Monomeric α-synuclein activates the plasma membrane calcium pump.

Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull-down experiments have pointed to plasma membrane Ca2+ -ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane-anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

Assessment of models for calculating the hydrodynamic radius of intrinsically disordered proteins.

Diffusion measurements by pulsed-field gradient NMR and fluorescence correlation spectroscopy can be used to probe the hydrodynamic radius of proteins, which contains information about the overall dimension of a protein in solution. The comparison of this value with structural models of intrinsically disordered proteins is nonetheless impaired by the uncertainty of the accuracy of the methods for computing the hydrodynamic radius from atomic coordinates. To tackle this issue, we here build conformational ensembles of 11 intrinsically disordered proteins that we ensure are in agreement with measurements of compaction by small-angle x-ray scattering. We then use these ensembles to identify the forward model that more closely fits the radii derived from pulsed-field gradient NMR diffusion experiments. Of the models we examined, we find that the Kirkwood-Riseman equation provides the best description of the hydrodynamic radius probed by pulsed-field gradient NMR experiments. While some minor discrepancies remain, our results enable better use of measurements of the hydrodynamic radius in integrative modeling and for force field benchmarking and parameterization.

Deletion of MyD88 in astrocytes prevents ß-amyloid-induced neuropathology in mice.

As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell-specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non-AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady-state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of ß-amyloid (Aß). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune-related proteins, and higher expression of synaptic-related proteins in response to Aß. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients.

Objective: To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. Design: A secondary analysis derived from multicenter, observational study. Setting: Critical Care Units. Patients: Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. Interventions: Corticosteroids vs. no corticosteroids. Main variables of interest: Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. Results: A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0; 95% CI: 0.98-1.15). Corticosteroids were administered in 298/537 (55.5%) patients of "A" phenotype and their use was not associated with ICU mortality (HR = 0.85 [0.55-1.33]). A total of 338/623 (54.2%) patients in "B" phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49-1.05]). Finally, 535/857 (62.4%) patients in "C" phenotype received corticosteroids. In this phenotype HR (0.75 [0.58-0.98]) and sHR (0.79 [0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. Conclusion: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

Objetivo: Evaluar si el uso de corticoesteroides (CC) se asocia con la mortalidad en la unidad de cuidados intensivos (UCI) en la población global y dentro de los fenotipos clínicos predeterminados. Diseño: Análisis secundario de estudio multicéntrico observacional. Ámbito: UCI. Pacientes: Pacientes adultos con COVID-19 confirmado ingresados en 63 UCI de España. Intervención: Corticoides vs. no corticoides. Variables de interés principales: A partir del análisis no supervisado de grupos, 3 fenotipos clínicos fueron derivados y clasificados como: A grave, B crítico y C potencialmente mortal. Se efectuó un análisis multivariado después de un propensity optimal full matching (PS) y una regresión ponderada de Cox (HR) y análisis de Fine-Gray (sHR) para evaluar el impacto del tratamiento con CC sobre la mortalidad en la población general y en cada fenotipo clínico. Resultados: Un total de 2.017 pacientes fueron analizados, 1.171 (58%) con CC. Después del PS, el uso de CC no se relacionó significativamente con la mortalidad en UCI (OR: 1,0; IC 95%: 0,98-1,15). Los CC fueron administrados en 298/537 (55,5%) pacientes del fenotipo A y no se observó asociación significativa con la mortalidad (HR = 0,85; 0,55-1,33). Un total de 338/623 (54,2%) pacientes del fenotipo B recibieron CC sin efecto significativo sobre la mortalidad (HR = 0,72; 0,49-1,05). Por último, 535/857 (62,4%) pacientes del fenotipo C recibieron CC. En este fenotipo, se evidenció un efecto protector de los CC sobre la mortalidad HR (0,75; 0,58-0,98). Conclusión: Nuestros hallazgos alertan sobre el uso indiscriminado de CC a dosis moderadas en todos los pacientes críticos con COVID-19. Solamente pacientes con elevado estado de inflamación podrían beneficiarse con el tratamiento con CC.

[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

[Management of infectious complications associated with coronavirus infection in severe patients admitted to ICU]. / Manejo de las complicaciones infecciosas asociadas con la infección por coronavirus en pacientes graves ingresados en UCI.

Infections have become one of the main complications of patients with severe SARS-CoV-2 pneumonia admitted in ICU. Poor immune status, frequent development of organic failure requiring invasive supportive treatments, and prolonged ICU length of stay in saturated structural areas of patients are risk factors for infection development. The Working Group on Infectious Diseases and Sepsis GTEIS of the Spanish Society of Intensive Medicine and Coronary Units SEMICYUC emphasizes the importance of infection prevention measures related to health care, the detection and early treatment of major infections in the patient with SARS-CoV-2 infections. Bacterial co-infection, respiratory infections related to mechanical ventilation, catheter-related bacteremia, device-associated urinary tract infection and opportunistic infections are review in the document.

