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Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Flame retardants (FRs) are widely used in consumer products including furniture foam and electronic equipment such as computers, monitors and TVs. Over time, FRs can easily migrate into the surrounding environments. Since brominated FRs (BFRs) has been determined of high concern due to their environmental persistence, bioaccumulation and potential toxicity, novel FRs have emerged. The present study was aimed at identifying and quantifying the indoor levels of 41 legacy and novel FRs, which include 20 OPFRs and 21 HFRs (8 PBDEs, 3 HBCDDs, 5 NBFRs and 5 DECs) in Tarragona Province (Catalonia, Spain). The results have confirmed the presence of both legacy and novel FRs in air and dust of homes, schools and offices. To the best of our knowledge, this is the first European study measuring OPFRs at office environments and also confirming the presence of the following OPFRs: TEP, TCIPP, T2IPPP, TPPO, DCP, TMCP and B4IPPPP in indoor air, even some of them at high levels. OPFRs in general and TCIPP in particular showed high concentrations in air (94,599 pg/m 3 and 72,281 pg/m 3 , respectively) and dust (32,084 ng/g and 13,496 ng/g, respectively) samples collected in indoor environments. HBCDDs were found at high levels in dust (32,185 ng/g), whereas the presence of PBDEs and DECs were low in both matrices (<160 pg/m 3 in air and <832 ng/g in dust). NBFRs showed higher levels than the two legacy FRs groups, which is supported by the current restrictions of these FRs (640 pg/m 3 in air and 1291 ng/g in dust). Samples of schools had significantly lower levels of NBFRs, but significantly higher concentrations of HFRs in air than in home samples, while dust levels of HFRs were significantly lower than those in samples of offices. Regarding human health risks, the current assessment suggests that those derived from exposure to FRs were lower -although close- to assumable risks, evidencing the potential of FRs for non-carcinogenic and carcinogenic risks, mainly due to the exposure to TCIPP, which was the main contributor together with ΣHBCDDs and also EHDPP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Living-donor kidney transplant (LDKT) recipients undergoing desensitization for Human Leukocyte Antigen (HLA)-incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The purpose of the study is to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles (BEVs). Methods: BEVs were isolated by Sepharose-based size exclusion chromatography and defined as CD19+ and HLA-II+ extracellular vesicles. We analyzed stored serum samples from positive crossmatch LDKT recipients before and after desensitization at first post-transplant biopsy and at 12-month protocol biopsy ( n = 11). Control groups were formed by hypersensitized patients who were not submitted to desensitization ( n = 10) and by low-risk recipients ( n = 9). A prospective validation cohort of 11 patients also included the analysis of B cells subpopulations in recipients' blood and lymph nodes recovered upon graft implantation, along with BEVs analysis before and after desensitization. Results: We found out that CD19+ and HLA-II+BEVs dropped significantly after desensitization and relapse in patients who later developed ABMR was evident. We validated these findings in a proof-of-concept prospective cohort of 6 patients who received the same desensitization protocol and also in a control group of 5 LDKT recipients. In these patients, B cell subpopulations were also studied in recipients' blood and lymph nodes that were recovered before the graft implantation. We confirmed the significant drop in BEVs after desensitization and that this paralleled the reduction in CD19+cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable. Conclusions: BEVs reflected B cell residual activity after desensitization and this could be a valid surrogate of humoral alloreactivity in this setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cucchiari, Tubita, Rovira, Ramirez-Bajo, Banon-Maneus, Lazo-Rodriguez, Hierro-Garcia, Borràs, Ventura-Aguiar, Piñeiro, Martorell, Peri, Musquera, Hertig, Oppenheimer, Campistol, Diekmann and Revuelta.)

Breastfeeding is the best way to feed an infant, although it can also be a source of abiotic contaminants such as heavy metals or bisphenol A (BPA). The early life exposure to these compounds can lead to serious toxic effects in both the short and long-term. These substances can reach breast milk through the mother's habits, diet being one of the main routes of exposure. The aim of the present work was to analyse possible associations between the dietary habits of women and the content of major trace elements, BPA, fatty acids and lipids, and the microbiological and immunological profiles of human milk. Possible associations between major trace elements and BPA and the lipid, microbiological and immunological profiles were also analysed. The results of this study support that the microbiological composition of human milk is associated with the dietary habits of the women, and that the consumption of canned drinks is related to the presence of BPA in human milk. Furthermore, some relationships were found between the amount of major trace elements and the microbiological and immunological profile of the milk samples. Finally, the presence of BPA was associated with changes in the immunological profile of human milk.

Periodic calibrations of Energy Measurement Systems (EMS) installed in locomotives must be carried out to demonstrate the required accuracy established in the EN 50463-2 standard according to European Parliament and Council Directive 2008/57/EC on the interoperability of rail systems within the Community. As a result of the work performed in the "MyRailS" EURAMET project an AC calibration facility was developed consisting of a fictive power source was developed. This fictive power source can generate distorted sinusoidal voltages up to 25 kV-50 Hz and 15 kV-16.7 Hz as well as distorted sinusoidal currents up to 500 A with harmonic content up to 5 kHz or phase-fired current waveform stated in EN50463-2 standard. These waveforms are representative of those that appear during periods of acceleration and breaking of the train. Reference measuring systems have been designed and built consisting of high voltage and high current transducers adapted to multimeters, which function as digital recorders to acquire synchronized voltage and current signals. An approved procedure has been developed and an in-depth uncertainty analysis has been performed to achieve a set of uncertainty formulas considering the influence parameters. Different influence parameters have been analyzed to evaluate uncertainty contributions for each quantity to be measured: rms voltage, rms current, active power, apparent power and non-active power of distorted voltage and current waveforms. The resulting calculated global expanded uncertainty for the developed Energy Measuring Function calibration set up has been better than 0.5% for distorted waveforms. This paper is focused on presenting the complete set of expressions and formulas developed for the different influence parameters, necessary for uncertainty budget calculation of an Energy Measuring Function calibration.

Background: Despite recent advances in immunosuppression treatment, antibody-mediated rejection (ABMR) remains the leading cause of kidney graft loss. Information about prognostic markers and the efficacy of treatment is scarce. Methods: Retrospective study with kidney recipients diagnosed an active ABMR from January 1, 2004 to December 31, 2019 to explore the influence of persistent inflammation in follow-up biopsies on graft survival after ABMR treatment. Results: About 116 patients were included. Active ABMR were treated with a combination of plasma exchange (PE), intravenous immunoglobulin (IVIg), rituximab, and steroids. At 6 months of treatment, 63 (54.3%) patients presented a stabilization or improvement in kidney-graft function. The effectiveness varied depending on the timepoint of the presentation between transplantation and rejection, which is lower for those with late ABMR (63 vs. 21% for early vs. late ABMR, respectively). Ninety patients (77%) underwent a control biopsy after ABMR treatment, from which 46 (51%) responded to the treatment. Microvascular inflammation (MVI) persisted in 64 (71%) biopsies, whereas tubulitis persisted in 17 (19%) biopsies. Death-censored graft survival at 1 year was significantly lower in patients with persistent MVI (86% vs. 95% without persistent MVI, P = 0.002), or with persistent tubulitis (44% vs. 66% without tubulitis, P = 0.02). In the Cox Regression analysis, the persistence of MVI [hazard ratio (HR), 4.50 (95%CI, 1.35-14.96), P = 0.01] and tubulitis [HR 2.88 95%CI (1.24-6.69), P = 0.01) in follow-up biopsies significantly increased the risk of graft failure. Conclusion: Persistent inflammation in follow-up biopsies after ABMR treatment was associated with an increased risk of graft loss, even without meeting Banff rejection criteria. Study Registration: Agencia Española de Medicamentos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTRINM-2017-01., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Piñeiro, Montagud-Marrahi, Ríos, Ventura-Aguiar, Cucchiari, Revuelta, Lozano, Cid, Cofan, Esforzado, Palou, Oppenheimer, Campistol, Bayés-Genís, Rovira and Diekmann.)

