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The combination of diet, lifestyle, and the exposure to food obesogens categorized into "microbiota disrupting chemicals" (MDC) could determine obesogenic-related dysbiosis and modify the microbiota diversity that impacts on individual health-disease balances, inducing altered pathogenesis phenotypes. Specific, complementary, and combined treatments are needed to face these altered microbial patterns and the specific misbalances triggered. In this sense, searching for next-generation beneficial microbes or next-generation probiotics (NGP) by microbiota culturing, and focusing on their demonstrated, extensive scope and well-defined functions could contribute to counteracting and repairing the effects of obesogens. Therefore, this review presents a perspective through compiling information and key strategies for directed searching and culturing of NGP that could be administered for obesity and endocrine-related dysbiosis by (i) observing the differential abundance of specific microbiota taxa in obesity-related patients and analyzing their functional roles, (ii) developing microbiota-directed strategies for culturing these taxa groups, and (iii) applying the successful compiled criteria from recent NGP clinical studies. New isolated or cultivable microorganisms from healthy gut microbiota specifically related to obesogens' neutralization effects might be used as an NGP single strain or in consortia, both presenting functions and the ability to palliate metabolic-related disorders. Identification of holistic approaches for searching and using potential NGP, key aspects, the bias, gaps, and proposals of solutions are also considered in this review. Yes

Human gut microbiota harbors numerous microbial species with molecular enzymatic potential that impact on the eubiosis/dysbiosis and health/disease balances. Microbiota species isolation and description of their specific molecular features remain largely unexplored. In the present study, we focused on the cultivation and selection of species able to tolerate or biodegrade the endocrine disruptor bisphenol A (BPA), a xenobiotic extensively found in food plastic containers. Chemical xenobiotic addition methods for the directed isolation, culturing, Whole Genome Sequencing (WGS), phylogenomic identification, and specific gene-encoding searches have been applied to isolate microorganisms, assess their BPA metabolization potential, and describe encoded catabolic pathways. BPA-tolerant strains were isolated from 30% of infant fecal microbial culture libraries analyzed. Most isolated strains were phylogenetically related to the operational taxonomic group Bacillus amyloliquefaciens spp. Importantly, WGS analysis of microbial representative strain, Bacillus sp. AM1 identified the four complete molecular pathways involved on BPA degradation indicating its versatility and high potential to degrade BPA. Pathways for Exopolysaccharide (EPS) and Polyhydroxyalkanates (PHA) biopolymer synthesis were also identified and phenotypically confirmed by transmission electronic microscopy (TEM). These microbial biopolymers could generally contribute to capture and/or deposit xenobiotics., GP/EFSA/ENCO/380 2018/03/G04: OBEMIRISK: Knowledge platform for assessing the risk of Bisphenols on gut microbiota and its role in obesogenic phenotype: looking for biomarkers, FEDERInfrastructure: IE_2019-198, APC was funded by EIN-2019-103082

The aim was to evaluate the interactive effects on biochemistry and physiology of soybean plants exposed to simultaneous xenobiotic and water deficit stresses, and the possible attenuation of plant damage by an antioxidant agent. Soybean plants were submitted to eight different soil water potentials, in two experiments (first experiment: &minus, 0.96, &minus, 0.38, &minus, 0.07, &minus, 0.02 MPa, and second experiment: &minus, 3.09, &minus, 1.38, &minus, 0.69, &minus, 0.14 MPa), xenobiotic, and antioxidant agent applications. Was observed a reduction in water status, gas exchange, photosynthetic pigments, photosystem II quantum yield, and increased leaf temperature in plants under low water availability. Water deficit also induced oxidative stress by the increased production of reactive oxygen species, cellular and molecular damage, and induction of the antioxidant defense metabolism, reduction of gas exchange, water status, and photosynthetic efficiency. The xenobiotic application also caused changes, with deleterious effects more pronounced in low soil water availability, mainly the reactive oxygen species production, consequently the antioxidant activity, and the oxidative damages. This indicates different responses to the combination of stresses. Antioxidant enzyme activity was reduced by the application of the antioxidant agent. Principal Component Analysis showed a relation with the antioxidant agent and reactive oxygen species, which is probably due to signaling function, and with defense antioxidant system, mainly glutathione, represented by thiols.