EphA4 Regulates Hippocampal Neural Precursor Proliferation in the Adult Mouse Brain by d-Serine Modulation of N-Methyl-d-Aspartate Receptor Signaling.

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.

Inflammation: the link between comorbidities, genetics, and Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body's key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

Linking Spectral Induced Polarization (SIP) and Subsurface Microbial Processes: Results from Sand Column Incubation Experiments.

Geophysical techniques, such as spectral induced polarization (SIP), offer potentially powerful approaches for in situ monitoring of subsurface biogeochemistry. The successful implementation of these techniques as monitoring tools for reactive transport phenomena, however, requires the deconvolution of multiple contributions to measured signals. Here, we present SIP spectra and complementary biogeochemical data obtained in saturated columns packed with alternating layers of ferrihydrite-coated and pure quartz sand, and inoculated with Shewanella oneidensis supplemented with lactate and nitrate. A biomass-explicit diffusion-reaction model is fitted to the experimental biogeochemical data. Overall, the results highlight that (1) the temporal response of the measured imaginary conductivity peaks parallels the microbial growth and decay dynamics in the columns, and (2) SIP is sensitive to changes in microbial abundance and cell surface charging properties, even at relatively low cell densities (<108 cells mL-1). Relaxation times (τ) derived using the Cole-Cole model vary with the dominant electron accepting process, nitrate or ferric iron reduction. The observed range of τ values, 0.012-0.107 s, yields effective polarization diameters in the range 1-3 µm, that is, 2 orders of magnitude smaller than the smallest quartz grains in the columns, suggesting that polarization of the bacterial cells controls the observed chargeability and relaxation dynamics in the experiments.

Evidence of Coupled Carbon and Iron Cycling at a Hydrocarbon-Contaminated Site from Time Lapse Magnetic Susceptibility.

Conventional characterization and monitoring of hydrocarbon (HC) pollution is often expensive and time-consuming. Magnetic susceptibility (MS) has been proposed as an inexpensive, long-term monitoring proxy of the degradation of HC. We acquired repeated down hole MS logging data in boreholes at a HC-contaminated field research site in Bemidji, MN, USA. The MS data were analyzed in conjunction with redox conditions and iron availability within the source zone to better assess whether MS can serve as a proxy for monitoring HC contamination in unconsolidated sediments. The MS response at the site diminished during the sampling period, which was found to coincide with depletion of solid phase iron in the source zone. Previous geochemical observations and modeling at the site suggest that the most likely cause of the decrease in MS is the transformation of magnetite to siderite, coupled with the exhaustion of ferrihydrite. Although the temporal MS response at this site gives valuable field-scale evidence for changing conditions of iron cycling and stability of iron minerals it does not provide a simple proxy for long-term monitoring of biodegradation of hydrocarbons in the smear zone.

Complex conductivity response to silver nanoparticles in partially saturated sand columns.

The increase in the use of nanoscale materials in consumer products has resulted in a growing concern of their potential hazard to ecosystems and public health from their accidental or intentional introduction to the environment. Key environmental, health, and safety research needs include knowledge and methods for their detection, characterization, fate, and transport. Specifically, techniques available for the direct detection and quantification of their fate and transport in the environment are limited. Their small size, high surface area to volume ratio, interfacial, and electrical properties make metallic nanoparticles, such as silver nanoparticles, good targets for detection using electrical geophysical techniques. Here we measured the complex conductivity response to silver nanoparticles in sand columns under varying moisture conditions (0-30%), nanoparticle concentrations (0-10 mg/g), lithology (presence of clay), pore water salinity (0.0275 and 0.1000 S/m), and particle size (35, 90-210 and 1500-2500 nm). Based on the Cole-Cole relaxation models we obtained the chargeability and the time constant. We demonstrate that complex conductivity can detect silver nanoparticles in porous media with the response enhanced by higher concentrations of silver nanoparticles, moisture content, ionic strength, clay content and particle diameter. Quantification of the volumetric silver nanoparticles content in the porous media can also be obtained from complex conductivity parameters based on the strong power law relationships.

Recommendations of the Working Groups from the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) for the management of adult critically ill patients. / Recomendaciones para el tratamiento de los pacientes críticos de los Grupos de Trabajo de la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC).

