Pharmacokinetics and pharmacodynamics of antibacterial agents: on account of febrile neutropenic patients

La neutropenia febril es una complicación grave de la terapia antineoplásica que se presenta más frecuentemente en pacientes con neoplasias hematológicas, asociada a tasas elevadas de mortalidad. Uno de los factores descritos como causa de fracasos terapéuticos de la terapia antimicrobiana es la inadecuada concentración tisular de los antimicrobianos que a su vez se correlaciona con bajas concentraciones en el líquido intersticial en el caso de los fármacos hidrofílicos. En pacientes críticamente enfermos se puede presentar acumulación compartimental de líquidos que a su vez se puede asociar con aumento en el volumen de distribución de los medicamentos o alteraciones en la depuración de los mismos. Se revisan los parámetros farmacocinéticos y farmacodinámicos de los antimicrobianos que pueden ser usados como herramienta para optimizar la eficacia de la terapia antiinfecciosa en busca de disminuir la tasa de fracasos y la selección de cepas resistentes.Q4537-545Febrile neutropenia is a serious complication of antineoplastic therapy and it is more commonly found in hematologic patients, associated with high mortality rates. Inadequate tissue concentration of antimicrobials has been described as a cause of therapeutic failure which also has been related to a low interstitial concentration for hydrophilic antibiotics. In critically ill patients it may occur an accumulation of compartmental fluids which can be related to an increase in the distribution volume or changes in clearance of antimicrobials. Pharmacokinetic and pharmacodynamic parameters of antimicrobials are reviewed, which can be used as a tool to optimize the efficacy of antimicrobial therapy in order to avoid failures and resistance selection

Análisis de los servicios de test del VIH de cinco centros comunitarios españoles para la mejora de nuevas estrategias de promoción del diagnóstico precoz

Background: In recent years, the number of people tested for HIV has experienced a significant increase. The purpose of this study is to analyze data obtained in Spain in the HIV testing services of five Community Centres members of Agrupación Prueba de VIHda throughout 2014 and 2015,to determine its effectiveness and to characterize the subpopulation with a HIV reactive result. Study design and methods: agrupación Prueba de VIHda performed free, anonymous and confidential HIV tests according to the Consolidated guidelines on HIV testing services of WHO (2015). Data were collected using the questionnaire of the COBATEST network, developed by the COBATEST Project, and its significance was determined statistically. Results: 3061 HIV tests were performed during 2014 and 2015, with a prevalence of reactive results of 2.5%. Heterosexual and bisexual men got tested at older ages than homosexual men and women. Non-Spanish origin seems to be a risk factor for HIV infection within the sample. Bisexual men showed as high prevalence of reactive test as homosexual men, as well as they reported less previous HIV tests. Finally, index testing performed by HIV positive peer educators to the sexual partners of newly diagnosed patients showed higher prevalence than that of the classical Voluntary Counselling and Testing approach outreach most at risk populations. Conclusion:The analysis of the data shows higher prevalence of reactive results in people of non-Spanish origin compared to that of the Spanish subgroup, the former still facing barriers to access the public health system in Spain. It also demonstrates the need of new and adapted approaches for promoting early diagnosis specifically in bisexual men. Index testing by peer HIV positive educators is a highly effective method for testing people at high risk of acquiring HIV infection.Antecedentes: En los últimos años, el número de personas sometidas a pruebas frente al VIH ha experimentado un aumento significativo. El propósito de este estudio es analizar los datos de prevalencia de la infección por VIH obtenidos por cinco centros comunitarios en España pertenecientes a la Agrupación Prueba de VIHda entre 2014 y 2015, determinar su efectividad y caracterizar la subpoblación con un resultado preliminar reactivo. Diseño experimental y métodos: La Agrupación Prueba de VIHda realizó pruebas de VIH gratuitas, anónimas y confidenciales de acuerdo con las directrices consolidadas por la OMS (2015). Los datos fueron recogidos mediante el cuestionario desarrollado por el Proyecto COBATEST y su significación se determinó estadísticamente. Resultados: Durante 2014 y 2015 se realizaron un total de 3061 pruebas frente al VIH, obteniendo una prevalencia de resultados preliminares positivos del 2,5%. Los hombres heterosexuales y bisexuales se realizaron la prueba a edades más avanzadas que los hombres homosexuales y las mujeres. Las personas de origen no español parecieron mostrar un mayor riesgo de infección frente al VIH. Hombres bisexuales mostraron una prevalencia elevada similar a la de hombres homosexuales, así como declararon menos pruebas anteriores frente al VIH. Finalmente, las pruebas realizadas a través de indextesting por los educadores pares de VIH a parejas sexuales de pacientes recién diagnosticados mostraron una prevalencia superior a la obtenida por el modelo tradicional de counselling y testado voluntario ofrecido desde los centros comunitarios a poblaciones de mayor riesgo. Conclusión: El análisis de los datos muestra mayores prevalencias de resultados preliminares reactivos en personas de origen no español comparadas con aquellas del subgrupo de personas españolas, el primero de ellos todavía enfrentando barreras de acceso al sistema sanitario público en España, El análisis también demuestra la necesidad de nuevos enfoques adaptados para promover el diagnóstico precoz especialmente entre hombres bisexuales. Las pruebas realizadas a través de indextesting por educadores pares VIH positivos es un método muy eficaz para el testado de las personas con alto riesgo de contraer la infección por VIH