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed compounds with two or more fused aromatic ring, being some of them classified as carcinogenic. In the present study, the concentrations of 16 PAHs and the sum of them (∑PAHs) were determined in samples of food, feed, plant and soil collected in six different heavily polluted areas (Choba, Khana, Trans Amadi, Eleme, Uyo and Yenagoa) of the Niger Delta Region (Nigeria). Principal component analysis (PCA) was then used to identify groups of variables (PAHs) and groups of samples that were the best in rendering the environmental pollution in that Region of Nigeria. In addition, PAHs food consumption and the derived carcinogenic risks were assessed in a probabilistic way. The highest ∑PAHs (mg/kg) were: 16.7 in cow meat, 8.06 in goat meat, 25.4 in chicken meat, 7.72 in fish, 28.70 in fish feed, 15.3 in chicken feed, 8.42 in plant, and 8.80 in soil. In most of the Nigerian areas, cooked cow meat, chicken and chicken feed presented the highest impact regarding PAHs contamination. The highest intake of PAHs was through meat consumption, with a very high and unassumable carcinogenic risk, which is quite above 10 -5 for some PAHs, including benzo [a]pyrene. The results of the present survey highlight the importance of reducing PAHs content in food, specially in meat, in the Niger Delta region., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chemical industries and oil refineries are known emission sources of environmental contaminants, such as metals/metalloids, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), among others. Based on the toxicological potential of these pollutants, harmful health effects can be expected for the population living near these facilities. One of the largest chemical/petrochemical complexes in Europe is located in Tarragona County (Catalonia, Spain). In the last two decades, a number of investigations aimed at assessing the environmental impact of air pollutants potentially emitted by this industrial complex have been carried out. The present paper is a review of the available scientific information on the levels of air pollutants related with the activities of this chemical/petrochemical complex. Although there are currently some data on the environmental burdens of metals/metalloids, PAHs, VOCs and PCDD/Fs, there is an evident lack of specific biological monitoring studies on human health. Taking into account the amount of chemicals released to air and their toxicity, it is essential to perform an in-depth analysis of the current health status of the population living in Tarragona County., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Mediterranean Sea has been proposed as the sixth greatest accumulation zone for marine litter and the most affected regarding to microplastics (MPs). Tarragona (Catalonia, NE Spain) coastal region suffers high pressure due to urbanization, tourism, industrial harbour and petrochemical/plastic industries. The present study aims to quantify and characterize in size, morphology and composition the MPs present in sandy beaches, marine sediments, and surface seawaters of Tarragona coastal region. MPs mean abundance were 1.30 items/m 3 in surface seawaters, 32.4 items/kg in marine sediments, and 10.7 items/kg in sandy beaches. Polyester fibres were dominant MPs in bottom sediments and seawater meanwhile polyethylene and polypropylene fragments were the main MPs in beaches. The fibres balls associated with bottom sediments, organic matter and plankton were abundant, masking the real quantity of fibres in each reservoir. The abundance by volume of seawater MPs was higher to those found in oceanic areas and similar to other areas of Mediterranean Sea, corroborating that Western Mediterranean Sea as a region of MPs accumulation. MPs composition and abundance suggested the input of numerous land-base-sources, WWTP (wastewater treatment plants) effluents discharges, and emissaries as the most important. Marine MPs pollution were studied from an integrative point of view, that includes superficial sea water, sand from beaches and sediments. The dynamics of MPs in Tarragona coast were characterized by seawater as the media that receive and facilitate dispersion and fragmentation. The shoreline acts as an intermediate reservoir with constant weathering and active exchange with seawater surface and the sediments acts as a significant sink for medium MPs sizes. It is necessary to develop protocols and guidelines for MPs analysis to obtain harmonized and comparable results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study evaluate the potential of plasmatic CXCL-10 (pCXCL-10) as a pre&post transplantation prognostic and diagnostic biomarker of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and subclinical rejection (SCR) risk in adult kidney recipients considering BKV and CMV infections as possible clinical confounder factors. Twenty-eight of 100 patients included experienced rejection (TCMR:14; ABMR:14); 8 SCR; 13 and 16 were diagnosed with BKV and CMV infection, respectively. Pre-transplantation pCXCL-10 was significantly increased in TCMR and ABMR and post-transplantation in TCMR, ABMR and SCR compared with nonrejectors. All CMV + patients showed pCXCL-10 levels above the cutoff values established for rejection whereas the 80% of BKV + patients showed pCXCL-10 concentration < 100 pg/mL. pCXCL-10 could improve pre-transplantation patient stratification and immunosuppressive treatment selection according to rejection risk; and after kidney transplantation could be a potential early prognostic biomarker for rejection. Clinical confounding factor in BKV + and particularly in CMV + patients must be discarded., (Copyright © 2021 Elsevier Inc. All rights reserved.)

According to preliminary data, seroconversion after mRNA SARS-CoV-2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop at least a cellular response that could offer a certain grade of protection against SARS-CoV-2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney-pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS-CoV-2-pre-immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS-CoV-2-naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S-ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA-1273 SARS-CoV-2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This article presents part of the work within Work Package 3 (WP3) of Impact HTA (Improved methods and actionable tools for enhancing HTA), a H2020 EU-funded research project, intended to enhance and promote collaboration in HTA across EU MS. Amongst other objectives, and in close collaboration with WP4, WP3 addressed setting up a multi-country unit-cost database: the European health care and social costs database (EU HCSCD). The purpose of the database is to facilitate the transference of healthcare economic evaluation analyses across countries, jurisdictions and settings. WP3 concentrates on healthcare costs; WP4 on social costs. This paper discusses the state of the art on this topic, building an appropriate conceptual and theoretical framework for Database development. We conducted a broad, but not systematic, literature and gray-literature review (LR), identifying existing practices and problems, and their implications, described in the Results section. We discuss practical implications and draw important conclusions behind the construction, and future evolution, of this database., (© 2021. The Author(s).)

