Utilización de infusores elastoméricos de antibióticos en hospitalización a domicilio

[Abstract] Objective: To describe the avoided costs and to analyze the effectiveness of intravenous antibiotic treatment in continuous perfusion in patients at Hospital at Home Units (HHU) administered using elastomeric infusion pumps (EIP) prepared in a Hospital Pharmacy Service (HPS). Methods: Retrospective observational study of the number and type of EIP prepared in the HPS and of the treated patients. Study period: January 2017-December2018. Analyzed data: demographic data of patients, location of infection, responsible microorganism, medication and type of EIP, dose and duration of treatment and its effectiveness in terms of cure or non-cure or patient's death. Economic valuation considering: costs of EIP, nursing time needed for preparation and cost of HHU care. Results: A total of 1,688 EIP to treat 102 patients resulted in 106 episodes of outpatient treatment of parenteral antibiotic therapy (OPAT) for 1,409 days, thereby avoiding 1,409 days of hospital admission. A total of 59.8% of the patients were men and the mean age was 70.5 ± 17 years. A 31.1% and 68.9% of the cases were empirical and pathogen-directed treatments, respectively. The most used antimicrobials were piperacillin/tazobactam (42.7%), ceftazidime (24.5%), meropenem (19.8%), ceftolozane/tazobactam (2.8%), and cloxacillin (1.9%). Mean duration of treatment was 13.29 ± 8.60 days. Location of infection: respiratory (42.5%), urinary (17.9%), skin and soft tissue (12.3%), bacteraemia (11.3%), osteomyelitis (7.5%), abdominal (3.8%) and 4.7% in other locations. The cure rate was 84%. Total avoided cost: 580,788.28€ in the 24 months studied. Conclusions: This program represents very important economic savings for the health system, and the effectiveness of the antibiotic treatment has not been compromised.[Resumen] Objetivo. Describir los costes evitados y analizar la efectividad del tratamiento con antibióticos por vía intravenosa en perfusión continua en pacientes en unidades de Hospitalización a Domicilio (HD) administrados con bombas de infusión elastoméricas (BIE) preparadas en un Servicio de Farmacia Hospitalaria (SFH). Método. Estudio observacional retrospectivo del número y tipo de BIE preparados en el SFH y pacientes tratados entre enero 2017 y diciembre 2018. Los datos analizados fueron: datos demográficos de pacientes, localización de la infección, microorganismo, medicación y tipo de BIE, dosis y duración del tratamiento y efectividad en términos de curación o no curación o muerte. Valoración económica: coste de BIE, tiempo de enfermería necesario para la preparación y coste de la atención en HD. Resultados. Se analizaron 1.688 BIE preparados para tratar 102 pacientes que resultaron en 106 episodios de tratamiento ambulatorio durante 1.409 días, evitando así 1.409 días de ingreso hospitalario. El 59,8% de los pacientes eran hombres y la edad media 70,5±17 años. El 31,1% de los tratamientos fueron empíricos versus 68,9% dirigidos por patógeno. Los antimicrobianos más empleados fueron piperacilina-tazobactam (42,7%), ceftazidima (24,5%), meropenem (19,8%), ceftolozano-tazobactam (2,8%) y cloxacilina (1,9%). La duración media del tratamiento fue de 13,29 ± 8,60 días. Localización de la infección: respiratorias (42,5%), urinarias (17,9%), piel y partes blandas (12,3%), bacteriemias (11,3%), osteomielitis (7,5%), abdominales (3,8%) y un 4,7% en otras localizaciones. La tasa de curación del 84%. El coste total evitado fue de 580.788,28€ durante los 24 meses de estudio. Conclusiones. Este programa representa un ahorro económico muy importante para el sistema de salud, y la efectividad del tratamiento con antibióticos no se ha visto comprometida

Optimized molecular resolution of cross-contamination alerts in clinical mycobacteriology laboratories

