraining the introduction of the central authorities’ solution: a new type of medical care was being promoted, to which the indigenous and newly arrived people of Transbaikal had to grow accustomed. At the same time, by the beginning of the 20th century, the heterogeneous population of Transbaikal, which traditionally used folk methods as well as Tibetan medicine, gradually began to understand the advantages of official medicine and science-based hygiene for improving and preserving human potential, which is the basis of the physical and intellectual development of any nation, and to master their leading principles. From the beginning of November 1920, under the conditions found in the Far Eastern Republic, measures were taken for the first time to organize free and preventive medicine for all population groups on the territory of Transbaikal, which marked the beginning of positive changes in the sphere of health care in terms of ensuring the real availability of medical care. Thus, the long process if creating a treatment and prevention system in pre-revolutionary Transbaikal took place within the framework of the all-Russian model of state medical care. It was continuous in nature and had a number of significant differences from the health care system established in European Russia.

© 2018 Hubail et al. Purpose: The aim of this study was to evaluate the progression of a case of a patient with epidermolysis bullosa (EB) since early age who survived to adulthood, presenting with recurrent skin blisters and disfiguring scars and disabling musculoskeletal deformities. Background: EB is a rare group of inherited diseases that affect the skin fragility causing it to blister in response to even minor trauma. Established novel treatments are limited in the literature due to its rarity, and more research is needed to set a global management approach. Clinical manifestations range widely from localized to generalized blistering. Methods: A rare case of EB surviving to adulthood despite the complications, which has been evaluated, treated during a relapse, and followed up. Conclusion: The described case is of considerable clinical interest due to its rarity and severity. Optimal management requires a multidisciplinary approach and revolves around the protection of the skin against slightest injury, use of careful wound care dressings, aggressive nutritional support, and early medical or surgical interventions if needed to manage any complications. Prognosis varies considerably depending on each case.

© 2018 Pirogov Russian National Research Medical University. All rights reserved. Early detection of dorsopathies is an urgent task for primary care physicians, since such conditions can combine with other chronic noncommunicable diseases (NСD) and adversely affect the course all comorbidities, consequently disimproving the quality of life of patients and increasing the frequency of their requests for medical assistance. This study aimed to determine the value of routine checkups in the context of detection of dorsopathies, NCD, and identification of risk factors (RF). We have retrospectively analyzed the patient records database of a rural outpatient clinic in the Tver region (years 2015 to 2017). The prevalence of dorsopathies and NCD RF were the subjects investigated. Fisher's exact test and Spearman's rank correlation coefficient (SRCC) were applied for the purposes of statistical processing of the results. We discovered that dorsopathy most often was a comorbidity to arterial hypertension and gastrointestinal tract diseases; it was strongly related to the NCD (SRCC = 0.506), age (SRCC = 0.383), slightly less so - to hypodynamia (SRCC = 0.146), type of the patient's occupation (intellectual or physical labor) (SRCC = 0.07). Routine checkups improve the rate of detection of dorsopathy: the more patients undergo such examinations, the more cases of dorsopathy are diagnosed. Thus, it is necessary to increase the number of working people attending the checkups in order to detect dorsopathies early and prevent them effectively.

© 2018 Paediatrician Publishers, LLC. All Rights Reserved. The article provides the characteristic of a tumor from cells of cartilaginous tissue - chondroblastoma. Current data on etiology, key links of pathogenesis, types of tumor, General clinical manifestations, approaches to diagnosis and treatment in children are analyzed.