Cryo-EM and single-particle analysis with Scipion

Cryo-electron microscopy has become one of the most important tools in biological research to reveal the structural information of macromolecules at near-atomic resolution. In single-particle analysis, the vitrified sample is imaged by an electron beam and the detectors at the end of the microscope column produce movies of that sample. These movies contain thousands of images of identical particles in random orientations. The data need to go through an image processing workflow with multiple steps to obtain the final 3D reconstructed volume. The goal of the image processing workflow is to identify the acquisition parameters to be able to reconstruct the specimen under study. Scipion provides all the tools to create this workflow using several image processing packages in an integrative framework, also allowing the traceability of the results. In this article the whole image processing workflow in Scipion is presented and discussed with data coming from a real test case, giving all the details necessary to go from the movies obtained by the microscope to a high resolution final 3D reconstruction. Also, the power of using consensus tools that allow combining methods, and confirming results along every step of the workflow, improving the accuracy of the obtained results, is discussed

Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study

Background: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability.Aims: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome.Methods: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed.Results: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300 mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24 h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality.Conclusions: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases

Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors.Methods This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC.Results Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed.Conclusions The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier.Thrombosis and Hemostasi

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women.This work has received support from the Fundación Alicia Koplowitz to realize the epigenetic wide association study and to the clinical assessment to the children. This work has also received public support from the Consejería de Salud y Familias para la financiación de la investigación, desarrollo e innovación (i + d + i) biomédica y en ciencias de la salud en Andalucía (CSyF 2021 - FEDER). Grant Grant number PECOVID- 0195-2020. Convocatoria financiada con Fondo Europeo de Desarrollo Regional (FEDER) al 80% dentro del Programa Operativo de Andalucía FEDER 2014-2020. Andalucía se mueve con Europa. NG-T received payment under Rio Hortega contract CM20-00015 with the Carlos III Health Institute.Peer reviewe

Micobacteriosis sistémica por Mycobacterium avium en paciente con SIDA Systemic mycobacteriosis for Mycobacterium avium in a AIDS patient

Se analizaron repetidas muestras procedentes de un paciente cubano con SIDA, para descartar la presencia de bacilos ácido alcohol resistente (BAAR), pasadas 2-3 semana en las muestras de esputo, líquido cefalorraquídeo y de hemocultivo que habían sido procesadas y cultivadas se detecta la presencia de algunas colonias, como resultado se obtuvo el aislamiento de una cepa micobacteriana no pigmentada, de crecimiento lento perteneciente al Grupo III de Runyon, esta cepas fueron clasificadas como Mycobacterium avium por los métodos convencionales establecidos para la identificación de cepas micobacterianas, como técnica confirmativa diagnóstica se utilizó el análisis de las fracciones de ácido micólicos por la técnica de cromatografía en capa delgada bidimensional. El objetivo fundamental de este estudio ha sido reportar el primer caso de micobacteriosis sistémica en un paciente cubano con SIDA.Several sputum and blood culture simples from a Cuban HIV/AIDS patient were analyzed to discard the presence of alcohol acid resistant bacillus. After 2-3 weeks the culture revealed in both kinds of samples some colonies from non-pigmented mycobacterium strain with slow growth and belonging to III Runyon Group. This strain was classified as Mycobacterium avium by conventional methods established for mycobacterium identification. To diagnostic confirmative method was used the analysis of fraction mycolic acid by bi-dimensional thin layer chromatography. The main objective of this study was to report the first case of systemic mycobacteriosisin a Cuban HIV/AIDS patient