Qualidade de vida de pacientes com câncer do trato gastrointestinal em um hospital oncológico / Quality of life of patients with cancer of the gastrointestinal tract in an oncological hospital / Calidad de vida de pacientes con cáncer del tracto gastrointestinal en un hospital oncológico

O objetivo deste estudo foi avaliar a qualidade de vida de pacientes com câncer do trato gastrointestinal em um hospital oncológico no Maranhão. Trata-se de um estudo transversal de abordagem quantitativa realizado em um serviço oncológico com pacientes em tratamento, aplicando-se o European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) para avaliação da qualidade de vida. Os dados foram analisados por meio de estatística descritiva e do teste t, considerando nível de significância de 5%. A maior parte dos participantes eram do sexo masculino (62,7%), na faixa etária de 50 a 79 anos (74,5%), de raça/cor parda (86,2%), casados/em união estável (47,0%), católicos (52,9%), com ensino fundamental (58,8%) e renda de um a dois salários-mínimos (58,8%). Com relação às variáveis clínicas, a neoplasia de estômago predominou em 58,8%, sendo diagnosticados entre seis meses e dois anos (52,9%). Quanto ao tratamento, 47,0% iniciaram-no em até três meses, além disso, havia aqueles que estavam no segundo tratamento (72,5%). O tratamento quimioterápico representou 94,1% dos pacientes e, quanto aos fatores de risco, não fumantes representavam 54,9%, etilistas 60,7%, e sem histórico familiar de câncer 49,0%. Em relação aos escores de saúde global, a média foi de 64,5%, o sintoma da insônia de 39,2%. Já em escala funcional, o comprometimento físico foi de 78,8% dos pacientes. A qualidade de vida foi considerada satisfatória pelos pacientes. Apesar disso, o funcionamento físico apresentou menor impacto que o emocional, o que representa melhores tratamentos com menores efeitos físicos, visto que os pacientes oncológicos tendem a apresentar mais limitações na função física, o que torna inferior sua qualidade de vida.

This study aimed to evaluate the quality of life of patients with cancer of the gastrointestinal tract in an oncology hospital in Maranhão (Brazil). This is a cross-sectional study with a quantitative approach, carried out in an oncology service with patients undergoing treatment, applying the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) to assess the quality of life, the data were analyzed by using descriptive statistics and T test considering a significance level of 5%. 51 male patients participated (62.7%), in the age group from 50 to 79 years old (74.5%), of brown color (86.2%), married/in stable union (47.0%), Catholics (52.9%), having elementary schooling (58.8%), and income of 1 to 2 minimum wages (58.8%). Regarding the clinical variables, stomach neoplasms predominated in 58.8%, they were diagnosed between six months and two years (52.9%). As for treatment, 47.0% started with up to three months, were in the second treatment (72.5%), 94.1% had chemotherapy, and as for risk factors, non-smokers were 54.9%, alcoholics were 60.7%, and those without family history of cancer were 49.0%. Regarding the global health scores, the average was 64.5%, insomnia symptom was 39.2%, and in the functional scale, physical impairment was 78.8%. The quality of life was considered satisfactory by the patients. Despite this, physical functioning had less impact than emotional functioning, which represents better treatments with less physical effects, since cancer patients tend to have more limitations in physical function, which worsens their quality of life.

Este estudio tuvo por objetivo evaluar la calidad de vida de pacientes con cáncer del tracto gastrointestinal en un hospital oncológico de Maranhão (Brasil). Se trata de un estudio transversal con enfoque cuantitativo, realizado en un servicio de oncología con pacientes en tratamiento, aplicando el European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) para evaluar la calidad de vida, los datos se analizaron mediante estadística descriptiva y prueba T considerando un nivel de significación del 5%. Participaron 51 pacientes del sexo masculino (62,7%), del grupo etario de 50 a 79 años (74,5%), el color pardo (86,2%), casado/unión estable (47,0%), católicos (52,9%), nivel de estudios primaria (58,8%) e ingresos de 1 a 2 salarios (58,8%). En cuanto a las variables clínicas, predominó el cáncer de estómago en el 58,8%, se diagnosticaron entre los seis meses y los dos años (52,9%). En cuanto al tratamiento, el 47,0% lo inició con hasta tres meses, el 72,5% estaba en el segundo tratamiento, el 94,1% realizaba quimioterapia, y en cuanto a los factores de riesgo, el 54,9% eran no fumadores, el 60,7% alcohólicos y el 49,0% no tenía antecedentes familiares de cáncer. En cuanto a los puntajes globales de salud, el promedio fue del 64,5%, el síntoma de insomnio del 39,2%, y en la escala funcional, el deterioro físico fue del 78,8%. La calidad de vida fue considerada satisfactoria por los pacientes. A pesar de esto, el funcionamiento físico tuvo un impacto menor que el funcionamiento emocional, lo que representa mejores tratamientos con menos efectos físicos, ya que los pacientes con cáncer tienden a presentar más limitaciones en la función física, lo que empeora su calidad de vida.

