Direct toxicity of six antibiotics on soil bacterial communities affected by the addition of bio-adsorbents

Reducing the toxicity caused by antibiotics on bacterial communities in the soil is one of the great challenges of this century. For this, the effectiveness of amending the soil with different bioadsorbents such as crushed mussel shell (CMS), pine bark (PB) and biomass ash (BA), as well as combinations of them (CMS + PB and PB + BA) was studied at different doses (0 g kg−1 to 48 g kg−1). Soil samples were spiked, separately, with increasing doses (0–2000 mg kg−1) of cefuroxime (CMX), amoxicillin (AMX), clarithromycin (CLA), azithromycin (AZI), ciprofloxacin (CIP) and trimethoprim (TMP). Their toxicity on bacterial growth was estimated using the tritium-labeled leucine (3H) incorporation method. Toxicity was observed to behave differently depending on the antibiotic family and bioadsorbent, although in different magnitude and at different doses. The toxicity of β-lactams (AMX and CXM) was reduced by up to 54% when the highest doses of bio-adsorbents were added due to the increase in pH (CMS and BA) and carbon (PB) contribution. Macrolides (CLA and AZI) showed slight toxicity in un-amended soil samples, which increased by up to 65% with the addition of the bio-adsorbents. The toxicity of CIP (a fluoroquinolone) increased with the dose of the bio-adsorbents, reaching up to 20% compared with the control. Finally, the toxicity of TMP (a diaminopyrimidine) slightly increased with the dose of bio-adsorbents. The by-products that increase soil pH are those that showed the highest increases of CLA, AZI, CIP and TMP toxicities. These results could help to prevent/reduce environmental pollution caused by different kinds of antibiotics, selecting the most appropriated bio-adsorbents and doses.Agencia Estatal de Investigación | Ref. RTI2018-099574-B-C21Agencia Estatal de Investigación | Ref. RTI2018-099574-B-C22Ministerio de Economía, Industria y Competitividad | Ref. RYC-2016-20411Xunta de Galicia | Ref. ED481B-2022-081Xunta de Galicia | Ref. ED481A-2021/309Financiado para publicación en acceso aberto: Universidade de Vigo/CISU

1-Butanol adsorption in poly(styrene-divinylbenzene) ion exchange resins for catalysis

The swelling behaviour of poly(styrene-co-divinylbenzene), P(S-DVB), ion exchange resins in 1-butanol (BuOH) has been studied by means of atomistic classical molecular dynamics simulations (MD). The topological characteristics reported for the resin in the dry state, which exhibited complex internal loops (macropores), were considered for the starting models used to examine the swelling induced by BuOH contents ranging from 10% to 50% w/w. Experimental measurements using a laser diffraction particle size analyzer indicate that swelling causes a volume variation with respect to the dry resin of 21%. According to MD simulations, such a volume increment corresponds to a BuOH absorption of 31-32% w/w, which is in excellent agreement with the indirect experimental estimation (i.e. 31% w/w). Simulations reveal that, independently of the content of BuOH, the density of the swelled resin is higher than that of the dry resin, evidencing that the alcohol provokes important structural changes in the polymeric matrix. Thus, BuOH molecules cause a collapse of the resin macropores when the content of alcohol is ≤20% w/w. In contrast, when the concentration of BuOH is close to the experimental value (∼30% w/w), P(S-DVB) chains remain separated by pores faciliting the access of the reactants to the reaction centers. On the other hand, evaluation of both bonding and non-bonding interactions indicates that the mixing energy is the most important contribution to the absorption of BuOH into the P(S-DVB) resin. Overall, the results displayed in this work represent a starting point for the theoretical study of the catalytic conversion of BuOH into di-n-butyl ether in P(S-DVB) ion exchange resins using sophisticated electronic methods

Identification of Novel Type 2 Diabetes Candidate Genes Involved in the Crosstalk between the Mitochondrial and the Insulin Signaling Systems

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein–protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10−5). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases

Artificial pancreas using a personalized rule-based controller achieves overnight normoglycemia in patients with type 1 diabetes