Blending amphiphilic copolymers and lipids constitutes a novel approach to combine the advantages of polymersomes and liposomes into a new single hybrid membrane. Efforts have been made to design stimuli-responsive vesicles, in which the membrane&rsquo, s dynamic is modulated by specific triggers. In this investigation, we proposed the design of pH-responsive hybrid vesicles formulated with poly(dimethylsiloxane)-block-poly(ethylene oxide) backbone (PDMS36-b-PEO23) and cationic switchable lipid (CSL). The latter undergoes a pH-triggered conformational change and induces membrane destabilization. Using confocal imaging and DLS measurements, we interrogated the structural changes in CSL-doped lipid and hybrid polymer/lipid unilamellar vesicles at the micro- and nanometric scale, respectively. Both switchable giant unilamellar lipid vesicles (GUV) and hybrid polymer/lipid unilamellar vesicles (GHUV) presented dynamic morphological changes, including protrusions and fission upon acidification. At the submicron scale, scattered intensity decreased for both switchable large unilamellar vesicles (LUV) and hybrid vesicles (LHUV) under acidic pH. Finally, monitoring the fluorescence leakage of encapsulated calcein, we attested that CSL increased the permeability of GUV and GHUV in a pH-specific fashion. Altogether, these results show that switchable lipids provide a pH-sensitive behavior to hybrid polymer/lipid vesicles that could be exploited for the triggered release of drugs, cell biomimicry studies, or as bioinspired micro/nanoreactors.

The main goal of this work is the study of the skin wound healing efficacy of an antioxidant cocktail consisting of vitamins A, D, E and the endogenous pineal hormone melatonin (MLT), with all of these loaded into a thermosensitive hydrogel delivery system. The resulting formulation was characterized by scanning electron microscopy. The antioxidant efficacy and microbiological activity against Gram positive and Gram negative strains were also assayed. The skin healing efficacy was tested using an in vivo model which included histological evaluation. Furthermore, atomic force microscopy was employed to evaluate the wound healing efficacy of rat skin burns through the determination of its elasticity at the nanoscale using force spectroscopy analysis. The resulting hydrogel exhibited sol state at low temperature and turned into a gel at 30 &plusmn, 0.2 &deg, C. The hydrogel containing the antioxidant cocktail showed higher scavenging activity than the hydrogel containing vitamins or MLT, separately. The formulation showed optimal antimicrobial activity. It was comparable to a commercial reference. It was also evidenced that the hydrogel containing the antioxidant cocktail exhibited the strongest healing process in the skin burns of rats, similar to the assayed commercial reference containing silver sulfadiazine. Histological studies confirmed the observed results. Finally, atomic force microscopy demonstrated a similar distribution of Young&rsquo, s modulus values between burned skin treated with the commercial reference and burned skin treated with hydrogel containing the antioxidant cocktail, and all these with healthy skin. The use of an antioxidant cocktail of vitamins and MLT might be a promising treatment for skin wounds for future clinical studies.

The present study investigated Staphylococcus aureus ATCC25923 surfaceomes (cell surface proteins) during prolonged growth by subjecting planktonic and biofilm cultures (initiated from exponential or stationary cells) to label-free quantitative surfaceomics and phenotypic confirmations. The abundance of adhesion, autolytic, hemolytic, and lipolytic proteins decreased over time in both growth modes, while an opposite trend was detected for many tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) scavenging, Fe-S repair, and peptidolytic moonlighters. In planktonic cells, these changes were accompanied by decreasing and increasing adherence to hydrophobic surface and fibronectin, respectively. Specific RNA/DNA binding (cold-shock protein CspD and ribosomal proteins) and the immune evasion (SpA, ClfA, and IsaB) proteins were notably more abundant on fully mature biofilms initiated with stationary-phase cells (SDBF) compared to biofilms derived from exponential cells (EDBF) or equivalent planktonic cells. The fully matured SDBF cells demonstrated higher viability in THP-1 monocyte/macrophage cells compared to the EDBF cells. Peptidoglycan strengthening, specific urea-cycle, and detoxification enzymes were more abundant on planktonic than biofilm cells, indicating the activation of growth-mode specific pathways during prolonged cultivation. Thus, we show that S. aureus shapes its surfaceome in a growth mode-dependent manner to reach high levofloxacin tolerance (&gt, 200-times the minimum biofilm inhibitory concentration). This study also demonstrates that the phenotypic state of the cells prior to biofilm formation affects the immune-evasion and persistence-related traits of S. aureus.