Factores asociados a complicaciones quirúrgicas en pacientes adultos mayores con neoplasias gastrointestinales del Centro Médico Naval / Factors associated with surgical complications in elderly patients with gastrointestinal neoplasms at the Centro Médico Naval

RESUMEN Objetivo Determinar los factores asociados a complicaciones quirúrgicas en pacientes adultos mayores con diagnóstico de neoplasias gastrointestinales del Centro Médico Naval del Perú. Materiales y métodos Estudio de cohorte retrospectiva y análisis secundario de una base de datos. Se evaluaron los factores asociados a complicaciones postoperatorias de 245 pacientes con diagnóstico de cáncer gastrointestinal entre 2013 y 2015. Las variables fueron edad, fragilidad, vulnerabilidad, antecedentes patológicos, consumo de tabaco, perímetro de pantorrilla, dependencia funcional, caídas, polifarmacia y localización del cáncer. Resultados El 29,8 % presentó complicaciones quirúrgicas, que fueron más frecuentes en los casos de cáncer de colon/ recto con 82,19 %, la edad promedio fue de 86,3 años. Las complicaciones más frecuentes fueron dolor, hemorragia, trastornos hidroelectrolíticos e infección de sitio operatorio. Mediante el modelo de regresión ajustado, las variables que mostraron mayor asociación significativa fueron la presencia de 3 o más antecedentes patológicos, consumo de tabaco, perímetro de pantorrilla menor que 31 cm, dependencia funcional, caídas en el último año, polifarmacia, fragilidad, vulnerabilidad según VES-13 y localización del cáncer en colon/recto. Conclusiones Los factores que predisponen la aparición de complicaciones quirúrgicas fueron el cáncer en colon/ recto, ser vulnerable (según la escala VES-13), ser frágil (según el fenotipo de Fried), la polifarmacia, haber sufrido caídas, dependencia funcional, perímetro de pantorrilla delgado, antecedente de consumo de tabaco, y tener 3 o más comorbilidades.

ABSTRACT Objective To determine the factors associated with surgical complications in elderly patients diagnosed with gastrointestinal neoplasms at the Centro Médico Naval del Perú. Materials and methods A retrospective cohort study and a secondary database analysis were conducted. The factors associated with postoperative complications in 245 patients diagnosed with gastrointestinal neoplasms between 2013 and 2015 were evaluated. The variables were age, frailty, vulnerability, previous diseases, tobacco smoking, calf perimeter, functional dependence, falls, polypharmacy and cancer location. Results Twenty-nine point eight percent (29.8 %) of the patients presented surgical complications, which were more prevalent in cases of colorectal cancer (82.19 %) and an average age of 86.3 years. The most frequent complications were pain, hemorrhage, hydroelectrolytic disorders and surgical site infection. Using the adjusted regression model, the variables that showed the most significant association were presence of ≥ 3 previous diseases, tobacco smoking, calf perimeter < 31 cm, functional dependence, falls in the last year, polypharmacy, frailty, vulnerability according to the Vulnerable Elders Survey (VES-13) and cancer located in colon/rectum. Conclusions The predictive factors for developing surgical complications were colorectal cancer, vulnerability according to the VES-13, frailty according to the Fried frailty phenotype, polypharmacy, falls, functional dependence, thin calf perimeter, history of tobacco smoking, and presence of three or more comorbidities.