The standardization of the Intensive Care Medicine may improve the management of the adult critically ill patient. However, these strategies have not been widely applied in the Intensive Care Units (ICUs). The aim is to elaborate the recommendations for the standardization of the treatment of critical patients. A panel of experts from the thirteen working groups (WG) of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) was selected and nominated by virtue of clinical expertise and/or scientific experience to carry out the recommendations. Available scientific literature in the management of adult critically ill patients from 2002 to 2016 was extracted. The clinical evidence was discussed and summarised by the experts in the course of a consensus finding of every WG and finally approved by the WGs after an extensive internal review process that was carried out between December 2015 and December 2016. A total of 65 recommendations were developed, of which 5 corresponded to each of the 13 WGs. These recommendations are based on the opinion of experts and scientific knowledge, and are intended as a guide for the intensivists in the management of critical patients.

The impact of astrocytic NF-κB on healthy and Alzheimer's disease brains.

Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated ß-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients.

OBJECTIVE: To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. DESIGN: A secondary analysis derived from multicenter, observational study. SETTING: Critical Care Units. PATIENTS: Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. INTERVENTIONS: Corticosteroids vs. no corticosteroids. MAIN VARIABLES OF INTEREST: Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. RESULTS: A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0; 95% CI: 0.98-1.15). Corticosteroids were administered in 298/537 (55.5%) patients of "A" phenotype and their use was not associated with ICU mortality (HR=0.85 [0.55-1.33]). A total of 338/623 (54.2%) patients in "B" phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49-1.05]). Finally, 535/857 (62.4%) patients in "C" phenotype received corticosteroids. In this phenotype HR (0.75 [0.58-0.98]) and sHR (0.79 [0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. CONCLUSION: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

Usefulness of CURB-65 and pneumonia severity index for influenza A H1N1v pneumonia.

UNLABELLED: Usefulness of CURB-65 and pneumonia severity index for influenza A H1N1v pneumonia. A. Estella. BACKGROUND: Different prognostic scales have been documented to assess the severity and indications for hospitalization and ICU admissions of community acquired pneumonia. During the past two years Influenza A H1N1v infections have been commonly attended to in emergency departments. The aim of the study was to analyse the usefulness of the application of the Pneumonia Severity Index (PSI) and CURB-65 prognostic scales in patients with primary viral pneumonia caused by influenza A H1N1v. METHODS: A retrospective study was performed at a community hospital with a 17 bed-intensive care unit. Patients admitted in hospital with influenza A H1N1v pneumonia over a two year period were analysed. CURB 65 and PSI scales were applied in the emergency department and outcome and destination of admission were analysed. RESULTS: 24 patients were registered, 19 required ICU admission and 5 patients were admitted in medical wards. Most of the patients admitted to the intensive care unit (78.9%) required mechanical ventilation. Mortality was 21.1%. Most patients admitted to the ICU had CURB 65 scale of 1 (60%), 13.3% obtained 0 and 26.7% 2. PSI scale resulted class I in a 20%, class II 40%, 26.7% class IV and 13.3% class V. The scales CURB 65 and PSI showed no differences in scores according to the destination of admission and mortality. CONCLUSIONS: Use of CURB-65 and PSI in the emergency department may underestimate the risk of patients with Influenza A H1N1v pneumonia. Based in our results, the ability of these scales to predict ICU admissions for Influenza A H1N1v pneumonia is questioned.

[Analysis of 208 flexible bronchoscopies performed in an intensive care unit]. / Análisis de 208 fibrobroncoscopias realizadas en una unidad de cuidados intensivos.

OBJECTIVE: To describe the main indications, clinical results and complications associated with fibrobronchoscopy in the Intensive Care Unit (ICU). DESIGN: A retrospective, single-center observational study was carried out. Setting. Seventeen beds in a medical/surgical ICU. Patients. Consecutive patients undergoing fibrobronchoscopy during their stay in the ICU over a period of 5 years. INTERVENTIONS: Flexible bronchoscopy performed by an intensivist. Main variables of interest. Flexible bronchoscopy indications and complications derived from the procedure. RESULTS: A total of 208 flexible bronchoscopies were carried out in 192 patients admitted to the ICU. Most of the procedures (193 [92.8%]) were performed in mechanically ventilated patients. The average patient age was 58 ± 16 years, with an APACHE II score at admission of 19 ± 7. The most frequent indication for flexible bronchoscopy was diagnostic confirmation of initially suspected pneumonia (148 procedures), with positive bronchoalveolar lavage findings in 46%. The most frequent therapeutic indication was the resolution of atelectasis (28 procedures). Other indications were the diagnosis and treatment of pulmonary hemorrhage, the aspiration of secretions, control of percutaneous tracheotomy, and difficult airway management. The complications described during the procedures were supraventricular tachycardia (3.8%), transient hypoxemia (6.7%), and slight bleeding of the bronchial mucosal membrane (2.4%). CONCLUSIONS: A microbiological diagnosis of pneumonia and the resolution of atelectasis are the most frequent indications for flexible bronchoscopy in critically ill patients. Flexible bronchoscopy performed by an intensivist in ICU is a safe procedure.

