Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.

Effectiveness of an Acute Care for Elders unit at a long-term care facility for frail older patients with COVID-19.

The Acute Care for Elders (ACE) is a model of care addressed to reduce the incidence of loss of self-care abilities of older adults occurring during hospitalization for acute illness. This observational study aimed to describe the effectiveness of an ACE unit at a long-term care facility to prevent functional decline (decrease in the Barthel Index score of >5 points from admission to discharge) in older adults with frailty (Clinical Frailty Scale score ≥5) and symptomatic COVID-19. Fifty-one patients (mean age: 80.2 + 9.1 years) were included. Twenty-eight (54.9%) were women, with a median Barthel index of 50 (IQR:30-60) and Charlson of 6(IQR: 5-7), and 33 (64.7%) had cognitive impairment. At discharge, 36(70.6%) patients had no functional decline, 6 (11.7%) were transferred to hospital and 4(7.8%) died. An ACE unit at a long-term care facility constitutes an alternative to hospital care to prevent hospital-associated disability for frail older patients with COVID-19.

Use of Brassica juncea and Dactylis glomerata for the phytostabilization of mine soils amended with compost or biochar.

Phytostabilization of mine soils contaminated by potentially toxic elements (PTEs) requires plants tolerant to PTE toxicity and to the poor soil physico-chemical characteristics of these areas. A pot experiment was carried out to assess the phytostabilization potential of Brassica juncea and Dactylis glomerata in mine soils amended with compost and biochar. Furthermore, the Environmental Risk of the soils and the effects of the phytostabilization process on the microbiological population size and activity in the soils were also determined. According to the Ecological Risk Index (ERI) the soils studied presented "very high risk" and As, Cd and Pb were the target elements for phytostabilization. Both amendments improved soil conditions (e.g., increasing total-N and total organic-C concentrations) and contributed to PTE (Cd, Pb and Zn) immobilization in the soil. Compost showed a more marked effect on soil microbial biomass and nutrients release in soil, which led to higher B. juncea and D. glomerata biomass in compost treated soils. Biochar treatment showed a positive effect only on D. glomerata growth, despite it provoked strong PTE immobilization in both soils. The addition of both amendments resulted in an overall reduction of PTE concentration in the plants compared to the control treatment. In addition, both plant species showed higher accumulation of PTE in the roots than in the shoots (transfer factor<1) independently of the treatment received. Therefore, they can be considered as good candidates for the phytostabilization of PTE contaminated mine soils in combination with organic amendments like biochar and compost.

The combination of epigenetic drugs SAHA and HCI-2509 synergistically inhibits EWS-FLI1 and tumor growth in Ewing sarcoma.

PURPOSE: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments. RESULTS: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume. CONCLUSIONS: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.

Integrated Care on Leaving Hospital Against Medical Advice Among HIV-Infected People with Substance Use Disorders.

HIV-infected people with substance use disorders (HIV-SUDs) are at increased risk of leaving hospital against medical advice (LHAMA). The aim of this study was to evaluate the incidence of LHAMA in HIV-SUDs admitted to a patient-centered hospital where they receive integrated care, including healthcare, substance use treatment, and social support. Observational study was conducted at an urban acute-care university teaching hospital. Integrated care included a specialist in addiction medicine and a social worker incorporated into the medical staff. LHAMA was defined as participants leaving the hospital without the physician's permission and not returning within 6 h. Two hundred and ninety-nine HIV-SUDs were hospitalized, and 79 (26.4%) patients were readmitted, generating a total of 517 admissions during 2010-2016. Over the study period, 45 LHAMA were registered, yielding an incidence of 8.7%. On multiple logistic regression analysis, admission for malignancies (OR:4.2; p .02), retention in substance use treatment (OR:0.3; p .01), intravenous substance use (OR:3.1; 0.05), and marginally being foreign (OR:2.1; p .06) were independent factors associated with LHAMA. Despite the patient-centered hospital care, including integrated care, patients with lack of SUD treatment or with intravenous substance use are at increased risk of LHAMA. So, additional measures are necessary to reduce the risk of LHAMA among HIV-SUD.