Program of intestinal rehabilitation and early postoperative enteral nutrition: a prospective cohort study / Programa de reabilitação intestinal e introdução de nutrição enteral pós-operatória precoce: estudo de cohort prospectivo

ABSTRACT Background: Some factors can act on nutritional status of patients operated for a gastrointestinal cancer. A timely and appropriate nutritional intervention could have a positive effect on postoperative outcomes. Aim: To determine the effect of a program of intestinal rehabilitation and early postoperative enteral nutrition on complications and clinical outcomes of patients underwent gastrointestinal surgery for cancer. Methods: This is a prospective study of 465 patients underwent gastrointestinal surgery for cancer consecutively admitted in an oncological intensive care unit. The program of intestinal rehabilitation and early postoperative enteral nutrition consisted in: 1) general rules, and 2) gastrointestinal rules. Results: The mean age of analysed patients was 63.7±9.1 years. The most frequent operation sites were colon-rectum (44.9%), gynaecological with intestinal suture (15.7%) and oesophagus-gastric (11.0%). Emergency intervention was performed in 12.7% of patients. The program of intestinal rehabilitation and early postoperative enteral nutrition reduced major complication (19.2% vs. 10.2%; p=0.030), respiratory complications (p=0.040), delirium (p=0.032), infectious complications (p=0.047) and gastrointestinal complications (p<0.001), mainly anastomotic leakage (p=0.033). The oncological intensive care unit mortality (p=0.018), length of oncological intensive care unit (p<0.001) and hospital (p<0.001) stay were reduced as well. Conclusions: Implementing a program of intestinal rehabilitation and early postoperative enteral nutrition is associated with reduction in postoperative complications and improvement of clinical outcomes in patients undergoing gastrointestinal surgery for cancer.

RESUMO Racional: Alguns fatores podem atuar sobre o estado nutricional de pacientes operados por câncer gastrointestinal. Intervenção nutricional oportuna e adequada poderia ter efeito positivo nos resultados pós-operatórios. Objetivo: Determinar o efeito de um programa de reabilitação intestinal e nutrição enteral pós-operatória precoce em complicações e resultados clínicos de pacientes submetidos à cirurgia gastrointestinal para câncer. Métodos: É estudo prospectivo de 465 pacientes submetidos à cirurgia gastrointestinal para câncer consecutivamente admitido em uma unidade de terapia intensiva oncológica. O programa de reabilitação intestinal e nutrição enteral pós-operatória precoce consistiu em: 1) regras gerais e 2) regras gastrointestinais. Resultados: A idade média dos pacientes analisados ​​foi de 63,7±9,1 anos. Os locais de operação mais frequentes foram colorretais (44,9%), ginecológicos com sutura intestinal (15,7%) e esofagogástrico (11,0%). Intervenção de emergência foi realizada em 12,7% dos pacientes. O programa de reabilitação intestinal e nutrição enteral pós-operatória precoce reduziu complicações maiores (19,2% vs. 10,2%; p=0,030), complicações respiratórias (p=0,040), delírio (p=0,032), complicações infecciosas (p=0,047) e gastrointestinais complicações (p<0,001), principalmente vazamento anastomótico (p=0,033). A mortalidade da unidade oncológica de terapia intensiva (p=0,018), duração da unidade oncológica de terapia intensiva (p<0,001) e hospital (p<0,001) permaneceu também reduzida. Conclusões: A implantação de um programa de reabilitação intestinal e nutrição enteral pós-operatória precoce está associada à redução das complicações pós-operatórias e à melhora dos resultados clínicos em pacientes submetidos a operações gastrointestinais para câncer.

Associação entre o estado nutricional e alterações psicológicas em pacientes portadores de câncer gastrointestinal / Association between nutritional status and psychological changes in patients with gastrointestinal cancer

