Emergency department direct discharge compared to short-stay unit admission for selected patients with acute heart failure: analysis of short-term outcomes

Insuficiència cardíaca; Serveis d'urgències mèdiques; MortalitatHeart failure; Emergency service, hospital; MortalityInsuficiencia cardíaca; Servicio hospitalario de urgencias; MortalidadShort stay unit (SSU) is an alternative to conventional hospitalization in patients with acute heart failure (AHF), but the prognosis is not known compared to direct discharge from the emergency department (ED). To determine whether direct discharge from the ED of patients diagnosed with AHF is associated with early adverse outcomes versus hospitalization in SSU. Endpoints, defined as 30-day all-cause mortality or post-discharge adverse events, were evaluated in patients diagnosed with AHF in 17 Spanish EDs with an SSU, and compared by ED discharge vs. SSU hospitalization. Endpoint risk was adjusted for baseline and AHF episode characteristics and in patients matched by propensity score (PS) for SSU hospitalization. Overall, 2358 patients were discharged home and 2003 were hospitalized in SSUs. Discharged patients were younger, more frequently men, with fewer comorbidities, had better baseline status, less infection, rapid atrial fibrillation and hypertensive emergency as the AHF trigger, and had a lower severity of AHF episode. While their 30-day mortality rate was lower than in patients hospitalized in SSU (4.4% vs. 8.1%, p < 0.001), 30-day post-discharge adverse events were similar (27.2% vs. 28.4%, p = 0.599). After adjustment, there were no differences in the 30-day risk of mortality of discharged patients (adjusted HR 0.846, 95% CI 0.637-1.107) or adverse events (1.035, 0.914-1.173). In 337 pairs of PS-matched patients, there were no differences in mortality or risk of adverse event between patients directly discharged or admitted to an SSU (0.753, 0.409-1.397; and 0.858, 0.645-1.142; respectively). Direct ED discharge of patients diagnosed with AHF provides similar outcomes compared to patients with similar characteristics and hospitalized in a SSU.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The author(s) disclosed receipt of the following fnancial support for the research, authorship, and/or publication of this article: This study was partially supported by grants from the Instituto de Salud Carlos III supported with funds from the Spanish Ministry of Health and FEDER (PI15/01019, PI18/00393) and Fundació La Marató de TV3 (2015/2510). The Emergencies: Processes and Pathologies research group of the IDIBAPS receives fnancial support from the Catalonian government for consolidated groups of investigation (GRC 2009/1385 and 2014/0313)

Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice

This work is licensed under a Creative Commons Attribution 3.0 License.The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. However, BCR-ABL was expressed and active in telomerase heterozygous and null leukemic hematopoietic stem cells. These results demonstrate that telomerase is essential for oncogene-induced reprogramming of hematopoietic stem cells in CML development and validate telomerase and the genes it regulates as targets for therapy in CML.Research in ISG group was partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, and the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and by Proyecto en Red de Investigación en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER program. ISG is an API lab of the EuroSyStem project.Peer Reviewe

Renal Transplantation in Systemic Lupus Erythematosus: Outcome and Prognostic Factors in 50 cases from a Single Centre.

Background. End-stage renal disease (ESRD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Objectives. To analyze the outcome and prognostic factors of renal transplantation in patients with ESRD due to SLE from January 1986 to December 2013 in a single center. Results. Fifty renal transplantations were performed in 40 SLE patients (32 female (80%), mean age at transplantation 36 ± 10.4 years). The most frequent lupus nephropathy was type IV (72.2%). Graft failure occurred in a total of 15 (30%) transplantations and the causes of graft failure were chronic allograft nephropathy (), acute rejection (), and chronic humoral rejection (1). The death-censored graft survival rates were 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of study. The presence of deceased donor allograft () and positive anti-HCV antibodies () negatively influence the survival of the renal transplant. The patient survival rate was 91.4% at the end of the study. Recurrence of lupus nephritis in renal allograft was observed in one patient. Conclusion. Renal transplantation is a good alternative for renal replacement therapy in patients with SLE. In our cohort, the presence of anti-HCV antibodies and the type of donor source were related to the development of graft failure

Predicting the Impact of Climate Change on the Distribution of Rhipicephalus sanguineus in the Americas