Valor pronóstico de los instrumentos de evaluación de enfermedad avanzada y de final de vida en ancianos ingresados en un centro sociosanitario / Prognostic value of assessment tools on elderly patients with chronic advanced disease and end of life, admitted to an intermediate care centre

Objetivo. Aplicar 3instrumentos de evaluación de enfermedad avanzada en ancianos ingresados en un centro sociosanitario y evaluar su relación con la mortalidad. Métodos. Se aplicaron los instrumentos NECPAL, índice PROFUND e índice de comorbilidad de Charlson a 87 pacientes. Resultados. El instrumento NECPAL identificó a 31 pacientes (35,6%) en situación de necesidad de atención paliativa; según el índice PROFUND, 45 (54,7%) tenían riesgo alto/muy alto de mortalidad (≥7 puntos) y según el índice de Charlson, 31 (35,6%) tenían carga de morbilidad alta (≥4 puntos). Pacientes NECPAL positivos: el 80,5% tenían puntuación ≥7 en índice PROFUND y 48,3% un Charlson ≥ 4; dichas proporciones fueron 34,4 y 28,5% en los NECPAL negativos (p<0,001 y p≤0,06, respectivamente). Correlaciones entre los 3instrumentos: cuantitativas (Spearman): número de respuestas NECPAL con PROFUND (r=0,57; p<0,001); con Charlson (r=0,214; p=0,047) y entre PROFUND y Charlson (r=0,157; p=0,148). Cualitativas (kappa) NECPAL (positivo/negativo) con PROFUND (corte 6/7) (0,40; p<0,001), con Charlson (corte 3/4) (0,19; p=0,080) y entre PROFUND y Charlson (0,08; p=0,399). Predicción de mortalidad (área bajo la curva): NECPAL 3 meses 0,81 (IC: 0,62-1,00); 6 meses 0,71 (IC: 0,53-0,89) y 12 meses 0,67 (IC: 0,52-0,82). PROFUND 3 meses 0,71 (IC: 0,50-0,91); 6 meses 0,73 (IC: 0,58-0,87) y 12 meses 0,69 (IC: 0,57-0,81). Charlson 3 meses 0,72 (IC: 0,52-0,91); 6 meses 0,62 (IC: 0,45-0,80) y 12 meses 0,64 (IC: 0,50-0,78). Conclusiones. Los 3instrumentos se relacionaron de forma significativa con una mayor mortalidad. La concordancia entre los resultados de los distintos instrumentos fue baja (AU)

Objective. To apply 3advanced chronic disease evaluation tools in elderly patients admitted to an intermediate and long-term care centre, and evaluate its relationship with mortality. Methods. The NECPAL tool, PROFUND prognostic index, and Charlson comorbidity index were applied to 87 patients. Results. The NECPAL tool identified 31 patients (35.6%) in need of palliative care, and according to the PROFUND index, 45 (54.7%) had high/very high risk of mortality (≥7 points), and according to Charlson index, 31 (35.6%) had high comorbidity (≥4 points). Of the NECPAL positive patients, 80.5% had a PROFUND index score ≥7, and 48.3% a Charlson index ≥ 4. These percentages were 34.4% and 28.5% in negative NECPAL patients (P<.001 and P≤.06, respectively). Correlations between the 3tools: quantitative (Spearman) number of responses in NECPAL with PROFUND (r=.57; P<.001); with Charlson (r=.214; P<.047) and between PROFUND and Charlson (r=.157; P=.148). Qualitative (kappa) NECPAL (positive/negative) with PROFUND (cut-off 6/7) (0.40; P<.001), and Charlson (cut-off 3/4) (0.19; P=.080) and between PROFUND and Charlson (0.08; P=.399). Mortality prediction (area under the curve): NECPAL 3 months 0.81 (95% CI: 0.62-1.00); 6 months 0.71 (95% CI: 0.53-0.89) and 12 months 0.67 (95% CI: 0.52-0.82). PROFUND 3 months 0.71 (95% CI: 0.50-0.91); 6 months 0.73 (95% CI: 0.58-0.87), and 12 months 0.69 (95% CI: 0.57-0.81). Charlson 3 months 0.72 (95% CI: 0.52-0.91); 6 months 0.62 (95% CI: 0.45-0.80), and 12 months 0.64 (95% CI: 0.50-0.78). Conclusions. The 3tools were significantly associated with high mortality. A low concordance was found between the results of the different tools (AU)

[Prognostic value of assessment tools on elderly patients with chronic advanced disease and end of life, admitted to an intermediate care centre]. / Valor pronóstico de los instrumentos de evaluación de enfermedad avanzada y de final de vida en ancianos ingresados en un centro sociosanitario.