This study was aimed at determining mainly the concentrations of As and other metals (Cd, Cu, Hg, Pb, V and Zn) in samples of feed, soil, plants and foods (fish, chicken, goat and cow meat) grown and consumed in six areas of Niger Delta, Nigeria (Choba, Khana, Trans Amadi, Eleme, Uyo and Yenagoa). Principal Component Analysis (PCA) models were used for identifying groups of variables (i.e., elements) based on the loadings and groups of samples (i.e., plants, soil, fish, meet, feed) according to the scores that contributed most to the environmental pollution in each Nigerian area. In Choba and Khana sites, the results showed a cluster of elements like As, Pb, V and Zn, mostly associated with samples of goat and cow meat, as well as soils, and separated from another cluster of metals composed by Cu and Hg with different origin. In Trans Amadi area, a clustering of As, Cd and V was found associated to different types of meat (chicken, goat, and cow) located in the opposite side of Cu and Hg, which correlated to plants and soil. In Eleme, the strongest loadings were obtained for V and Zn associated with soil and meat (goat and cow) samples and separated from As and Cd. Finally, in Uyo and Yenagoa, dominant elements were As, Cu, Pb and Zn, with proximity to cow and goat liver samples, while Cd and V corresponded to a different pollution pattern. Lead intake trough meat and fish consumption for adults and children were much higher than the tolerable limits set by international organizations. The results of this study should allow a better understanding of the complex phenomenon of metal pollution in the feed-to-food chain and human health in Nigeria, which should help to manage a pollution reduction strategy and give priorities of research and monitoring., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Previous research has established the lack of motivation by primary education students vis-à-vis the acquisition of the necessary key competencies compulsory in the Spanish school curriculum and this is closely linked to poor academic performance on the part of the aforesaid students. Based on this current educational reality, we present a quantitative study regarding the perception of students after the implementation of a new gamified experience in the classroom such that it integrates, for the first time and jointly, the benefits of gamification (Deterding et al., 2011a; Deterding & Zagal, 2018) with interdisciplinary methodologies (Candel, 2018; Cruz-Pichardo & Cabero-Almenara, 2020; Flores-Aguilar, 2019) and technology-enhanced transmedia narratives (Scolari 2018a, 2018b; Jenkins, 2003; Scolari 2018a, 2018b). This integrative and innovative proposal was implemented in a primary school in Valencia (Spain) between October 2019 and February 2020. The research is designed based on survey-type studies, employing an experimental cross-sectional quantitative methodology with pretest and posttest, in addition to experimental and control groups. Regarding the cross-sectional approach, descriptive analyses (means and standard deviation) have been conducted, together with histograms of each of the items in the questionnaire, as well as the Student's t test and an analysis of variance, which is of significant value when working with independent samples from a normal distribution, as in our case. The instrument utilised in the present study confirms the existence of a high and adequate internal consistency (Alpha = .873). The results obtained, as presented herein, confirm that the incorporation of the gamified proposals in primary school classes, unprecedentedly intertwined with the benefits provided by interdisciplinary work and transmedia narratives, notably improves the students' training process and their motivation, while also contributing to the better acquisition of compulsory curricular contents and enhanced academic performance., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

Purpose: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia., Methods: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling., Results: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters)., Conclusion: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.

Air pollution by airborne particles is a serious health problem worldwide. The present study was aimed at investigating the concentrations and composition of total suspended particles (TSPs) and PM 2.5 at various industrial/commercial sites of Guangzhou, a megacity of Southern China. Major and trace elements, ions and carbonaceous fraction were determined and main components were calculated. In addition, in order to assess the potential toxic on the respiratory system of these PM, cytotoxicity of size-fractionated particles (PM 10-5.6 , PM 5.6-3.3 , PM 3.3-1.1 , PM 1.1-0.43 ) for a human lung cancer cell line (A549) was also investigated. Correlations between PM constituents and toxicity were assessed. Median levels of TSPs and PM 2.5 in industrial/commercial sites were 206 and 57.7 μg/m 3 , respectively. Nickel, Cu, Mo, Mn, Pb, and Ti were the most abundant metals in TSPs and PM 2.5 . Industrial activities and coal combustion were the most important sources of carbonaceous particles in the zone. MTT assays showed that PM 10-5.6 and PM 1.1-0.43 had the highest and the lowest cytotoxicity to A549 cell lines, respectively. Inhalable particles around the manufacturing of metal facilities and formal waste treatment plants showed a high cytotoxicity to A549 cell lines. In general terms, no significant correlations were found between main components of PM and toxicity. However, W showed a significant correlation with cell viability., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study was aimed at reconstructing the exposure to bisphenol (BPA) of 60 pregnant women from the EXHES-Spain cohort. A biomonitoring study was conducted by determining BPA levels in urine samples over the three trimesters of pregnancy. Moreover, the correlations between BPA levels and the role of different potential exposure sources, with special emphasis on the dietary intake, were also studied. Urine samples were subjected to dispersive liquid-liquid microextraction and the subsequent analysis via gas chromatography-mass spectrometry. BPA was detected in 76% of the urine samples. A significant decrease of urinary BPA levels was observed along pregnancy, as mean concentrations of creatinine-adjusted BPA were 4.64, 4.84 and 2.51 μg/g in the first, second and third trimester, respectively. This decrease was essentially associated with changes in the dietary habits of the pregnant women, including a lower intake of canned food and drinks. However, the potential role of other pregnancy-related biochemical or physiological factors should not be disregarded. Very interestingly, significant differences in urine BPA levels were found according to the fruit consumption pattern, as women who ate more citrus fruits showed lower BPA concentrations in urine. The reconstructed exposure to BPA was estimated in 0.072, 0.069 and 0.038 μg BPA/kg of body weight/day in the first, second and third trimesters, respectively. These values are far below the temporary tolerable daily intake (t-TDI) established by the EFSA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite the commercial success of high pressure processing (HPP) in the juice industry, some regulatory agencies still require process validation. However, there is a lack of consensus on various aspects regarding validation protocols, including the selection of representative strains to be used in challenge tests. This study characterized the variable response of Escherichia coli O157:H7 (34 strains), Listeria monocytogenes (44 strains) and Salmonella enterica (45 strains) to HPP, and identified potential candidates to use in process validation. Stationary phase cells were submitted to 500 MPa for 1 min at 10 °C in model solutions consisting of tryptic soy broth + 0.6% yeast extract (TSBYE) adjusted to pH 4.5 and 6.0 with citric acid. At pH 6.0, pressure resistance widely varied between species and within strains of the same species. E. coli O157:H7 and L. monocytogenes were the most pressure resistant and showed high variability at strain level, as the total count range given by minimum and maximum counts spread between 2.0 and 6.5 log 10 CFU/ml. S. enterica was the least resistant pathogen with more than 82% of the isolates displaying non-detectable counts after HPP. Recovery through storage at 12 °C was also variable for all pathogens, but eventually most strains recovered with median counts on day 14 between 8.3 and 8.9 log 10 CFU/ml. For pH 4.5 solutions, 26 E. coli O157:H7 strains displayed survivors after HPP but did not adapt, registering non-detectable counts in the next sampling dates. None of the L. monocytogenes and S. enterica strains survived HPP or incubation at pH 4.5 (<2.0 log 10  CFU/ml), suggesting that citric acid at 4.16 g/l is a safe barrier for pathogen control under moderate HPP conditions. Principal component and cluster analyses served to propose strain cocktails for each species based on their pressure resistant and adaptation phenotypes. Additionally, S. enterica was identified as less pressure resistant and less prone to recover following HPP than E. coli O157:H7 and L. monocytogenes, so its relevance in process validation for juices should be questioned. Future work will validate the proposed strain cocktails on real food systems., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL)., Experimental Design: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available., Results: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P < 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses., Conclusions: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment., (©2020 American Association for Cancer Research.)