How phosphorylation impacts intrinsically disordered proteins and their function.

Phosphorylation is the most common post-translational modification (PTM) in eukaryotes, occurring particularly frequently in intrinsically disordered proteins (IDPs). These proteins are highly flexible and dynamic by nature. Thus, it is intriguing that the addition of a single phosphoryl group to a disordered chain can impact its function so dramatically. Furthermore, as many IDPs carry multiple phosphorylation sites, the number of possible states increases, enabling larger complexities and novel mechanisms. Although a chemically simple and well-understood process, the impact of phosphorylation on the conformational ensemble and molecular function of IDPs, not to mention biological output, is highly complex and diverse. Since the discovery of the first phosphorylation site in proteins 75 years ago, we have come to a much better understanding of how this PTM works, but with the diversity of IDPs and their capacity for carrying multiple phosphoryl groups, the complexity grows. In this Essay, we highlight some of the basic effects of IDP phosphorylation, allowing it to serve as starting point when embarking on studies into this topic. We further describe how recent complex cases of multisite phosphorylation of IDPs have been instrumental in widening our view on the effect of protein phosphorylation. Finally, we put forward perspectives on the phosphorylation of IDPs, both in relation to disease and in context of other PTMs; areas where deep insight remains to be uncovered.

Clindamycin but not Intravenous Immunoglobulins reduces mortality in a retrospective cohort of critically ill patients with bacteremic Group A Streptococcal infections.

OBJECTIVE: Mortality of patients requiring Intensive Care Unit (ICU) admission for an invasive group A streptococcal (GAS) infection continues being high. In critically ill patients with bacteremic GAS infection we aimed at determining risk factors for mortality. METHODS: Retrospective multicentre study carried out in nine ICU in Southern Spain. All adult patients admitted to the participant ICUs from January 2014 to June 2019 with one positive blood culture for S. pyogenes were included in this study. Patient characteristics, infection-related variables, therapeutic interventions, failure of organs, and outcomes were registered. Risk factors independently associated with ICU and in-hospital mortalities were determined by multivariate regression analyses. RESULTS: Fifty-seven patients were included: median age was 63 (45-73) years, median SOFA score at admission was 11 (7-13). The most frequent source was skin and soft tissue infection (n=32) followed by unknown origin of bacteremia (n=12). In the multivariate analysis, age (OR 1.079; 95% CI 1.016-1.145), SOFA score (OR 2.129; 95% CI 1.339-3.383) were the risk factors for ICU mortality and the use of clindamycin was identified as a protective factor (OR 0.049; 95% CI 0.003-0.737). Age and SOFA were the independent factors associated with hospital mortality however the use of clindamycin showed a strong trend but without reaching statistical significance (OR 0.085; 95% CI 0.007-1.095). CONCLUSIONS: In this cohort of critically ill patients the use of intravenous immunoglobulin was not identified as a protective factor for ICU or hospital mortality treatment with clindamycin significantly reduced mortality after controlling for confounders.

Prior influenza vaccine is not a risk factor for bacterial coinfection in patients admitted to the ICU due to severe influenza.

OBJECTIVE: To determine whether the prior usage of the flu vaccine is a risk factor for bacterial co-infection in patients with severe influenza. DESIGN: This was a retrospective observational cohort study of subjects admitted to the ICU. A propensity score matching, and logistic regression adjusted for potential confounders were carried out to evaluate the association between prior influenza vaccination and bacterial co-infection. SETTINGS: 184 ICUs in Spain due to severe influenza. PATIENTS: Patients included in the Spanish prospective flu registry. INTERVENTIONS: Flu vaccine prior to the hospital admission. RESULTS: A total of 4175 subjects were included in the study. 489 (11.7%) received the flu vaccine prior to develop influenza infection. Prior vaccinated patients were older 71 [61-78], and predominantly male 65.4%, with at least one comorbid condition 88.5%. Prior vaccination was not associated with bacterial co-infection in the logistic regression model (OR: 1.017; 95%CI 0.803-1.288; p=0.885). After matching, the average treatment effect of prior influenza vaccine on bacterial co-infection was not statistically significant when assessed by propensity score matching (p=0.87), nearest neighbor matching (p=0.59) and inverse probability weighting (p=0.99). CONCLUSIONS: No association was identified between prior influenza vaccine and bacterial coinfection in patients admitted to the ICU due to severe influenza. Post influenza vaccination studies are necessary to continue evaluating the possible benefits.