OBJECTIVE: To apply 3advanced chronic disease evaluation tools in elderly patients admitted to an intermediate and long-term care centre, and evaluate its relationship with mortality. METHODS: The NECPAL tool, PROFUND prognostic index, and Charlson comorbidity index were applied to 87 patients. RESULTS: The NECPAL tool identified 31 patients (35.6%) in need of palliative care, and according to the PROFUND index, 45 (54.7%) had high/very high risk of mortality (≥7 points), and according to Charlson index, 31 (35.6%) had high comorbidity (≥4 points). Of the NECPAL positive patients, 80.5% had a PROFUND index score ≥7, and 48.3% a Charlson index ≥ 4. These percentages were 34.4% and 28.5% in negative NECPAL patients (P<.001 and P≤.06, respectively). Correlations between the 3tools: quantitative (Spearman) number of responses in NECPAL with PROFUND (r=.57; P<.001); with Charlson (r=.214; P<.047) and between PROFUND and Charlson (r=.157; P=.148). Qualitative (kappa) NECPAL (positive/negative) with PROFUND (cut-off 6/7) (0.40; P<.001), and Charlson (cut-off 3/4) (0.19; P=.080) and between PROFUND and Charlson (0.08; P=.399). Mortality prediction (area under the curve): NECPAL 3 months 0.81 (95% CI: 0.62-1.00); 6 months 0.71 (95% CI: 0.53-0.89) and 12 months 0.67 (95% CI: 0.52-0.82). PROFUND 3 months 0.71 (95% CI: 0.50-0.91); 6 months 0.73 (95% CI: 0.58-0.87), and 12 months 0.69 (95% CI: 0.57-0.81). Charlson 3 months 0.72 (95% CI: 0.52-0.91); 6 months 0.62 (95% CI: 0.45-0.80), and 12 months 0.64 (95% CI: 0.50-0.78). CONCLUSIONS: The 3tools were significantly associated with high mortality. A low concordance was found between the results of the different tools.

Metabolic syndrome among individuals with heroin use disorders on methadone therapy: Prevalence, characteristics, and related factors.

BACKGROUND: Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy. METHODS: A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. RESULTS: One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m2 (interquartile range [IQR]: 21.2-28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5-20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6-31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m2 increase odds ratio [OR]: 1.49, 95% CI: 1.27-1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28-1.48) were associated with metabolic syndrome. CONCLUSIONS: Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be recommended to prevent metabolic syndrome in subjects on methadone therapy.

[Delirium prevention and treatment in elderly hip fracture]. / Prevención y tratamiento del delírium en ancianos con fractura de cadera.

The fracture of the proximal femur or hip fracture in the elderly usually happens after a fall and carries a high morbidity and mortality. One of the most common complications during hospitalization for hip fracture is the onset of delirium or acute confusional state that in elderly patients has a negative impact on the hospital stay, and prognosis, worsening functional ability, cognitive status and mortality. Also the development of delirium during hospitalization increases health care costs. Strategies to prevent and treat delirium during hospitalization for hip fracture have been less studied. In this context, this paper aims to conduct a review of the literature on strategies that exist in the prevention and treatment of delirium in elderly patients with hip fracture.

Tratamiento farmacológico de la demencia: cuándo, cómo y hasta cuándo. Recomendaciones del Grupo de Trabajo de Demencias de la Sociedad Catalana de Geriatría y Gerontología / Pharmacological treatment of dementia: When, how and for how long. Recommendations of the Working Group on Dementia of the Catalan Society of Geriatrics and Gerontology

La demencia en general y la enfermedad de Alzheimer (EA) en particular, están llamadas a ser uno de los principales problemas sanitarios, sociales y de salud pública en el siglo xxi . La EA tiene un curso progresivo que el tratamiento específico adecuado puede enlentecer pero no detener. Existe evidencia suficiente para recomendar este tratamiento en las fases leves, moderadas y moderadamente graves. En la fase final de la enfermedad habrá que tomar decisiones en cuanto a la retirada de dicho tratamiento. En el presente artículo, el Grupo de Trabajo de Demencias de la Sociedad Catalana de Geriatría y Gerontología, revisa la utilización del tratamiento farmacológico especifico para la EA y basándose en la evidencia científica, realiza recomendaciones de cuando, como y hasta cuando se debe utilizar el tratamiento farmacológico específico existente en la actualidad (tanto los inhibidores de la acetil colinesterasa como la memantina)(AU)

Dementia in general −and Alzheimer's disease (AD) in particular− are bound to loom large among the most acute healthcare, social, and public health problems of the 21st century. AD shows a degenerative progression that can be slowed down −yet not halted− by today's most widely accepted specific treatments (those based on cholinesterase inhibitors as well as those using memantine). There is enough evidence to consider these treatments advisable for the mild, moderate and severe phases of the illness. However, in the final stage of the disease, a decision has to be made on whether to withdraw such treatment or not. In this paper, the Working Group on Dementia for the Catalan Society of Geriatrics and Gerontology reviews the use of these specific pharmacological treatments for AD, and, drawing on the scientific evidence thus gathered, makes a series of recommendations on when, how, and for how long, the currently existing specific pharmacological treatments should be used(AU)

[Pharmacological treatment of dementia: when, how and for how long. Recommendations of the Working Group on Dementia of the Catalan Society of Geriatrics and Gerontology]. / Tratamiento farmacológico de la demencia: cuándo, cómo y hasta cuándo. Recomendaciones del Grupo de Trabajo de Demencias de la Sociedad Catalana de Geriatría y Gerontología.