<p>Abstract</p> <p>Background</p> <p>The phenomenon of misdiagnosing tuberculosis (TB) by laboratory cross-contamination when culturing <it>Mycobacterium tuberculosis </it>(MTB) has been widely reported and it has an obvious clinical, therapeutic and social impact. The final confirmation of a cross-contamination event requires the molecular identification of the same MTB strain cultured from both the potential source of the contamination and from the false-positive candidate. The molecular tool usually applied in this context is IS6110-RFLP which takes a long time to provide an answer, usually longer than is acceptable for microbiologists and clinicians to make decisions. Our purpose in this study is to evaluate a novel PCR-based method, MIRU-VNTR as an alternative to assure a rapid and optimized analysis of cross-contamination alerts.</p> <p>Results</p> <p>MIRU-VNTR was prospectively compared with IS6110-RFLP for clarifying 19 alerts of false positivity from other laboratories. MIRU-VNTR highly correlated with IS6110-RFLP, reduced the response time by 27 days and clarified six alerts unresolved by RFLP. Additionally, MIRU-VNTR revealed complex situations such as contamination events involving polyclonal isolates and a false-positive case due to the simultaneous cross-contamination from two independent sources.</p> <p>Conclusion</p> <p>Unlike standard RFLP-based genotyping, MIRU-VNTR i) could help reduce the impact of a false positive diagnosis of TB, ii) increased the number of events that could be solved and iii) revealed the complexity of some cross-contamination events that could not be dissected by IS6110-RFLP.</p

The transcriptional and mutational landscapes of lipid metabolism-related genes in colon cancer

Metabolic alterations encountered in tumors are well recognized and considered as a hallmark of cancer. In addition to Warburg Effect, epidemiological and experimental studies support the crucial role of lipid metabolism in colorectal cancer (CRC). The overexpression of four lipid metabolism-related genes (ABCA1, ACSL1, AGPAT1 and SCD genes) has been proposed as prognostic marker of stage II CRC (ColoLipidGene signature). In order to explore in depth the transcriptomic and genomic scenarios of ABCA1, ACSL1, AGPAT1 and SCD genes, we performed a transcriptomic meta-analysis in more than one thousand CRC individuals. Additionally we analyzed their genomic coding sequence in 95 patients, to find variants that could orchestrate CRC prognosis. We found that genetic variant rs3071, located on SCD gene, defines a 9.77% of stage II CRC patients with high risk of death. Moreover, individuals with upregulation of ABCA1 and AGPAT1 expression have an increased risk of CRC recurrence, independently of tumor stage. ABCA1 emerges as one of the main contributors to signature's prognostic effect. Indeed, both high ABCA1 expression and presence of tumoral genetic variants located in ABCA1 coding region, seem to be associated with CRC risk of death. In addition the non-synonymous polymorphism rs2230808, located on ABCA1, is associated with gene expression. Patients carrying at least one copy of minor allele showed higher levels of ABCA1 expression than patients carrying homozygous major allele. This study broaden the prognostic value of ABCA1, ACSL1, AGPAT1 and SCD genes, independently of CRC tumor stage, leading to future precision medicine approaches and "omics"-guided therapiesMinisterio de Economía y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL2016-76736-C3), Gobierno regional de la Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM) and EU Structural Fund

Small Molecules as Dream Modulators: New Avenues for the Search of Drugs for Neurodegenerative Diseases

Trabajo presentado en el 9th drug Design and Medicinal Chemistry, celebrado en Berlín (Alemania) del 05 al 06 de mayo de 2015.Altered neuronal calcium homeostasis and early compensatory changes in transcriptional programs are common features of many neurodegenerative pathologies including Alzheimer¿s disease, Down syndrome and Huntington¿s disease. DREAM (Downstream Regulatory Element Antagonist Modulator), also known as calsenilin or KChIP-3 (potassium channel interacting protein-3), is a multifunctional calcium binding protein that controls the expression level and/or the activity of several proteins related to calcium homeostasis, neuronal excitability and neuronal survival. This protein is widely expressed in the brain and, depending on the cell type and physiological conditions, shows multiple subcellular localizations, in the nucleus, cytosol or cell membrane. The interest in DREAM is based on its key role in the regulation of intracellular calcium levels. As a calcium-dependent transcriptional repressor, DREAM is a master regulator of activity-dependent gene expression and controls genes important for calcium homeostasis such as the sodium/calcium exchanger-3 (NCX3), IP3R and L-type calcium channels. As an auxiliary protein in the plasma membrane, DREAM interacts with and regulates the gating of Kv4 potassium channels, L- and T-type voltage-dependent calcium channels and NMDA receptors. These findings suggest that DREAM could be a novel and versatile target for therapeutic intervention in neurodegeneration and that molecules able to bind to DREAM and block its physiological functions could be candidates for drugs to treat neurodegenerative diseases. Moreover, up to now, only two DREAM-binding molecules have been identified. In this communication we report the rational design and the synthesis of novel DREAM-binding molecules and their effects on the modulation of DREAM/protein interactions