This paper was aimed at reviewing recent studies related with the impact on environment and human health of metals and PCDD/Fs near cement plants. It has been particularly focused on the impact of cement plants located in Catalonia, Spain, which have been monitored by our research for more than ten years. Environmental monitoring studies were performed under different cement plant conditions. While some of our studies examined temporal trends of the levels of the above indicated pollutants, the main goal of other surveys was to assess the impact of implementing alternative fuels in the facilities. Even one of the studies was performed before and after the cement plant temporally ceased its industrial activity. The impact of cement plants burning alternative fuels on the emissions of metals and PCDD/Fs elsewhere was also reviewed. Regarding the cement plants in Catalonia, no significant differences were found, neither in the long-term follow-up studies, nor when alternative fuels are used, nor when a cement plant temporally stopped its activity. These results are in agreement with those reported for several stack emissions of other cement plants working under different conditions. We conclude that emissions of metals and PCDD/Fs by cement plants working with the best available techniques (BAT), should not cause a significant negative impact neither on the surrounding environment, nor on the human health of the population living in the neighborhood.

The number of studies published on COVID-19 in recent months is certainly impressive. However, there are still important gaps to know a great number of characteristics of this disease. Among these, some potential ways of transmission of the SARS-CoV-2 and the different reasons for the severity of the disease in different people. Various studies have suggested that certain air pollutants could be increasing the transmission of the coronavirus, as well as the risks of COVID-19 incidence and mortality. In the present preliminary case-study conducted in Tarragona Province (Catalonia, Spain), we studied the potential association of COVID-19 with PM 10 , NO 2 and O 3 , as well as the differences in the incidence and lethality of this disease. This Province is divided into two "health regions": Camp de Tarragona, with an important industrial complex, and Terres de l'Ebre, with a great agricultural component. In spite of the notable limitations of the current study, our preliminary findings indicate that the industrialized/urban areas of Tarragona Province show a higher incidence and mortality of COVID-19 than the agricultural/rural zones. These - and previous - results would highlight the importance of conducting specific investigations focused on directly assessing whether air pollutants such as particulate matter can act as carriers of the SARS-CoV-2. If confirmed, the recommendation on keeping the "social distance" (1.5-2 m) might need to be adapted to this situation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The dialysis-based definition of Delayed Graft Function (dDGF) is not necessarily objective as it depends on the individual physician's decision. The functional definition of DGF (fDGF, the failure of serum creatinine to decrease by at least 10% daily on 3 consecutive days during the first week post-transplant), may be more sensitive to reflect recovery after the ischemia-reperfusion injury. We retrospectively analyzed both definitions in 253 deceased donor kidney transplant recipients for predicting death-censored graft failure as primary outcome, using eGFR < 25 ml/min/1.73 m 2 as a surrogate end-point for graft failure. Secondary outcome was a composite outcome that included graft failure as above and also patient's death. Median follow-up was 3.22 [2.38-4.21] years. Seventy-nine patients developed dDGF (31.2%) and 127 developed fDGF (50.2%). Sixty-three patients fulfilled criteria for both definitions (24.9%). At multivariable analysis, the two definitions were significantly associated with the primary [HR (95%CI) 2.07 (1.09-3.94), P = 0.026 for fDGF and HR (95%CI) 2.41 (1.33-4.37), P = 0.004 for dDGF] and the secondary composite outcome [HR (95%CI) 1.58 (1.01-2.51), P = 0.047 for fDGF and HR (95%CI) 1.67 (1.05-2.66), P = 0.028 for dDGF]. Patients who met criteria for both definitions had the worst prognosis, with a three-year estimates (95%CI) of survival from the primary and secondary outcomes of 2.31 (2.02-2.59) and 2.20 (1.91-2.49) years for fDGF+/dDGF+, in comparison with the other groups (P < 0.01 for trend). fDGF provides supplementary information about graft outcomes on top of the dDGF definition in a modern series of kidney transplantation., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Extracellular vesicles (EVs) are a heterogeneous group of membranous vesicles that differ on their biogenesis and release pathways, such as exosomes, microvesicles and apoptotic bodies. They are involved in cell-to-cell communication delivering signal molecules (proteins, nucleic acids, lipids, etc. ) that can regulate different physiological processes, as well as the development and progression of several diseases. There are different methods and commercial kits to isolate EVs and depending on the methodology one could obtain EVs with different degrees of efficiency, purity and it can be more or less time-consuming. Then, the choice has to be according to the different advantages and disadvantages, and their use for downstream applications. Here, we describe the EVs isolation method from mesenchymal stromal cells by ultracentrifugation. This EVs isolation can be performed using common media and buffers, and only with the requirement of an analytical ultracentrifuge. Moreover, this method can be used to obtain large quantity of EVs with a good reproducibility for developing in vitro and in vivo experiments and studying their biological actions., Competing Interests: Competing interestsThe authors declare no conflicts of interests., (Copyright © 2020 The Authors; exclusive licensee Bio-protocol LLC.)

Since 2008, the environmental levels of polychlorinated compounds near a municipal solid waste incinerator in Mataró (Catalonia, Spain) have been periodically monitored. The present study aimed at updating the data regarding the temporal changes occurred between 2015 and 2017, when air and soil samples were collected again, and the concentrations of the same chemical pollutants (i.e., polychlorinated dibenzo- p -dioxins and dibenzofurans (PCDD/Fs), and polychlorinated biphenyls (PCBs)) were analysed. Furthermore, the health risks associated with their human exposure were also evaluated. The levels of all the contaminants in soil were far below the threshold established by regional and national legislations, also being lower than those observed in previous surveys. A similar trend was also noted for PCDD/Fs in air samples, while airborne PCBs were the only group of chemicals whose levels significantly increased. In any case, the global assessment of the data regarding the different pollutants and matrices indicates that there has not been a general increase in the environmental pollution around the facility. In addition, the environmental exposure to PCDD/Fs and PCBs by the population living nearby is still clearly lower than the dietary intake of these same chemical pollutants.