Objective: This study assessed the efficacy of a closed-loop (CL) system consisting of a predictive rule-based algorithm (pRBA) on achieving nocturnal and postprandial normoglycemia in patients with type 1 diabetes mellitus (T1DM). The algorithm is personalized for each patient’s data using two different strategies to control nocturnal and postprandial periods. Research Design and Methods: We performed a randomized crossover clinical study in which 10 T1DM patients treated with continuous subcutaneous insulin infusion (CSII) spent two nonconsecutive nights in the research facility: one with their usual CSII pattern (open-loop [OL]) and one controlled by the pRBA (CL). The CL period lasted from 10 p.m. to 10 a.m., including overnight control, and control of breakfast. Venous samples for blood glucose (BG) measurement were collected every 20 min. Results: Time spent in normoglycemia (BG, 3.9–8.0 mmol/L) during the nocturnal period (12 a.m.–8 a.m.), expressed as median (interquartile range), increased from 66.6% (8.3–75%) with OL to 95.8% (73–100%) using the CL algorithm (P<0.05). Median time in hypoglycemia (BG, <3.9 mmol/L) was reduced from 4.2% (0–21%) in the OL night to 0.0% (0.0–0.0%) in the CL night (P<0.05). Nine hypoglycemic events (<3.9 mmol/L) were recorded with OL compared with one using CL. The postprandial glycemic excursion was not lower when the CL system was used in comparison with conventional preprandial bolus: time in target (3.9–10.0 mmol/L) 58.3% (29.1–87.5%) versus 50.0% (50–100%). Conclusions: A highly precise personalized pRBA obtains nocturnal normoglycemia, without significant hypoglycemia, in T1DM patients. There appears to be no clear benefit of CL over prandial bolus on the postprandial glycemi

Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases

MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy

Malaltia d'Alzheimer; Biomarcadors; Microdissecció de captura làserAlzheimer's disease; Biomarkers; Laser capture microdissectionEnfermedad de Alzheimer; Biomarcadores; Microdisección por captura láserBrain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.This work was funded by the Instituto de Salud Carlos III (ISCIII), (PI20/00465), co-financed by the European Regional Development Fund (FEDER). The Neurovascular Research Laboratory is part of the INVICTUS + network, ISCIII, Spain (RD16/0019/0021). P.M. held a predoctoral fellowship from the Vall d’Hebron Research Institute. MMV is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMW as part of ‘Memorabel’, the research and innovation program for dementia, as part of the Dutch national ‘Deltaplan for Dementia’:the CAFÉ project (the National Institutes of Health, USA, grant number 5R01NS104147-02), and a grant from the Selfridges Group Foundation (NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University

Evaluation of integrated care services in Catalonia:population-based and service-based real-life deployment protocols

BackgroundComprehensive assessment of integrated care deployment constitutes a major challenge to ensure quality, sustainability and transferability of both healthcare policies and services in the transition toward a coordinated service delivery scenario. To this end, the manuscript articulates four different protocols aiming at assessing large-scale implementation of integrated care, which are being developed within the umbrella of the regional project Nextcare (2016-2019), undertaken to foster innovation in technologically-supported services for chronic multimorbid patients in Catalonia (ES) (7.5M inhabitants).Whereas one of the assessment protocols is designed to evaluate population-based deployment of care coordination at regional level during the period 2011-2017, the other three are service-based protocols addressing: i) Home hospitalization; ii) Prehabilitation for major surgery; and, iii) Community-based interventions for frail elderly chronic patients. All three services have demonstrated efficacy and potential for health value generation. They reflect different implementation maturity levels. While full coverage of the entire urban health district of Barcelona-Esquerra (520k inhabitants) is the main aim of home hospitalization, demonstration of sustainability at Hospital Clinic of Barcelona constitutes the core goal of the prehabilitation service. Likewise, full coverage of integrated care services addressed to frail chronic patients is aimed at the city of Badalona (216k inhabitants).MethodsThe population-based analysis, as well as the three service-based protocols, follow observational and experimental study designs using a non-randomized intervention group (integrated care) compared with a control group (usual care) with a propensity score matching method. Evaluation of cost-effectiveness of the interventions using a Quadruple aim approach is a central outcome in all protocols. Moreover, multi-criteria decision analysis is explored as an innovative method for health delivery assessment. The following additional dimensions will also be addressed: i) Determinants of sustainability and scalability of the services; ii) Assessment of the technological support; iii) Enhanced health risk assessment; and, iv) Factors modulating service transferability.DiscussionThe current study offers a unique opportunity to undertake a comprehensive assessment of integrated care fostering deployment of services at regional level. The study outcomes will contribute refining service workflows, improving health risk assessment and generating recommendations for service selection.Trials registrationNCT03130283 (date released 04/06/2018), NCT03768050 (date released 12/05/2018), NCT03767387 (date released 12/05/2018).</p