Climate change may influence the incidence of infectious diseases including those transmitted by ticks. Rhipicephalus sanguineus complex has a worldwide distribution and transmits Rickettsial infections that could cause high mortality rates if untreated. We assessed the potential effects of climate change on the distribution of R. sanguineus in the Americas in 2050 and 2070 using the general circulation model CanESM5 and two shared socioeconomic pathways (SSPs), SSP2-4.5 (moderate emissions) and SSP2-8.5 (high emissions). A total of 355 occurrence points of R. sanguineus and eight uncorrelated bioclimatic variables were entered into a maximum entropy algorithm (MaxEnt) to produce 50 replicates per scenario. The area under the curve (AUC) value for the consensus model (\u3e0.90) and the partial ROC value (\u3e1.28) indicated a high predictive capacity. The models showed that the geographic regions currently suitable for R. sanguineus will remain stable in the future, but also predicted increases in habitat suitability in the Western U.S., Venezuela, Brazil and Bolivia. Scenario 4.5 showed an increase in habitat suitability for R. sanguineus in tropical and subtropical regions in both 2050 and 2070. Habitat suitability is predicted to remain constant in moist broadleaf forests and deserts but is predicted to decrease in flooded grasslands and savannas. Using the high emissions SSP5-8.5 scenario, habitat suitability in tropical and subtropical coniferous forests and temperate grasslands, savannas, and shrublands was predicted to be constant in 2050. In 2070, however, habitat suitability was predicted to decrease in tropical and subtropical moist broadleaf forests and increase in tropical and subtropical dry broadleaf forests. Our findings suggest that the current and potential future geographic distributions can be used in evidence-based strategies in the design of control plans aimed at reducing the risk of exposure to zoonotic diseases transmitted by R. sanguineus

Validation of Cognitive Rehabilitation as a Balance Rehabilitation Strategy in Patients with Parkinson’s Disease: Study Protocol for a Randomized Controlled Trial.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. This disease is characterized by motor symptoms, such as bradykinesia, tremor, and rigidity. Although balance impairment is characteristic of advanced stages, it can be present with less intensity since the beginning of the disease. Approximately 60% of PD patients fall once a year and 40% recurrently. On the other hand, cognitive symptoms affect up to 20% of patients with PD in early stages and can even precede the onset of motor symptoms. There are cognitive requirements for balance and can be challenged when attention is diverted or reduced, linking a worse balance and a higher probability of falls with a slower cognitive processing speed and attentional problems. Cognitive rehabilitation of attention and processing speed can lead to an improvement in postural stability in patients with Parkinson’s. Methods: We present a parallel and controlled randomized clinical trial (RCT) to assess the impact on balance of a protocol based on cognitive rehabilitation focused on sustained attention through the NeuronUP platform (Neuronup SI, La Rioja, Spain) in patients with PD. For 4 weeks, patients in the experimental group will receive cognitive therapy three days a week while the control group will not receive any therapy. The protocol has been registered at trials.gov NCT04730466. Conclusions: Cognitive therapy efficacy on balance improvement may open the possibility of new rehabilitation strategies for prevention of falls in PD, reducing morbidity, and saving costs to the health care system.post-print1014 K

Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis

In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.Research at C.C.’s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias, CSIC P.I.E., Junta de Castilla y León, and from an institutional grant from the Fundación Ramón Areces. Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program), by Junta de Castilla y León (BIO/SA06/13) and by “Proyecto en red de investigación en células madre tumorales” supported by Obra Social Kutxa y Consejería de Sanidad de la Junta de Castilla y Leon. C.V.D.’s research is supported by Junta de Castilla y León (proyecto de investigación en biomedicina SAN/39/2010). J.A.M.C.’s research is supported by the Instituto de Salud Carlos III (ISCIII), grants FIS-PI12/00202 and RTICC-RD12/0036/0063. All Spanish funding is co-sponsored by the European Union FEDER program. I.S.G. is an API lab of the EuroSyStem project and a partner of DECIDE European network. F.A.-J. and E.C.S. were supported by Spanish Ministry of Science and Innovation fellowships. E.C.-S. was a “Residencia de Estudiantes” Fellow. A.T.N. was the recipient of a “Beca de Postgrado de la Fundación Ramón Areces/UAM.”Peer Reviewe