Background: Internationally, midwives’ professional autonomy is being challenged, resulting in their inability to practice to their full scope of practice. This situation contrasts with the increasing international calls for strengthening the midwifery profession. The aim of this study therefore is to explore Belgian midwives’ views on their current and future autonomy. Methods: An online survey among Belgian midwives was performed. Data were collected and analyzed using a quantitative approach, while quotes from respondents were used to contextualize the quantitative data. Results: Three hundred and twelve midwives from different regions and professional settings in Belgium completed the questionnaire. Eighty-five percentage of respondents believe that they are mostly or completely autonomous. Brussels’ midwives feel the most autonomous, while those in Wallonia feel the least. Primary care midwives feel more autonomous than hospital-based midwives. Older midwives and primary care midwives feel less recognized and respected by other professionals in maternity care. The majority of our respondents believe that in future midwives should be able to work more autonomously in constructive collaboration with other professionals. Conclusion: While Belgian midwives generally rated their own professional autonomy as high, a significant majority of respondents desire more autonomy in future. In addition, our respondents want to be recognized and respected by society and other health professionals in maternity care. It is recommended to prioritize efforts in enhancing midwives’ autonomy, while also addressing the need for increased recognition and respect from society and other maternity care professionals.

Advancement towards the professionalism of midwifery is closely linked to midwives’ professional autonomy. Although the perspectives of Belgian midwives on their professional autonomy have been studied, the views of other maternity care stakeholders are a blind spot. The aim of this study, therefore, was to explore maternity care stakeholders’ views on Belgian midwives’ professional autonomy. A qualitative exploratory study was performed using focus group interviews. A heterogenous group of 27 maternity care stakeholders participated. The variation between midwives, with different levels of autonomy, was reported. The analysis of the data resulted in five themes: (1) The autonomous midwife is adequately educated and committed to continuous professional further education, (2) The autonomous midwife is competent, (3) The autonomous midwife is experienced, (4) The autonomous midwife assures safe and qualitative care, and (5) The autonomous midwife collaborates with all stakeholders in maternity care. A maternity collaborative framework, where all maternity care professionals respect each other’s competences and autonomy, is crucial for providing safe and quality care. To achieve this, it is recommended to implement interprofessional education to establish strong foundations for interprofessional collaboration. Additionally, a regulatory body with supervisory powers can help ensure safe and quality care, while also supporting midwives’ professional autonomy and professionalisation.

Background: The lack of thermally and mechanically performant biomaterials represents the major limit for 3D-printed surgical guides, aimed at facilitating complex surgery and ablations. Methods: Cryosurgery is a treatment for cardiac arrhythmias. It consists of obtaining cryolesions, by freezing the target tissue, resulting in selective and irreversible damage. MED625FLX and TPU95A are two biocompatible materials for surgical guides; however, there are no data on their response to cryoenergy delivery. The study purpose is to evaluate the biomaterials' thermal properties, examining the temperature changes on the porcine muscle samples (PMS) when the biomaterials are in place during the cryoablation. Two biomaterials were selected, MED625FLX and TPU95A, with two thicknesses (1.0 and 2.5 mm). To analyze the biomaterials' behavior, the PMS temperatures were measured during cryoablation, firstly without biomaterials (control) and after with the biomaterials in place. To verify the biomaterials' suitability, the temperatures under the biomaterial samples should not exceed a limit of -30.0 °C. Furthermore, the biomaterials' geometry after cryoablation was evaluated using the grid paper test. Results: TPU95A (1.0 and 2.5 mm) successfully passed all tests, making this material suitable for cryoablation treatment. MED625FLX of 1.0 mm did not retain its shape, losing its function according to the grid paper test. Further, MED625FLX of 2.5 mm is also suitable for use with a cryoenergy source. Conclusions: TPU95A (1.0 and 2.5 mm) and MED625FLX of 2.5 mm could be used in the design of surgical guides for cryoablation treatment, because of their mechanical, geometrical, and thermal properties. The positive results from the thermal tests on these materials and their thickness prompt further clinical investigation. ispartof: JOURNAL OF CLINICAL MEDICINE vol:12 issue:3 ispartof: location:Switzerland status: published