Assessment of a Novel Automatic Real-Time PCR Assay on the Cobas 4800 Analyzer as a Screening Platform for Hepatitis C Virus Genotyping in Clinical Practice : Comparison with Massive Sequencing

The unequivocal identification of hepatitis C virus (HCV) subtypes 1a/1b and genotypes 2 to 6 is required for optimizing the effectiveness of interferon-free, direct-acting antiviral therapies. We compared the performance of a new real-time HCV genotyping assay used on the Cobas 4800 system (C4800) with that of high-resolution HCV subtyping (HRCS). In total, 502 samples were used, including 184 samples from chronic HCV patients (from routine laboratory activity during April 2016), 5 stored samples with double HCV genotype infections for testing the limitations of the method, and 313 samples from a screening protocol implemented in our hospital (from May to August 2016) based on the new method to further determine its genotyping accuracy. A total of 282 samples, including 171 from April 2016 (the 13 remaining had too low of a viral load for HRCS), 5 selected with double infections, and 106 from screening, were analyzed by both methods, and 220 were analyzed only by the C4800. The C4800 correctly subtyped 125 of 126 1a/1b samples, and the 1 remaining sample was reported as genotype 1. The C4800 correctly genotyped 38 of 45 non-1a/1b samples (classified by HRCS), and it reported the remaining 7 samples as indeterminate. One hundred two of 106 non-1a/1b genotype samples that were identified using the C4800 for screening were confirmed by HRCS. In the 4 remaining samples, 3 were correctly reported as genotype 1 (without defining the subtype) and 1 was reported as indeterminate. None of the samples were misgenotyped. Four of 7 samples with double HCV infections were correctly genotyped by the C4800. Excluding the 5 selected double-infected samples, the C4800 showed 95.7% concordant results for genotyping HCVs 2 to 6 and 1a/1b subtyping, and 99.2% concordance for subtyping 1a/1b single infections in clinical samples. To improve laboratory workflow, we propose using the C4800 as a first-line test for HCV genotyping and 1a/1b classification, followed by transferring non-1a/1b samples to a center where HRCS is available, if further characterization is needed

Pre‐screening models for patient engagement: The MOPEAD project

AbstractBackgroundAlzheimer's disease (AD) is a devastating condition that not only impacts greatly on the patient's health but also poses an important burden on the patient's immediate family circle. Early detection of AD allows patients to have an active role in managing their condition, and to plan how to minimize the strain on their dear ones. Despite known benefits, a large proportion of dementia cases remains undiagnosed or receives a late stage diagnosis. The MOPEAD project aims to address this issue by exploring innovative strategies to emerge "hidden" cases of cognitive impairment.MethodMemory clinics located in five different European countries participated in the project. Four innovative pre‐screening strategies were implemented to detect cognitive decline among individuals aged 65‐85 years who had never received a dementia related diagnosis: a) a web‐based pre‐screening tool along with an online marketing campaign, b) open house initiatives where people with memory complaints were invited to receive a quick evaluation at participating memory clinics, c) a primary care‐based protocol for early detection of cognitive decline using easily administered tools, and d) a tertiary care‐based pre‐screening at diabetologist clinics specifically designed to assess risk of dementia among patients with diabetes. A positive pre‐screening result implied that individuals were at high risk of having mild cognitive impairment or AD.ResultThe number of individuals enrolled, and the proportion of those with positive pre‐screening results varied across strategies. The web‐based tool evaluated the largest number of individuals (n=1487) and yielded 547 positive results (36.8%). The Open house initiative pre‐screened 661 subjects of whom 235 (35.6%) obtained a positive result. A total of 435 patients were pre‐screened in the primary care‐based strategy and 193 of them (44.4%) were found to have a positive result. Finally, 264 patients from diabetes clinics underwent pre‐screening and 154 (58.3%) showed a positive result.ConclusionUsing innovative pre‐screening strategies, we were able to identify 1129 individuals at high risk of having dementia who had otherwise remained unnoticed. Initiatives like this, show us the way to go in order to shift the paradigm of AD towards an earlier diagnosis