Introdução: A etiologia do câncer é variada, proveniente tanto de fatores externos quanto internos ao organismo. O diagnóstico de câncer causa um grande impacto aos pacientes, conduzindo a mudanças físicas, além de interferir no cotidiano e imagem que o paciente possui de si mesmo, com isso, ameaçando seu equilíbrio psicológico e, consequentemente, a qualidade de vida. Método: Estudo descritivo, transversal, quantitativo e analítico, com amostra constituída de 30 pacientes, no período de fevereiro a abril de 2017, na Unidade de Alta Complexidade em Oncologia do Hospital Universitário João de Barros Barreto. Foram selecionados para a pesquisa pacientes diagnosticados com câncer do trato gastrointestinal, de ambos os sexos, idade entre 19 e 60 anos, em acompanhamento ambulatorial e que faziam o tratamento de quimioterapia. Para a coleta dos dados, aplicaram-se dois questionários, sendo estes a Avaliação Subjetiva Global Produzida pelo Próprio Paciente e um questionário específico de aspectos psicológicos relacionados ao diagnóstico de câncer. Resultados: Nesta pesquisa, avaliaram-se 30 pacientes com cânceres do trato gastrointestinal, cujas categorias das variáveis estudadas foram inerentes à Avaliação Subjetiva Global produzida pelo paciente e Associações Psicológicas. Quanto à significância das variáveis em estudo, prevaleceram a de ASG-PPP versus Associação Psicológica, com significância 84,53%; Associação Psicológica versus aversão a certos alimentos, com 73,16%; Associação Psicológica versus Mudança no comportamento alimentar, com 90,11%; Associação Psicológica versus Capacidade Funcional, com 84,70%; Associação Psicológica versus desconforto limitam a alimentação, com 88,76% e de associação Psicológica versus causou sofrimento físico, mental e financeiro, com 88,76%. Conclusão: Diante do estudo, tornou-se possível analisar o estado nutricional dos pacientes, além de detectar o quanto o estado psicológico está ligado com o prognóstico. Portanto, a detecção do estado nutricional e dos aspectos psicológicos é válida para a melhoria da saúde e qualidade de vida dos pacientes.(AU)

Introduction: The etiology of cancer is varied, coming from both external and internal factors. The diagnosis of cancer causes a great impact to the patients, leading to physical changes, besides interfering in the daily life and image that the patient has of himself, with that, threatening his psychological balance and consequently the quality of life. Methods: A descriptive, cross-sectional, quantitative and analytical study with a sample consisting of 30 patients from February to April 2017 at the High Complexity in Oncology Unit of the João de Barros Barreto University Hospital. Patients diagnosed with cancer of the gastrointestinal tract, of both sexes, aged between 19 and 60 years in outpatient follow-up and undergoing chemotherapy treatment were selected for the research. For the data collection, two questionnaires were applied: The Global Subjective Evaluation Produced by the Patient and a specific questionnaire on psychological aspects related to the diagnosis of cancer. Results: In this study 30 patients with gastrointestinal tract cancers were evaluated, whose categories of variables were inherent to the Global Subjective Evaluation produced by the patient and Psychological Associations. Regarding the significance of the variables under study, the prevalence of ASG-PPP versus Psychological Association, with significance was 84.53%; Psychological Association versus aversion to certain foods, with 73.16%; Psychological Association versus Change in eating behavior, with 90.11%; Psychological Association versus Functional Capacity, with 84.70%; Psychological association versus discomfort limit feeding, with 88.76% and Psychological association versus causing physical, mental and financial suffering, with 88.76%. Conclusion: Before the study, it became possible to analyze the nutritional status of the patients, in addition to detecting how much the psychological state is linked to the prognosis. Therefore, the detection of nutritional status and psychological aspects is valid for the improvement of patients' health and quality of life.(AU)

Queratosis seborreica eruptiva y su asociación con cáncer gastrointestinal. Un estudio de casos y controles / Eruptive seborrheic keratosis and its association with gastrointestinal cancer. A case-control study