Current standard EN 50463-2 indicates the tests and the requirements to be satisfied for an energy measurement system of a traction unit for railway applications. Some of these tests are to be done with several harmonics superposed on the rated voltage, respectively current. However, no calibration systems satisfying the standard requirements were available few years ago. The work performed in the EURAMET project "MyRailS" leads to the development of fictive power sources and reference measurement systems described in this paper. Therefore, it is possible to generate distorted 25 kV-50 Hz voltages with harmonics up to 5 kHz and 90° phase-fired currents up to 500 A with harmonics up to 5 kHz. The generated power is measured by developed traceable reference systems with accuracy better than 0.5%.

Home-based rehabilitation after an acute episode or following an exacerbation of a chronic disease is often problematic with a clear lack of continuity of care between hospital and home care. Secondary prevention is an essential element of long-term rehabilitation where strategies oriented toward risk reduction, treatment adherence, and optimization of quality of life need to be applied. Frail and sometimes isolated, the patient fails to adhere to the proposed post-discharge clinical pathway due to lack of appropriate clinical, emotional, and informational support. Providing a suitable rehabilitation after an acute episode or a chronic disease is a major issue, as it helps people to live independently and enhance their quality of life. However, as the rehabilitation period usually lasts some months, the continuity of care is often interrupted in the transition from hospital to home. Virtual coaches could help these patients to engage in a personalized rehabilitation program that complies with age-related conditions. These coaches could be a key technology for empowering patients toward increasing their adherence to the care plan and to improve their secondary prevention measures. In this paper, we are presenting a novel virtual coaching system that will address these challenges by combining recent technological advances with clinical pathways, based on joint research and validation activities from researchers from the medical and information and communication technology (ICT) domains., (Copyright © 2020 Kyriazakos, Schlieter, Gand, Caprino, Corbo, Tropea, Judica, Sterpi, Busnatu, Philipp, Rovira, Martínez, Lange, Gabilondo, Del Pino, Carlos Gomez-Esteban, Pannese, Bøttcher and Lynggaard.)

Objective: Social determinants and health inequalities have a huge impact on health of populations. It is important to study their role in the management of the Covid-19 epidemic, especially in cities, as certain variables like the number of tests and the access to health system cannot be assumed as equal. The aim of this work was to determine the relation of social determinants in the incidence of Covid-19 in the city of Barcelona., Methods: An observational retrospective ecological study was performed, with the neighbourhood as the population unit, based on data of cumulative incidence published at May 14th, 2020 by the Public Health Agency of Barcelona. Covid-19 incidence disparities depending on the income of the neighbourhoods, the Pearson linear correlation of the variables selected (age, sex, net density, immigrants, comorbidities, smokers, Body Mass Index [BMI] and Available Income per Family Index [AIFI]) with the incidence and the correlation with a multivariant Generalized Linear Model (GLM) were estimated., Results: It was found that neighbourhoods belonging to the lowest quintile of income had a 42% more incidence than those belonging to the highest quintile: 942 cases per 100,000 inhabitants versus 545 per 100,000 inhabitants of the highest quintile. The Pearson correlation was statistically significative between the incidence of Covid-19 and the percentage of population over 75 (r=0.487), the percentage of immigration of the neighbourhood and the origin of the immigrants (r=-0.257), the AIFI (r=-0.462), the percentage of smokers (r=0.243) and the percentage of people with BMI over 25 (r=0.483). The GLM showed that the most correlated variables with the incidence are the percentage of people over 75 (Z-score=0.258), the percentage of people from Maghreb (Z-score=-0.206) and Latin America (Z-score=0.19) and the percentage of people with BMI over 25 (Z-score=0.334). The results of the GLM were significative., Conclusions: Social determinants are correlated with the modification of the incidence of Covid-19 in the neighbourhoods of Barcelona, with special relevance of the prevalence of BMI over 25 and the percentage of immigrants and its origin., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In recent years, a number of epidemiological studies have demonstrated that exposure to air pollution is associated with several adverse outcomes, such as acute lower respiratory infections, chronic obstructive pulmonary disease, asthma, cardiovascular diseases, and lung cancer among other serious diseases. Air pollutants such as sulfur oxides, nitrogen oxides, carbon monoxide and dioxide, particulate matter (PM), ozone and volatile organic compounds (VOCs) are commonly found at high levels in big cities and/or in the vicinity of different chemical industries. An association between air concentrations of these pollutants and human respiratory viruses interacting to adversely affect the respiratory system has been also reported. The present review was aimed at assessing the potential relationship between the concentrations of air pollutants on the airborne transmission of SARS-CoV-2 and the severity of COVID-19 in patients infected by this coronavirus. The results of most studies here reviewed suggest that chronic exposure to certain air pollutants leads to more severe and lethal forms of COVID-19 and delays/complicates the recovery of patients of this disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment., Methods: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3-8 ng/mL)., Results: Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277)., Conclusions: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.