Synthesis, conformational analysis, and cytotoxicity of conformationally constrained aplidine and tamandarin A analogues incorporating a spirolactam β-turn mimetic

With the aim of studying the contribution of the β II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam β II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1−2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl9−spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl9−Pro8 amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.This work was supported by CICYT (Grant SAF2000-0147), MCYT-FEDER (Grant BIO2002-2301), Generalitat de Catalunya (Group Consolidat 1999SGR0042 and Centre de Referència en Biotecnologia), and Pharma Mar, S.A

Sirt1 protects from K-Ras-driven lung carcinogenesis.

The NAD+-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-RasG12V-driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs.We thank Jesus Herranz for his biostatistical advice; and Alba de Martino, Patricia Gonzalez, Maria Gomez, and Zaira Vega, from the Histopathology Unit at the CNIO, for their work in mouse histopathology. Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food, the Spanish Association against Cancer (aecc) and the Ramon Areces (CIVP18A3891) Foundation. Work in the laboratory of M.S. was funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF project), the European Research Council (ERC Advanced Grant), the European Union (RISK-IR project), and the Botin Foundation and Banco Santander (Santander Universities Global Division). Work in the laboratory of DH was funded by Rutgers Cancer Institute of New Jersey, the Alex's Lemonade Stand Foundation Shark Tank Award and by the National Institutes of Health Grant K99/R00 CA197869. Work in the laboratory of M.S.C. was supported by a grant (SAF2012-40026) from the Spanish Ministry of Science and Innovation. L.F.C-M. was supported by a PhD Fellowship from the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016).S

A novel strategy based on genomics and specific PCR reveals how a multidrug resistant Mycobacterium tuberculosis strain became prevalent in Equatorial Guinea 15 years after its emergence.

OBJECTIVE: Molecular epidemiology techniques in tuberculosis (TB) can identify high-risk strains that are actively transmitted. We aimed to implement a novel strategy to optimize the identification and control of multidrug-resistant (MDR) TB in a specific population. METHODS: We developed a strain-specific PCR tailored from whole genome sequencing (WGS) data to track a specific MDR prevalent strain in Equatorial Guinea (EG-MDR). RESULTS: The PCR was applied prospectively on remnants of GeneXpert reaction mixtures owing to the lack of culture facilities in Equatorial Guinea. In 147 (93%) of 158 cases, we were able to differentiate between infection by the EG-MDR strain or by any other strain and found that 44% of all rifampicin-resistant TB cases were infected by EG-MDR. We also analysed 93 isolates obtained from Equatorial Guinea 15 years ago, before MDR-TB had become the problem it is today. We found that two of the scarce historical MDR cases were infected by EG-MDR. WGS revealed low variability-six single nucleotide polymorphisms acquired by this strain over 15 years-likely because of the lack in the country of a specific program to treat MDR-TB. CONCLUSIONS: Our novel strategy, which integrated WGS analysis and strain-specific PCRs, represents a low-cost, rapid and transferable strategy that allowed a prospective efficient survey and fast historical analysis of MDR-TB in a population

The parthenocarpic hydra mutant reveals a new function for a SPOROCYTELESS-like gene in the control of fruit set in tomato

