Catheter-related bloodstream infections: predictive factors for Gram-negative bacteria aetiology and 30 day mortality in a multicentre prospective cohort

PROBAC REIPI/GEIH-SEIMC/SAEI.[Background] Catheter-related bloodstream infections (CRBSIs) increase morbidity and mortality, prolong hospitalization and generate considerable medical costs. Recent guidelines for CRBSI recommend empirical therapy against Gram-positive bacteria (GPB) and restrict coverage for Gram-negative bacteria (GNB) only to specific circumstances.[Objectives]To investigate predictors of GNB aetiology in CRBSI and to assess the predictors of outcome in patients with CRBSI.[Methods] Patients with CRBSI were selected from the PROBAC cohort, a prospective, observational, multicentre national cohort study including patients with bloodstream infections consecutively admitted to 26 Spanish hospitals in a 6 month period (October 2016–March 2017). Outcome variables were GNB aetiology and 30 day mortality. Adjusted analyses were performed by logistic regression.[Results] Six hundred and thirty-one episodes of CRBSI were included in the study. Risk factors independently related to GNB aetiology were central venous catheter (CVC) [OR 1.60 (95% CI: 1.05–2.44), P = 0.028], sepsis/septic shock [OR: 1.76 (95% CI: 1.11–2.80), P = 0.016], antibiotic therapy in the previous 30 days [OR: 1.56 (95% CI: 1.02–2.36), P = 0.037], neutropenia <500/μL [OR: 2.01 (95% CI: 1.04–3.87), P = 0.037] and peripheral vascular disease [OR: 2.04 (95% CI: 1.13–3.68), P = 0.018]. GNB were not associated with increased mortality in adjusted analysis, while removal of catheter [OR: 0.24 (95% CI: 0.09–0.61), P = 0.002] and adequate empirical treatment [OR: 0.37 (95% CI: 0.18–0.77), P = 0.008] were strong protective factors.[Conclusions] Our study reinforces the recommendation that empirical coverage should cover GNB in patients presenting with sepsis/septic shock and in neutropenic patients. Catheter removal and adequate empirical treatment were both protective factors against mortality in patients with CRBSI.This study was funded by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, through the following grants: Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001; RD16/0016/0007; RD16/0016/0008; RD16/0016/0012), co-financed by European Development Regional Fund ‘A way to achieve Europe’, Operative Program Intelligent Growth 2014–2020, and PI16/01432. F. Caló enjoyed an ESCMID Observership grant at Hospital Universitario Virgen Macarena to develop this research

Revisiting the epidemiology of bloodstream infections and healthcare-associated episodes: results from a multicentre prospective cohort in Spain (PRO-BAC Study)

PROBAC REIPI/GEIH-SEIMC/SAEI Group.The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60–81 years) and 3656 (58.3%; 95% confidence interval 57.1–59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients’ profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.This work was financed by grants from Plan Nacional de I+D+i 2013–2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades [PI16/01432] and the Spanish Network for Research in Infectious Diseases (REIPI) [RD16/0016/0001; RD16/0016/0008], co‐financed by the European Development Regional Fund ‘A way to achieve Europe’, Operative program Intelligent Growth 2014–2020

Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques

Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%), followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%), whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTPinduced degeneration, our data clearly demonstrated that these neurons are not giving rise to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal projections

Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases

Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases

A large chimeric deletion associates with impairement of cuticle development in a dark berry somatic variant of Tempranillo Tinto

Trabajo presentado en el XIII International Symposium on Grapevine Breeding and Genetics, celebrado en Landau in der Pfalz (Alemania), del 10 al 17 de julio de 2022Color intensity is a relevant feature for red wine quality, which depends on the accumulation of athocyanins during berry ripening and their interaction with other compunds present in the wine. While grape color is a varietal feature, emerging spontaneous somatic variation for this trait can be selected for cultivar improvement. Here we studied the genomic origin of a darker berry clone (VN21) selected in `Tempranillo Tinto¿ (TT) cultivar, which enables the production of wines with higher color intensity. Using a diploid genome assembly of TT produced following a trio binning approach from PacBio and Nanopore sequencing, and genome re-sequencing data of VN21 compared to other TT clones, we identified a 10 Mb deletion in chromosome 11 that likely affected only the L1 meristem cell layer of VN21. An RNA-seq analysis identified a general down-regulation of genes within the chimeric hemizygous segment in the berry skin of VN21. Down-regulated genes where also enriched in wax biosynthesis functional category genes, including one CER1 and one ABCG32 homologs located in the hemizygous segment. SEM images showed that wax accumulation is impaired in the berry cuticle of VN21, which likely leads to the shiny color of VN21 berries. Candidate loss of function polymorphisms remaing hemizygous in VN21 after the chimeric deletion were also detected from TT haplotype comparison. Our findings show that very large hemizygous deletions can stabilize as periclinal chimeras in grapevine clones, giving rise to pleiotropic mutant phenotypes that can be exploited for cultivar innovation

Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques

Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%), followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%), whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTPinduced degeneration, our data clearly demonstrated that these neurons are not giving rise to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal projections

Epidemiologic changes in bloodstream infections in Andalucía (Spain) during the last decade

[Objectives]: During the last decade, some changes in the epidemiology of invasive infections have been reported; however, specific studies with patient-level data are scarce. The aim of this study was to describe and evaluate the epidemiologic changes in bloodstream infections (BSI) during the last decade in Andalucía, Spain.[Methods]: Data from two prospective cohorts of BSI in adults with the same methodology performed 10 years apart in 11 hospitals (eight tertiary and three community) in Andalucía, Spain, were compared; the 2006–7 cohort study was performed between October 2006 and March 2007, and the 2016–17 cohort study was performed between October 2016 and March 2017. Population-based incidence rates were calculated and extrapolated for 1 year. Relative risk ratios were calculated between the 2 periods. Multivariate analyses were performed by logistic regression.[Results]: Overall, 1262 episodes of BSI were included, 563 (44.6%) in 2006–7 and 699 (55.3%) in 2016–17. Multivariate models selected the following changes in patients' features in 2016–17, after controlling for type of acquisition: higher age (odds ratio (OR) = 1.02; 95% confidence interval [CI] 1.01–1.03), lower urinary catheter (OR = 0.37; 95% CI, 0.26–0.48) and lower Pitt score (OR = 0.76; 95% CI, 0.71–0.82). Adjusted estimations considering patients' features and exposure to procedures showed a reduction in coagulase-negative staphylococci (OR = 0.47; 95% CI, 0.32–0.69), and an increase in Proteus spp. (OR = 3.12; 95% CI, 1.18–8.23) and Candida spp. (OR = 3.01; 95% CI, 1.03–8.86).[Conclusions]: We found relevant epidemiologic changes in BSI in our area, including rates, frequency of acquisition types, changes in patient's profiles and aetiologic agents

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P &lt; 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.MyD88- and IRAK-4-deficient patients have a higher risk of hypoxemic COVID-19 pneumonia than individuals of similar age in the general population, due to impaired TLR7-dependent type I IFN production