Terapias selectivas contra cáncer hepático y de seno, dirigidas a la bioenergética mitocondrial

El Cáncer Hepático o Carcinoma Hepatocelular (HCC) y el Cáncer de Seno Triple Negativo (por sus siglas en inglés TNBC, Triple Negative Breast Cancer), son problemas de salud pública en el mundo, por su difícil tratamiento y alta resistencia a la quimioterapia. En el caso del HCC, dado la aparición tardía de los síntomas y signos de la enfermedad, rara vez se diagnóstica a tiempo, siendo fatal dentro de los 3 a 6 meses siguientes a su diagnóstico. TNBC representa aproximadamente el 15-20% de todos los casos de cáncer de mama, y generalmente se considera como el más severo subgrupo, dado que no expresa los genes para los receptores de estrógenos, progesterona y HER2 (por sus siglas en inglés, Human Epidermal Growth Factor Receptor 2), por lo tanto, no responde a la hormonoterapia (como tamoxifeno o inhibidores de la aromatasa) ni a las terapias dirigidas a los receptores de HER2, como Herceptin (nombre genérico: trastuzumab), conllevando un mayor riesgo de recaída y una tasa de mortalidad más alta en comparación con otros subtipos de cáncer de mama.En la actualidad, los fármacos utilizados para el tratamiento del cáncer, como la doxorubicina, son agentes citostáticos que causan arresto celular, y que inducen apoptosis por aumento de niveles de Bax y p38 MAPK, mediados por la inhibición de Akt. Desafortunadamente, la Doxorrubicina, a pesar de sus propiedades contra el cáncer, induce miocardiopatía severa, aparentemente por la inhibición de la Citocromo C oxidasa Subunidad Vb y por aumentar la producción de ROS. Otros enfoques incluyen inhibidores de la vía MAPK kinasa como el Nexavar® (Sorafenib), e inhibidores Tirosin-Kinasa con actividad contra los receptores del factor de crecimiento epidérmico 1 y 2, como el Tacerva® (Erlotinib). Sin embargo, ninguno de ellos son eficaces, no sólo porque no son capaces de inhibir totalmente la proliferación tumoral, sino también porque afectan a las células normales conduciendo en la mayoría de los casos a insuficiencia renal aguda y muerte.Se conoce que tanto el HCC y el TNBC se caracterizan por la disfunción mitocondrial, la glicólisis elevada, el aumentó en el metabolismo glutaminólisis, la producción de lactato y la generación de especies reactivas de oxígeno (ROS). Actualmente, está ampliamente aceptado que el metabolismo mitocondrial está normalmente reprogramado para permitir el crecimiento de células de cáncer y la proliferación. Por ejemplo, la fosforilación oxidativa mitocondrial en el cáncer es esencial para satisfacer la creciente demanda de la biosíntesis de metabolitos necesarios para la proliferación de células tumorales sin restricciones. Del mismo modo, los niveles alterados de ciertos subproductos metabólicos de las mitocondrias, tales como ROS, han sido implicados en la iniciación del tumor y mantenimiento, así como son esenciales para tumorigenecidad mediada por Kras.Las terapias selectivas dirigidas a la afectación de la bioenergética mitocondrial de HCC y TNBC, se convierten en una estrategia potencial con resultados prometedores.Recientemente hemos sintetizado dos compuestos dirigidos a la mitocondria MTA (Mitochondria Target Agent), MitoSG1 y Mitometformina, cuyos compuestos parenterales son SG1 y Metformina respectivamente, son conjugado a un catión de alkyl triphenylphosphonium. Dado las diferencias del potencial de membrana de las células tumorales, estos compuestos tienen una acumulación selectiva permitiendo su acción directa sobre la mitocondria de las células de HCC y TNBC.En nuestros resultados preliminares encontramos que MitoSG1 inhibe el crecimiento de la línea celular de HCC HepG2, a concentraciones de 2.5µM a las 24 horas de tratamiento. MitoSG1 ejerce efectos citotóxicos con una IC50 de 3.6µM, con intervalos entre 2.28µM y 5.9µM. Adicionalmente MitoSG1 genera una afectación del potencial de membrana a las 24 horas de tratamiento, evidenciando una inducción temprana a apoptosis vía mitocondrial. Por su parte la Mitometformina presentó sobre la línea celular HepG2 una IC50 de 358.7µM, una concentración mayor que la requerida por MitoSG1, concluyendo en HCC que la línea celular es más susceptible al desequilibro del estado REDOX ocasionado por MitoSG1, que a la posible afectación causada por la activación de AMPK o inhibición de la Glicerofosfato Deshidrogenasa, ocasionada por Mitometformina.MitoSG1 genera efectos citotóxicos en las líneas celulares Triple Negativas de seno MDA MB231 y MDA MB468, con IC50 que oscilan entren 1 y 2µM del compuesto, así como una afectación del potencial de membrana, indicándonos que la mitocondria es su blanco de acción.MitoSG1 presentó efectos sinérgicos con Erlotinib y Doxorubicina en la línea Celular HepG2, así como un efecto aditivo con Sorafenib. En el caso de MDA MB231, MitoSG1 potencia los efectos citotóxicos &nbsp;de &nbsp;Doxorubicina, sugiriéndonos su potencial uso como coadyuvante del tratamiento.Aspectos éticos.En el desarrollo de esta investigación no se incluyeron estudios en humano o animales, por lo que su desarrollo no implicó ningún tipo de riesgo y por ende, no le aplican las consideraciones de las Resolución 8430 de 1993. Los experimentos fueron realizados en líneas celulares comerciales