[EN] Fruit set is an essential process to ensure successful sexual plant reproduction. The development of the flower into a fruit is actively repressed in the absence of pollination. However, some cultivars from a few species are able to develop seedless fruits overcoming the standard restriction of unpollinated ovaries to growth. We report here the identification of the tomato hydra mutant that produces seedless (parthenocarpic) fruits. Seedless fruit production in hydra plants is linked to the absence of both male and female sporocyte development. The HYDRA gene is therefore essential for the initiation of sporogenesis in tomato. Using positional cloning, virus-induced gene silencing and expression analysis experiments, we identified the HYDRA gene and demonstrated that it encodes the tomato orthologue of SPOROCYTELESS/NOZZLE (SPL/NZZ) of Arabidopsis. We found that the precocious growth of the ovary is associated with changes in the expression of genes involved in gibberellin (GA) metabolism. Our results support the conservation of the function of SPL-like genes in the control of sporogenesis in plants. Moreover, this study uncovers a new function for the tomato SlSPL/HYDRA gene in the control of fruit initiation.This work was supported by grants from the Spanish Ministerio de Ciencia e Innovaci on (MICINN; AGL2009-07617 to C.G-M.; AGL2015-64991-C3-3-R to V.M.; and AGL2015-64991-C3-1-R to R.L.) and the Ram on y Cajal Program (RYC-2007-00627). We thank Rafael Martinez and Primitivo Murias for expert plant care; Marisol Gasc on for technical assistance with the microscope; and Dr Cristina Ferrandiz for critical reading of the manuscript. The authors declare no conflicts of interest.This work was supported by grants from the Spanish Ministerio de Ciencia e Innovaci on (MICINN; AGL2009-07617 to C.G-M.; AGL2015-64991-C3-3-R to V.M.; and AGL2015-64991-C3-1-R to R.L.) and the Ram on y Cajal Program (RYC-2007-00627). We thank Rafael Martinez and Primitivo Murias for expert plant care; Marisol Gasc on for technical assistance with the microscope; and Dr Cristina Ferrandiz for critical reading of the manuscript. The authors declare no conflicts of interest.Rojas-Gracia, P.; Roque Mesa, EM.; Medina Herranz, M.; Rochina Peñalver, MC.; Hamza, R.; Angarita-Diaz, MP.; Moreno Ferrero, V.... (2017). The parthenocarpic hydra mutant reveals a new function for a SPOROCYTELESS-like gene in the control of fruit set in tomato. New Phytologist. 214(3):1198-1212. https://doi.org/10.1111/nph.14433S11981212214

Survival analysis of time to SARS-CoV-2 PCR negativisation to optimise PCR prescription in health workers: the Henares COVID-19 healthcare workers cohort study.

Objectives Reverse transcriptase PCR (RT-PCR) is considered the gold standard in diagnosing COVID-19. Infected healthcare workers do not go back to work until RT-PCR has demonstrated that the virus is no longer present in the upper respiratory tract. The aim of this study is to determine the most efficient time to perform RT-PCR prior to healthcare workers’ reincorporation. Materials and methods This is a cohort study of healthcare workers with RT-PCR-confirmed COVID-19. Data were collected using the medical charts of healthcare workers and completed with a telephone interview. Kaplan-Meier curves were used to determine the influence of several variables on the time to RT-PCR negativisation. The impact of the variables on survival was assessed using the Breslow test. A Cox regression model was developed including the associated variables. Results 159 subjects with a positive RT-PCR out of 374 workers with suspected COVID-19 were included. The median time to negativisation was 25 days from symptom onset (IQR 20–35 days). Presence of IgG, dyspnoea, cough and throat pain were associated with significant longer time to negativisation. Cox logistic regression was used to adjust for confounding variables. Only dyspnoea and cough remained in the model as significant determinants of prolonged negativisation time. Adjusted HRs were 0.68 (0.48–096) for dyspnoea and 0.61 (0.42–0.88) for dry cough. Conclusions RT-PCR during the first 3 weeks leads to a high percentage of positive results. In the presence of respiratory symptoms, negativisation took nearly 1 week more. Those who developed antibodies needed longer time to negativisate.pre-print396 K

An acute infection due to hepatitis E in the context of a patient with rituximab and methotrexate therapy

Background: This report presents the influence of immunosuppression by new rheumatological therapies on hepatitis E virus infection in a 54-year-old male patient with an anti-synthetase syndrome and treatment with methotrexate and rituximab. Case description: The patient arrived at the Emergency Department with epigastric pain, vomiting and dark urine. Initial examination revealed signs of inflammation and hepatic dysfunction. Subsequent laboratory tests and imaging confirmed acute hepatitis E infection in the context of recent initiation of rituximab therapy. Despite initial suspicion of pancreatitis, subsequent investigations ruled out pancreatic involvement. Treatment with ribavirin, along with supportive measures, led to significant clinical improvement with resolution of jaundice, ascites, and oedema. Conclusions: This case underscores the importance of considering hepatitis E in patients with autoimmune conditions, especially when initiating immunosuppressive therapies, a situation that is not well described in scientific literature and is increasingly common, necessitating proper recognition