Particulate matter, sulfur dioxide, nitrogen oxides, ozone, carbon monoxide, volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) are among the outdoor air pollutants that are major factors in diseases, causing especially adverse respiratory effects in humans. On the other hand, the role of respiratory viruses in the pathogenesis of severe respiratory infections is an issue of great importance. The present literature review was aimed at assessing the potential effects of air pollutants on the transmission and severity of respiratory viral infections. We have reviewed the scientific literature regarding the association of outdoor air pollution and respiratory viruses on respiratory diseases. Evidence supports a clear association between air concentrations of some pollutants and human respiratory viruses interacting to adversely affect the respiratory system. Given the undoubted importance and topicality of the subject, we have paid special attention to the association between air pollutants and the transmission and severity of the effects caused by the coronavirus named SARS-CoV-2, which causes the COVID-19. Although to date, and by obvious reasons, the number of studies on this issue are still scarce, most results indicate that chronic exposure to air pollutants delays/complicates recovery of patients of COVID-19 and leads to more severe and lethal forms of this disease. This deserves immediate and in-depth experimental investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bacterial spores survive high pressure processing (HPP). Group II Clostridium botulinum is an obligate anaerobe spore-forming pathogen that can produce the botulinum neurotoxin under refrigeration. This study assessed nontoxigenic type E C. botulinum and Group II Clostridium sp. growth in raw and HPP (550 MPa, 3 min, 10 °C) Thai coconut water (CCW; pH 5.2). No spore germination or growth occurred in HPP CCW inoculated with 10 5 CFU/ml after 61 days regardless of oxygen concentration (<0.5 - 11 mg/l) or storage temperature (4 and 20 °C). Spore concentration decreased by 3.0 ± 0.1 log CFU/ml in a worst-case scenario consisting of non-HPP filter-sterilized CCW (pH 7.0) under anoxic incubation at 30 °C during 61 days, suggesting spore germination followed by cellular death. Supplementing filter-sterilized CCW (pH 7.0) with selected germinants and free amino acids did not support spore development, but the addition of nutrient-rich laboratory media (TPGY broth) at low concentrations (6.25%) promoted growth, suggesting that a lack of nutrients prevents C. botulinum development in CCW. Further risk assessment will require evaluating other CCW varieties and toxin production., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Phthalates are known endocrine disruptors (EDs) and are associated with potential diseases, such as obesity and diabetes. In 2002, the plasticizer 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced as an alternative to phthalates in the European market. The objective of this study was to evaluate the total exposure to phthalate and DINCH metabolites from EXHES Tarragona, Spain cohort of pregnant women. On the one hand, the analytical determination of phthalate and DINCH metabolites in urine was carried out. On the other hand, the reconstructed exposure was calculated for phthalates and DINCH using their metabolites concentration measured in the urine. Thirteen different phthalate metabolites and two metabolites of DINCH were measured and detected in almost all pregnant women's urine samples (n = 60). There were significant correlations between metabolites of the same parent compounds, and also between DEHP and MBzP metabolites, DiNP and BBZP metabolites, and DEHP and DiNP metabolites respectively. The exposure of pregnant women to phthalate and DINCH parent compounds were also back calculated using the levels of each metabolite found in pregnant women urine (reconstructed exposure). Besides, to demonstrate the utility of this approach, the physiologically based pharmacokinetic (PBPK) model was used to predict the cumulative amount of MEHP (a principal metabolite of DEHP in urine). To proceed with that, DEHP reconstructed exposure and estimated exposure from the same cohort (previously studied by the same authors) were simulated using the PBPK model. Results showed that the reconstructed-PBPK simulation was closer to the 24 h biomonitoring data than the estimated PBPK-simulation., This clearly shows that the combination of reconstructed exposure with the PBPK model is a good tool to predict chemicals exposure. However, some discrepancies between simulated and biomonitored values were found. This can be associated with other sources that contribute to the total exposure and emphasises the need to consider multi-routes exposure for the widely distributed chemicals like phthalates and DINCH., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The TRANSFORM study demonstrated that an immunosuppression based on a combination of calcineurin inhibitors and de-novo mTOR inhibitors (mTORi) is safe and effective in kidney transplant recipients. However, data that validate this approach in clinical practice are currently missing., Materials and Methods: Analysis of 401 kidney transplant recipients transplanted from June 2013 to December 2016. All patients received tacrolimus with prednisone in combination with either mycophenolate (n = 186) or mTORi (either everolimus or sirolimus, n = 215). A propensity score to receive mTORi was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age and sex of donor and recipient, BMI, previous transplants, diabetes, cPRA, dialysis before transplantation, dialysis vintage, type of donor, ABO-incompatibility, HLA-mismatches, induction and ischemia time. Median follow-up was 2.6 [1.9; 3.7] years., Results: Cox-regression analysis suggests good results for mTORi versus MPA in terms of 1-year biopsy-proven acute rejection (BPAR, P = 0.063), 1-year graft loss (P = 0.025) and patient survival (P < 0.001). Results observed for BPAR and graft failure were largely attributed to those patients that would have been excluded by the TRANSFORM because of some exclusion criteria (52.9% of the population, P = 0.003 for 1-year BPAR and P = 0.040 for graft loss). In patients who met selection criteria for TRANSFORM, no effect of treatment for BPAR or graft failure was observed, while the beneficial effect on overall survival persisted., Conclusions: In a real-life setting, a protocol based on de-novo mTORi with tacrolimus and prednisone could be employed as a standard immunosuppressive regimen and was associated with good outcomes.

This study was aimed at comparing the toxicity effects on cell viability and the obesogenic activity of Bisphenol A (BPA) and its analogues, Bisphenol S (BPS) and Bisphenol F (BPF), by in vitro assays with a preadipocytic 3T3-L1 cell line. To compare the toxic potential and select the concentrations of each chemical not showing a decrease in cell viability, MTT assay was performed. The cell phenotype was determined in differentiated 3T3-L1 adipocytes by red oil O staining. To determine the expression levels of the different adipogenic proteins the Western Blot test was performed. The results from MTT assay showed a greater toxic effect of BPA - at equal and even lower concentrations-than its analogues. However, BPS followed by BPF showed a greater neutral lipid storage capacity than BPA, which was reflected in the increase of the protein expression of CCAAT/enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor gamma γ (PPARγ) and acid-binding protein 4 (FABP4). In summary, these BPA analogues -especially BPS- present a greater endocrine potential activity than BPA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

According to the most traditional economic evaluation manuals, all "relevant" costs should be included in the economic analysis, taking into account factors such as the patient population, setting, location, year, perspective and time horizon. However, cost information may be designed for other purposes. Health care organisations may lack sophisticated accounting systems and consequently, health economists may be unfamiliar with cost accounting terminology, which may lead to discrepancy in terms used in the economic evaluation literature and management accountancy. This paper identifies new tendencies in costing methodologies in health care and critically comments on each included article. For better clarification of terminology, a pragmatic glossary of terms is proposed. A scoping review of English and Spanish language literature (2005-2018) was conducted to identify new tendencies in costing methodologies in health care. The databases PubMed, Scopus and EconLit were searched. A total of 21 studies were included yielding 43 costing analysis. The most common analysis was top-down micro-costing (49%), followed by top-down gross-costing (37%) and bottom-up micro-costing (14%). Resource data were collected prospectively in 12 top-down studies (32%). Hospital database was the most common way of collection of resource data (44%) in top-down gross-costing studies. In top-down micro-costing studies, the most resource use data collection was the combination of several methods (38%). In general, substantial inconsistencies in the costing methods were found. The convergence of top-down and bottom-up methods may be an important topic in the next decades.

Background: Cell therapies and derived products have a high potential in aiding tissue and organ repairing and have therefore been considered as potential therapies for treating renal diseases. However, few studies have evaluated the impact of these therapies according to the stage of chronic kidney disease. The aim of this study was to evaluate the renoprotective effect of murine bone marrow mesenchymal stromal cells (BM-MSCs), their extracellular vesicles (EVs) and EVs-depleted conditioned medium (dCM) in an aggressive mouse model of chronic cyclosporine (CsA) nephrotoxicity in a preventive and curative manner., Methods: After 4 weeks of CsA-treatment (75 mg/kg daily) mice developed severe nephrotoxicity associated with a poor survival rate of 25%, and characterized by tubular vacuolization, casts, and cysts in renal histology. BM-MSC, EVs and dCM groups were administered as prophylaxis or as treatment of CsA nephrotoxicity. The effect of the cell therapies was analyzed by assessing renal function, histological damage, apoptotic cell death, and gene expression of fibrotic mediators., Results: Combined administration of CsA and BM-MSCs ameliorated the mice survival rates (6-15%), but significantly renal function, and histological parameters, translating into a reduction of apoptosis and fibrotic markers. On the other hand, EVs and dCM administration were only associated with a partial recovery of renal function or histological damage. Better results were obtained when used as treatment rather than as prophylactic regimen i.e., cell therapy was more effective once the damage was established., Conclusion: In this study, we showed that BM-MSCs induce an improvement in renal outcomes in an animal model of CsA nephrotoxicity, particularly if the inflammatory microenvironment is already established. EVs and dCM treatment induce a partial recovery, indicating that further experiments are required to adjust timing and dose for better long-term outcomes., (Copyright © 2020 Ramírez-Bajo, Martín-Ramírez, Bruno, Pasquino, Banon-Maneus, Rovira, Moya-Rull, Lazo-Rodriguez, Campistol, Camussi and Diekmann.)

Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role., Methods: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327)., Results: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment., Conclusions: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets., (© 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The stress response of 11 strains of Listeria monocytogenes to oxidative stress was studied. The strains included ST1, ST5, ST7, ST6, ST9, ST87, ST199 and ST321 and were isolated from diverse food processing environments (a meat factory, a dairy plant and a seafood company) and sample types (floor, wall, drain, boxes, food products and water machine). Isolates were exposed to two oxidizing agents: 13.8 mM cumene hydroperoxide (CHP) and 100 mM hydrogen peroxide (H 2 O 2 ) at 10 °C and 37 °C. Temperature affected the oxidative stress response as cells treated at 10 °C survived better than those treated at 37 °C. H 2 O 2 at 37 °C was the condition tested resulting in poorest L. monocytogenes survival. Strains belonging to STs of Lineage I (ST5, ST6, ST87, ST1) were more resistant to oxidative stress than those of Lineage II (ST7, ST9, ST199 and ST321), with the exception of ST7 that showed tolerance to H 2 O 2 at 10 °C. Isolates of each ST5 and ST9 from different food industry origins showed differences in oxidative stress response. The gene expression of two relevant virulence ( hly ) and stress ( clp C) genes was studied in representative isolates in the stressful conditions. hly and clp C were upregulated during oxidative stress at low temperature. Our results indicate that conditions prevalent in food industries may allow L. monocytogenes to develop survival strategies: these include activating molecular mechanisms based on cross protection that can promote virulence, possibly increasing the risk of virulent strains persisting in food processing plants., Competing Interests: The authors declare no conflict of interest.