Dementia in general--and Alzheimer's disease (AD) in particular--are bound to loom large among the most acute healthcare, social, and public health problems of the 21st century. AD shows a degenerative progression that can be slowed down--yet not halted--by today's most widely accepted specific treatments (those based on cholinesterase inhibitors as well as those using memantine). There is enough evidence to consider these treatments advisable for the mild, moderate and severe phases of the illness. However, in the final stage of the disease, a decision has to be made on whether to withdraw such treatment or not. In this paper, the Working Group on Dementia for the Catalan Society of Geriatrics and Gerontology reviews the use of these specific pharmacological treatments for AD, and, drawing on the scientific evidence thus gathered, makes a series of recommendations on when, how, and for how long, the currently existing specific pharmacological treatments should be used.

La información del diagnóstico en la demencia / Informing of the diagnosis in dementia

La demencia es un síndrome caracterizado por un deterioro progresivo de las funciones cognitivas, acompañado de síntomas psiquiátrico y alteraciones comportamentales que provocan una discapacidad progresiva e irreversible. El modo en que se debe comunicar el diagnóstico en la demencia constituye un punto de debate clave, sobre el cual no existe un acuerdo unánime hasta el momento. La comunicación del diagnóstico de demencia es un tema complejo que afecta no sólo al paciente sino también, a los cuidadores y a los profesionales sanitarios que lo atienden, y que se debe ajustar a los principios éticos que rigen la práctica médica (autonomía, no maleficencia, beneficencia y justicia). Por todo ello, desde el Grupo de Trabajo de Demencia de la Sociedad Catalana de Geriatría surge la necesidad de realizar una revisión del tema y de proponer unas pautas de actuación frente a la revelación del diagnóstico(AU)

Dementia is a syndrome characterized by a progressive deterioration of cognitive functions, accompanied by psychiatric symptoms and behavioral disturbances that produce a progressive and irreversible disability. The way it should communicate the diagnosis of dementia is a key discussion point on which there is no unanimous agreement so far. The communicating of the diagnosis of dementia is a complex issue that affects not only, the patient but also to caregivers and health professionals who care and must conform to the ethical principles governing medical practice (autonomy, nonmaleficence, beneficence, and justice). Therefore, from the Dementia Working Group of the Catalan Geriatric Society (Grupo de Trabajo de Demencia de la Sociedad Catalana de Geriatría) arises the need to review the issue and propose a course of action for the disclosure of diagnosis(AU)

[Informing of the diagnosis in dementia]. / La información del diagnóstico en la demencia.

Dementia is a syndrome characterized by a progressive deterioration of cognitive functions, accompanied by psychiatric symptoms and behavioral disturbances that produce a progressive and irreversible disability. The way it should communicate the diagnosis of dementia is a key discussion point on which there is no unanimous agreement so far. The communicating of the diagnosis of dementia is a complex issue that affects not only, the patient but also to caregivers and health professionals who care and must conform to the ethical principles governing medical practice (autonomy, nonmaleficence, beneficence, and justice). Therefore, from the Dementia Working Group of the Catalan Geriatric Society (Grupo de Trabajo de Demencia de la Sociedad Catalana de Geriatría) arises the need to review the issue and propose a course of action for the disclosure of diagnosis.

Lower Barthel Index scores predict less prescription of pharmacological therapy in elderly patients with Alzheimer disease.

AIMS: To determine the factors associated with receiving specific treatment (cholinesterase inhibitors or/and memantine) for Alzheimer disease (AD) in elderly patients. METHODS: An observational study carried out in 289 consecutive outpatients aged >64 years with dementia. We collected data on specific AD therapy, sociodemographic variables, Barthel Index (BI), Lawton and Brody Index (LI), Mini Mental State Examination, Global Deterioration Scale (GDS), Charlson Index and the total number of drugs chronically prescribed. Patients receiving specific therapy for dementia were compared with the rest. RESULTS: Two hundred and thirty-three (80.6%) patients were receiving specific treatment for dementia, with 197 (84.5%) receiving monotherapy and the rest (15.4%) combined therapy. The bivariate analysis showed that age, marital status, place of residence, BI and LI, cognitive status and disease severity (GDS) were factors associated with receiving specific dementia therapy. Multiple stepwise logistic regression analysis showed that a lower BI (beta = -0.25; odds ratio 0.976, 95% confidence interval = 0.966-0.986; p < 0.0001) was the only factor independently associated with not receiving specific therapy for AD. CONCLUSIONS: Of the possible factors related to elderly patients receiving specific therapy for AD, a poor BI score was the most important factor associated with not receiving treatment.