Resumen Introducción: se ha propuesto la existencia de asociación entre queratosis seborreica eruptiva y algunas neoplasias malignas. Sin embargo, la evidencia acerca de esto es pobre: tres estudios europeos de casos y controles cuyos resultados no la apoyan. El objetivo del estudio es evaluar en población colombiana la existencia o no de esta asociación. Material y métodos: estudio de 130 casos y 260 controles pareados por edad y sexo en mayores de 18 años entre pacientes con cáncer gastrointestinal o pancreatobiliar (casos) u hospitalizados por otras razones no oncológicas (controles) en el Hospital Universitario de Santander, Bucaramanga (Colombia). A todos los pacientes se les realizó examen cutáneo minucioso, incluyendo dermatoscopia, para identificar la presencia y tiempo de evolución de queratosis seborreica en zonas cubiertas por ropa. Resultados: la prevalencia de queratosis seborreica entre los casos fue 26.9% (IC95% 19.5-35.4) y de 15.4% (IC95% 11.2-20.4) entre los controles (OR 1.94, IC95% 1.17-3.19). Siete pacientes con cáncer presentaban la queratosis seborreica en los seis meses previos al diagnóstico de la neoplasia (5.3%, IC95% 2.2-10.8) frente a ninguno entre los pacientes control (0.0%, IC95% 0.0-1.4; p<0.001); tres de ellos tenían 20 o más lesiones de menos de seis meses de aparición (2.3% de los casos, IC95% 0.5-6.6) frente a ninguno entre los controles (p=0.014). Discusión: este estudio trata de subsanar las debilidades de los únicos tres estudios previos que exploran la asociación entre queratoris seborreica y cáncer mediante la rigurosa selección de pacientes, la inclusión de pacientes con cáncer de un solo sistema corporal y un proceso estricto para evaluar las lesiones cutáneas con dermatoscopia. Esto permite concluir que en pacientes colombianos con cáncer gastrointestinal hay mayor frecuencia de queratosis seborreica y de queratoris seborreica eruptiva que en personas de igual edad y sexo sin cáncer. (Acta Med Colomb 2017; 42: 224-229).

Abstract Introduction: the association between eruptive seborrhoeic keratosis and some malignant neoplasms has been proposed. However, the evidence about this is poor: three European case-control studies whose results do not support it. The objective of the study is to evaluate the existence or not of this association in the Colombian population. Material and methods: study of 130 cases and 260 matched controls for age and sex in patients over 18 years of age among patients with gastrointestinal or pancreatobiliary cancer (cases) or hospitalized for other non-oncological reasons (controls) at the University Hospital of Santander, Bucaramanga (Colombia). All patients underwent meticulous skin examination including dermatoscopy, to identify the presence and time of evolution of seborrheic keratosis in areas covered by clothing. Results: the prevalence of seborrheic keratosis among the cases was 26.9% (95% CI 19.5-35.4) and 15.4% (95% CI 11.2-20.4) among the controls (OR 1.94, 95% CI 1.17-3.19). Seven patients with cancer presented seborrheic keratosis in the six months prior to the diagnosis of neoplasia (5.3%, 95% CI 2.2-10.8) compared to none among control patients (0.0%, 95% CI 0.0-1.4, p <0.001); three of them had 20 or more lesions less than six months of onset (2.3% of cases, 95% CI 0.5-6.6) compared to none among controls (p = 0.014). Discussion: this study tries to correct the weaknesses of the only three previous studies that explore the association between seborrheic keratosis and cancer by rigorous selection of patients, the inclusion of cancer patients from a single body system and a strict process to evaluate the skin lesions with dermatoscopy. This allows concluding that in Colombian patients with gastrointestinal cancer there is a greater frequency of seborrheic keratosis and eruptive seborrheic keratosis than in people of the same age and sex without cancer. (Acta Med Colomb 2017; 42: 224-229).

Utilidad de la endomicroscopia confocal láser basada en probes (Cellvizio) en gastroenterología / Utility of Probe-based (Cellvizio) Confocal Laser Endomicroscopy in Gastroenterology

La endomicroscopia confocal láser basada en probes (Cellvizio de Mauna Kea Technologies, París) es una nueva tecnología que permite, durante cualquier procedimiento endoscópico, realizar análisis histológicos en tiempo real (biopsia óptica), mejorando el diagnóstico y ayudando a definir el tratamiento de múltiples patologías digestivas. Es de resaltar, para nuestro medio, su utilidad en patologías de difícil diagnóstico como son las estenosis biliares indeterminadas y las neoplasias quísticas pancreáticas, cuyo diagnóstico temprano y exacto es muy difícil con las técnicas actualmente disponibles, y que es necesario para definir la realización o la exclusión de tratamientos quirúrgicos de alta morbimortalidad y alto costo, como por ejemplo, la cirugía de Whipple. En esta revisión se muestran los aportes actuales de esta tecnología, ya disponible en nuestro medio, para el diagnóstico y estudio de las patologías digestivas.