The TaqMan-based quantitative Polymerase Chain Reaction (qPCR) method and the Plate Count (PC) method are both used in combination with primary and secondary mathematical modeling, to describe the growth curves of Leuconostoc mesenteroides and Weissella viridescens in vacuum-packaged meat products during storage under different isothermal conditions. Vacuum-Packaged Morcilla (VPM), a typical cooked blood sausage, is used as a representative meat product, with the aim of improving shelf-life prediction methods for those sorts of meat products. The standard curves constructed by qPCR showed good linearity between the cycle threshold (C T ) and log 10 CFU/g, demonstrating the high precision and the reproducible results of the qPCR method. The curves were used for the quantification of L. mesenteroides and W. viridescens in artificially inoculated VPM samples under isothermal storage (5, 8, 13 and 18 °C). Primally, both the qPCR and the PC methods were compared, and a linear regression analysis demonstrated a statistically significant linear correlation between the methods. Secondly, the Baranyi and Roberts model was fitted to the growth curve data to estimate the kinetic parameters of L. mesenteroides and W. viridescens under isothermal conditions, and secondary models were used to establish the dependence of the maximum specific growth rate on the temperature. The results proved that primary and secondary models were adequate for describing the growth curves of both methods in relation to both bacteria. In conclusion, the results of all the experiments proved that the qPCR method in combination with the PC method can be used to construct microbial growth kinetics and that primary and secondary mathematical modeling can be successfully applied to describe the growth of L. mesenteroides and W. viridescens in vacuum-packaged morcilla and, by extension, other cooked meat products with similar characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recipients of simultaneous liver-kidney transplantations (SLKTs) have a lower risk of rejection compared with recipients of kidney transplants alone. However, there is disagreement about the impact of pretransplant anti-human leukocyte antigen sensitization on patient and kidney graft survival in the long term. The aim of the study was to evaluate the impact of the recipient immunological risk and comorbidities in renal graft outcomes on SLKT. We reviewed the SLKTs performed in our center from May 1993 until September 2017. Patient and graft survival were analyzed according to the immunological risk, comorbidities, liver and kidney rejection episodes, immunosuppression, and infections. A total of 20 recipients of SLKT were considered in the high immunological risk (HIR) group, and 68 recipients were included in the low immunological risk (LIR) control group. The prevalence of hepatitis C virus infection, second renal transplant, and time on dialysis prior to transplantation were significantly higher in the HIR group. The incidence of acute kidney rejection was higher in the HIR group (P<0.01). However, death-censored kidney graft survival as well as the estimated glomerular filtration rate at follow-up were not different between the 2 groups. Comorbidities, but not the immunological risk, impact negatively on patient survival. Despite the higher incidence of rejection in the HIR SLKT group, longterm renal function and graft survival were similar to the LIR group., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Hazardous waste landfills (HWLs) usually mean the end of non-reusable, non-recyclable and non-recoverable wastes derived from industrial activities. A number of hazardous compounds and toxic elements, such as PCDD/Fs, Cd, Cr, Hg, Pb and As, is associated to these wastes. The HWL of Castellolí (Catalonia, Spain) treats a variety of hazardous wastes, which include bottom ashes from waste incinerators and asbestos potentially containing those toxicants. In 2007, our group began a surveillance program inside the HWL and in nearby villages focused on assessing the environmental levels of PCDD/Fs and toxic elements. Here we summarize the most updated results, corresponding to data from samples collected between 2015 and 2018. The levels of most trace elements (As, Cd, Cr, Ni and Pb) in soils, as well as those of Cd and Pb in air, were significantly higher (p < 0.01) inside the HWL than outside. However, no relevant differences were noted in the concentrations of trace elements when comparing the results of villages near the HWL with those located farther. With respect to PCDD/Fs, a progressive decrease was observed between the first (2007) and most recent (2018) surveys. The human health risks associated with the exposure to trace elements and PCDD/Fs exposure were within acceptable ranges according to national and international legislations (HQ < 1 and Cancer risk < 10 -5 )., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The concentrations of organochlorine compounds (OCs), including pentachlorobenzene, hexachlorobenzene (HCB), hexachlorocyclohexanes (α-, β-, γ- and δ-HCH), polychlorobiphenyls (PCBs 28, 52, 101, 118, 138, 153 and 180), DDT and metabolites, were measured in maternal serum samples collected at the first trimester of pregnancy, at delivery and in umbilical cord from a cohort of mother-newborn pairs from Tarragona (Spain) (n = 50), representing general population of a Mediterranean area from Southern Europe. The observed concentrations were generally low in comparison with previous studies in other world areas. Higher OC concentrations were observed in the maternal serum collected at delivery than in the first trimester and the cord blood concentrations were lower than the maternal levels. These results show for the first time a small but statistically significant increase in maternal venous concentration of OCs between the first trimester and delivery when measured in ng/ml. HCB, β-HCH and the PCB congeners in cord blood were significantly correlated with the concentrations of these compounds in maternal venous blood and the coefficients were stronger for the samples collected at delivery which was consistent with OC transfer from mother to foetus. In the case of DDT compounds, only 4,4'-DDT showed maternal-cord blood correlation which documented the low metabolic capacity of newborns for OC transformation, e.g. DDT into DDE. Maternal age was the most significant driver of the observed maternal venous OC concentrations in both periods, older ages involving higher concentrations. Higher body mass index was only significantly correlated with higher 4,4'-DDE concentrations in maternal venous blood and cord blood. In some cases, social class and education level were significantly correlated with OC concentrations, e.g. 4,4'-DDE in maternal venous blood from the first trimester and cord blood and PCB153 in maternal venous blood at delivery. In these cases, highest concentrations were found in the women with highest education level and most affluent social class. Comparison of the maternal OC concentrations of this cohort with those observed in 2002 in population of the same geographic area and age range shows decreases between two and ten times over this fourteen-year period., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Campylobacter spp. are the leading causes of bacterial human gastroenteritis worldwide; being poultry farms the main source of infections. In order to obtain information on prevalence and diversity of Campylobacter-infected flocks in the North of Spain, fourteen farms were studied between autumn and spring in 2014 and 2015, respectively. Moreover, virulence genes involved in pathogenicity and antimicrobial resistance were investigated. A survey about preventive hygiene practices at farms was performed to determine the risky practices that could contribute to the presence of Campylobacter in this step of the poultry food chain. Testing the presence of Campylobacter spp. showed 43 % of the farms were positive during autumn, whereas only 31 % were positive in spring. A very high prevalence within-flock was observed (43.1 % to 88.6 %) and C. jejuni was the most prevalent species in both periods. Genotyping by pulsed field gel electrophoresis (PFGE) showed a high heterogeneity among farms (309 isolates clustered into 21 pulsotypes). Virulence genes were present in all C. jejuni isolates while cdtA and cdtC were absent in C. coli. On the contrary, the latter showed higher antimicrobial resistance than C. jejuni. This study suggests that environment might be one of the main sources for Campylobacter transmission, as water supply seemed to be a clear cause of the contamination in a specific farm. However, in other farms other environmental factors contributed to the contamination, confirming the multifactorial origin of Campylobacter colonization in broilers. Therefore, biosecurity measures in farms are crucial to reduce Campylobacter contamination, which may have important implications for human and animal health., Competing Interests: Declaration of Competing Interest The authors have not had any conflict of interest in the publication of this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The burden of organophosphate (OP) pesticides in pregnant women from Tarragona (n = 157), a Mediterranean area of intense agricultural activity, has been assessed from the study of hydroxylated organic metabolites in urine samples in the three trimesters of pregnancy. 2-Diethylamino-6-methylpyrimidin-4-ol (DEAMPY), a metabolite of pirimiphos, was the compound found in higher concentration, medians 0.66-2.8 μg/g creatinine. 4-Nitrophenol (PNP), a metabolite of parathion, medians 0.24-0.41 μg/g creatinine, was the second most abundant compound. 2-Isopropyl-6-methyl-4-pyrimidol (IMPY), a metabolite of diazinon, was also present but in lower concentrations. Except for DEAMPY, the concentrations found in this cohort were lower than those reported in studies from other countries. Intraclass correlation coefficients (ICCs) were calculated for the compounds found in more than the 35% of the samples, the reliability between trimesters was poor (<0.40) to fair (0.40-0.60). Statistically significant differences were observed for the creatinine adjusted concentrations of the most abundant OP metabolites in these trimesters when examined with the Wilcoxon signed rank test for paired data. In general, no association was found between urinary OP metabolites and most demographic and lifestyle predictors. However, a positive significant association was observed for women with vegetarian diet and for women of higher economic status and eventual consumption of organic food which showed higher PNP concentrations. These results suggest that higher fruit and vegetable consumption may involve higher OP pesticide ingestion but the overall association was weak., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Maternal exposure to toxic and essential trace elements represents a surrogate of exposure to the unborn child. Variables of exposure as sociodemographic, lifestyles and diet may contribute to different exposure of pregnant women to specific trace elements. Blood, urine and cord blood samples of 53 pregnant women of the HEALS-EXHES cohort, recruited in Reus (Catalonia, Spain) between 2016 and 2017, were analysed for the concentrations of As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Se and Zn. Univariate and multivariate models were built in order to assess associations between element concentrations in each matrix, and variables obtained by questionnaires on mothers' characteristics and dietary habits. Results showed several significant associations between various variables and essential trace and toxic elements. Age was associated with higher levels of Cd and Pb in cord blood samples. Multiparous women showed lower levels of Cd in maternal blood and Pb in both maternal and cord blood than nulliparous women. Hispanic mothers presented higher levels of blood As and lower levels of blood Se compared to mothers of different ethnicity. Higher education level was associated with higher As and Hg concentrations in both maternal and cord blood samples. Higher annual income diminished the level of Pb in maternal blood. Smoking in pregnancy incremented the levels of Cd in mothers' blood. Alcohol consumption may affect the absorption of Cu, Mn and Zn. Supplementations with multivitamins, folic acid and iron showed effects on elements as Cr, Mn, Se and Zn. Regarding food group intake, bluefish incremented Pb levels, while canned fish and seafood affected levels of some elements as As, Hg, Cu and Se. Other elements such as Mn and Pb were influenced by the intake of different kinds of foods. The present results showed that some modifiable lifestyles and food intakes could be the target of interventions to help pregnant women to maintain suitable concentrations of essential elements and lower levels of toxic ones, and to improve consequently neonatal health outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose of this study was to assess the impact to human health of air pollutants, through the integration of different technics: data statistics (spatial and temporal trends), population attributable fraction using AIRQ+ model developed by the WHO, and burden of disease using Disability-Adjusted Life Years (DALYs). The levels of SO 2 , NO, NO 2 , O 3 , H 2 S, benzene, PM 10 , PM 2.5 , CO, benzo(a)pyrene and metals, obtained between 2005 and 2017 from the air quality monitoring network across Camp de Tarragona County, were temporally and spatially determined. Health impacts were evaluated using the AIRQ+ model. Finally, the burden of disease was assessed through the calculation of Years of Lost life (YLL) and Years Lost due to Disability (YLD). In general terms, air quality was good according to European quality standards, but it did not fulfil the WHO guidelines, especially for O 3 , PM 10 and PM 2.5 . Several decreasing (NO, NO 2 , SO 2 , PM 10 and benzene) and an increasing (O 3 ) temporal trend were found. Correlation between unemployment rate and air pollutant levels was found, pointing that the economic crisis (2008-2014) was a factor influencing the air pollutant levels. Reduction of air pollutant levels (PM 2.5 ) to WHO guidelines in the Camp de Tarragona County would decrease the adult mortality between 23 and 297 cases per year, which means between 0.5 and 7% of all mortality in the area. In this County, for lung cancer, ischemic heart disease, stroke, and chronic obstructive pulmonary disease due to levels of PM 2.5 above the WHO threshold limits, DAYLs were 240 years. This means around 80 DALYs for 100,000 persons every year -between 2005 and 2017. Population attributable fraction (PAF) and burden of disease (DALYs) methodologies are suitable tools for regional and national policymakers, who must take decisions to prevent and to control air pollution and to analyse the cost-effectiveness of interventions., (Copyright © 2019. Published by Elsevier B.V.)