Application of a Pharmacogenetics-Based Precision Medicine Model (5SPM) to Psychotic Patients That Presented Poor Response to Neuroleptic Therapy

[EN] Antipsychotics are the keystone of the treatment of severe and prolonged mental disorders. However, there are many risks associated with these drugs and not all patients undergo full therapeutic profit from them. The application of the 5 Step Precision Medicine model(5SPM), based on the analysis of the pharmacogenetic profile of each patient, could be a helpful tool to solve many of the problematics traditionally associated with the neuroleptic treatment. In order to solve this question, a cohort of psychotic patients that showed poor clinical evolution was analyzed. After evaluating the relationship between the prescribed treatment and pharmacogenetic profile of each patient, a great number of pharmacological interactions and pharmacogenetical conflicts were found. After reconsidering the treatment of the conflictive cases, patients showed a substantial reduction on mean daily doses and polytherapy cases, which may cause less risk of adverse effects, greater adherence, and a reduction on economic costs

Evaluation of the impact of an intradialytic exercise programme on sarcopaenia in very elderly haemodialysis patients

Sarcopaenia is a highly prevalent condition in persons on haemodialysis (HD). In stable very elderly (75-95 years old) persons on chronic HD, we prospectively studied the European Working Group on Sarcopaenia in Older People (EWGSOP2) steps stability over time in 37 controls and their response to a 12-week intradialytic lower limb exercise programme in 23 persons. Overall dropout was 15% and the main cause for dropout was death (8%). Thus 33 controls and 18 exercise participants were evaluated at 12 weeks. In controls, comorbidity, nutrition, dependency and frailty scales, anthropometric assessments, EWGSOP2 step values and the prevalence of suspected, confirmed and severe sarcopaenia as assessed by EWGSOP2 remained stable. In contrast, in persons who completed the exercise programme, a significant improvement in the five times sit-to-stand (STS-5) test was noted at the end of the 12-week exercise programme (19.2 ± 4.9-15.9 ± 5.9 seconds; P =. 001), consistent with the lower limb nature of the exercise programme, that persisted 12 weeks after completion of the programme. Exercise also improved the Fried frailty scale (1.7 ± 1.0-1.1 ± 0.6; P =. 004). In conclusion, EWGSOP2 steps remain stable in stable very elderly persons on HD and STS-5 is responsive to a short-term intradialytic lower limb exercise programme. These results may help define EWGSOP2-based primary endpoints in future large-scale clinical trials assessing exercise interventionsThe authors would like to thank FRIAT for its support to the present study. The research groups of E.G.P., S.M.F. and A.O. are funded by the Ministerio de Economia, Industria y competitividad: FIS/Fondos FEDER (PI16/01298, PI18/01386, PI19/00588, PI19/00815, PI20/00487, PI21/01240, DTS18/00032), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009) and Sociedad Española de Nefrología, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-C