Probe based confocal laser endomicroscopy (Cellvizio Mauna Kea, Paris) is a new technology that allows performance of histological analysis (optical biopsy) during any endoscopic procedure. This improves diagnosis and helps define the treatment needed for multiple digestive diseases. Its utility for diseases that are difficult to diagnose such as indeterminate biliary strictures and pancreatic cystic neoplasms is noteworthy. Early and accurate diagnoses can be very difficult with currently available techniques, but they are exactly what are needed to determine whether or not expensive surgical treatments with great potential morbidity, for example the Whipple procedure, need to be performed. This review looks at the contribution that this technology can make in our country where it is now available for the diagnosis and study of digestive diseases.

Análisis de las aneuploidías del cromosoma 17 y deleción del gen TP53 en tumores gastrointestinales por FISH-bicolor / Analyses of numerical aberrations of chromosome 17 And TP53 gene deletion in gastrointestinal tumors by dual-color fluorescence in situ hybridization (FISH)

Introducción. Las alteraciones cromosómicas numéricas y estructurales son comunes en las neoplasias gastrointestinales; estas alteraciones se originan por la inestabilidad cromosómica que ocurre durante el desarrollo del cáncer, afectando la expresión de diversos genes como protooncógenes, genes supresores de tumores y genes de reparación.Objetivo. Evaluar las aneuploidías del cromosoma 17 y deleción del gen TP53 en tumores gastrointestinales primarios, mediante la técnica del FISH bicolor. Muestras y métodos. Se analizaron 15 muestras de tumores gastrointestinales primarios, se disociaron mecánica y enzimáticamente con colagenasa para obtener núcleos interfásicos. El FISH bicolor se realizó con sondas marcadas con fluorocromos para el centrómero del cromosoma 17 y para el locus 17p13.1 del gen TP53. Se analizaron 100 núcleos por cada muestra.Resultados. Se encontró que el 33,3% (5/15) de las muestras tenía aneuploidías para el cromosoma 17; la monosomía fue detectada en todos los casos (5/5). La mayoría de las muestras tenía subpoblaciones de núcleos heterogéneos (mosómicos, disómicos, trisómicos y tetrasómicos). El 93,3% (14/15) de los tumores tenían deleción del gen TP53. El estudio histopatológico mostró que 14 de las 15 muestras presentaban un estado avanzado del cáncer.Conclusiones. Se demostró un imbalance entre las señales del centrómero del cromosoma 17 y del gen TP53 por núcleo mediante el FISH bicolor. Aneuploidías del cromosoma 17 y deleciones en el locus 17p13.1 del gen TP53 son alteraciones muy frecuentes en tumores gastrointestinales. El FISH bicolor permite evidenciar la heterogeneidad genética intratumoral que se presenta en el desarrollo del cáncer.

Introduction. Numerical and structural chromosome aberrations are common in gastrointestinal cancers; these are originated by chromosomal Instability that happens during development of cancer. Thus, the expression of many genes is affected, such as protooncogene, tumor suppressor genes and repair genes. Aims. To evaluate aneuploidy of chromosome 17 and TP53 gene deletions in primary gastrointestinal tumors by dual- color fluorescence in situ hybridization (FISH).Samples and methods. 15 primary gastrointestinal tumor samples were analyzed, which were mechanically and enzimatically disaggregated with 0.2% collagenase in order to obtain interphase nuclei. Dual-color FISH assays was performed using direct fluorescent labeling probes for the chromosome 17 centromere and TP53 gene (17p13.1). Hybridized signals were counted in 100 interphase nuclei by each case.Results. Aneuploidy of chromosome 17 was found in 33.3% (5/15) of the samples. Monosomy was detected in 100% (5/5) of cases with aneuploidies. Most of tumor samples exhibited heterogeneous clones that were monosomic, disomic, trisomic and occasionally tetrasomic. The TP53 deletion was found in 93.3% (14/15) of the analyzed samples. The histopathological study showed that 14 out of 15 tumors samples displayed an advance stage of tumorigenesis.Conclusions. We found an imbalance of signals for chromosome 17 and TP53 per nucleus. Aneuploidy of chromosome 17 and TP53 gene deletion are very frequent aberrations in gastrointestinal tumors. Dual-color FISH analysis allow detect intratumoral genetic heterogeneity that had occurred in development of cancer.