The current study evaluated the feasibility and preliminary clinical impact of robot-led distraction during needle procedures in children with chronic diseases on pain-related memories. Participants were 22 children (8–12 years old) diagnosed with a chronic disease (e.g., chronic immune deficiency) and undergoing a needle procedure as part of their routine treatment. Children were randomized to the experimental group (i.e., robot-led distraction) or control group (i.e., usual care). For feasibility, we evaluated study- and needle-procedure-related characteristics, intervention fidelity and acceptability, and nurse perceptions of the intervention. Primary clinical outcomes included children’s memory bias for pain intensity and pain-related fear (1 week later). Results indicated that intervention components were >90% successful. Overall, the robot-led distraction intervention was perceived highly acceptable by the children, while nurse perceptions were mixed, indicating several challenges regarding the intervention. Preliminary between-group analyses indicated a medium effect size on memory bias for pain intensity (Hedges’ g = 0.70), but only a very small effect size on memory bias for pain-related fear (Hedges’ g = 0.09), in favor of the robot-led distraction intervention. To summarize, while feasible, certain challenges remain to clinically implement robot-led distraction during needle procedures. Further development of the intervention while accounting for individual child preferences is recommended.

Electrical isolation of pulmonary veins (PVI) is the cornerstone of invasive treatment of atrial fibrillation (AF). However, arrhythmia-free survival of a PVI only approach is suboptimal in patients with persistent and long-term persistent AF. Hybrid AF ablation has been developed with the aim of combining the advantages of a thoracoscopic surgical ablation (direct visualization of anatomical structures to be spared and the possibility to perform epicardial lesions) and endocardial ablation (possibility to check line block, confirm PVI, and possibility to perform cavotricuspid isthmus ablation). Patient selection is of utmost importance. In persistent and long-term persistent AF, hybrid AF ablation demonstrated promising results in terms of AF free survival. It has been associated with a relatively low complication rate if performed in centers with expertise in hybrid procedures and experience with both surgical and endocardial ablation. Different techniques have been described, with different approaches and lesion sets. The aim of this review is to provide a state-of-the-art overview of hybrid AF ablation.

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival. We identified all patients with advanced melanoma who were treated with Pembrolizumab in our medical center and underwent a baseline and at least one follow-up FDG-PET/CT. The total metabolic tumor volume (TMTV) was calculated, and the evolution was compared to survival parameters. A total of 77 patients underwent a baseline and at least one follow-up FDG-PET/CT, 36 patients had follow-up imaging within 2–4 months, and 21 patients an FDG-PET/CT 5–6 months after baseline. When the TMTV evolution was categorized into two subgroups (stable/decrease versus increase), an association was found between stability or decrease in TMTV and better PFS and OS. A similar trend, however non-significant, was observed at 5–6 months. The evolution in TMTV as assessed by FDG-PET/CT 2–4 months after treatment initiation is associated with long-term outcomes in patients with advanced melanoma treated with Pembrolizumab.

Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that allow for the direct sampling from the cerebral interstitial space. This review concerns the applicability of microdialysis and other approaches, such as cerebral open flow microperfusion and electrochemical biosensors, to monitor macromolecules (neuropeptides, proteins, …) in the brain. Microdialysis and cerebral open flow microperfusion can also be used to locally apply molecules at the same time at the site of sampling. Innovations in the field are discussed, together with the pitfalls. Moreover, the ‘nuts and bolts’ of the techniques and the current research gaps are addressed. The implementation of these techniques could help to improve drug development of brain-targeted drugs.

Patient-specific three-dimensional (3D) printed models have been increasingly used in many medical fields, including cardiac surgery for which they are used as planning and communication tools. To locate and plan the correct region of interest for the bypass placement during coronary artery bypass graft (CABG) surgery, cardiac surgeons can pre-operatively rely on different medical images. This article aims to present a workflow for the production of a patient-specific 3D-printed surgical guide, from data acquisition and image segmentation to final prototyping. The aim of this surgical guide is to help visualize the region of interest for bypass placement during the operation, through the use of dedicated surgical holes. The results showed the feasibility of this surgical guide in terms of design and fitting to the phantom. Further studies are needed to assess material biocompatibility and technical properties. ispartof: BIOENGINEERING-BASEL vol:9 issue:5 ispartof: location:Switzerland status: published

The aim of this study was to explore the underlying age-related differences in dynamic motor control during different step ascent conditions using muscle synergy analysis. Eleven older women (67.0 y &plusmn, 2.5) and ten young women (22.5 y &plusmn, 1.6) performed stepping in forward and lateral directions at step heights of 10, 20 and 30 cm. Surface electromyography was obtained from 10 lower limb and torso muscles. Non-negative matrix factorization was used to identify sets of (n) synergies across age groups and stepping conditions. In addition, variance accounted for (VAF) by the detected number of synergies was compared to assess complexity of motor control. Finally, correlation coefficients of muscle weightings and between-subject variability of the temporal activation patterns were calculated and compared between age groups and stepping conditions. Four synergies accounted for &gt, 85% VAF across age groups and stepping conditions. Age and step height showed a significant negative correlation with VAF during forward stepping but not lateral stepping, with lower VAF indicating higher synergy complexity. Muscle weightings showed higher similarity across step heights in older compared to young women. Neuromuscular control of young and community-dwelling older women could not be differentiated based on the number of synergies extracted. Additional analyses of synergy structure and complexity revealed subtle age- and step-height-related differences, indicating that older women rely on more complex neuromuscular control strategies.

From early 2020, a high demand for SARS-CoV-2 tests was driven by several testing indications, including asymptomatic cases, resulting in the massive roll-out of PCR assays to combat the pandemic. Considering the dynamic of viral shedding during the course of infection, the demand to report cycle threshold (Ct) values rapidly emerged. As Ct values can be affected by a number of factors, we considered that harmonization of semi-quantitative PCR results across laboratories would avoid potential divergent interpretations, particularly in the absence of clinical or serological information. A proposal to harmonize reporting of test results was drafted by the National Reference Centre (NRC) UZ/KU Leuven, distinguishing four categories of positivity based on RNA copies/mL. Pre-quantified control material was shipped to 124 laboratories with instructions to setup a standard curve to define thresholds per assay. For each assay, the mean Ct value and corresponding standard deviation was calculated per target gene, for the three concentrations (10(7), 10(5) and 10(3) copies/mL) that determine the classification. The results of 17 assays are summarized. This harmonization effort allowed to ensure that all Belgian laboratories would report positive PCR results in the same semi-quantitative manner to clinicians and to the national database which feeds contact tracing interventions. UZ/KU Leuven: as National Reference Center for Respiratory Pathogens, is supported by Sciensano, which is gratefully acknowledged. We would like to acknowledge additional staff members of the participating laboratories that contributed to this study: Jean-Luc Gala, Benoit Kabamba, Elsa Wiam, Valentin Coste, Paul Blanpain, Jean Ruelle, Ari Serbetciyan, Nicolas Pinte, Ophélie Simon and the entire UCLouvain federal testing platform COVID-19 team (all affiliation 4), Aurore Demars (affiliation 7), Laura Vanden Daele (affiliation 9), Hanne Valgaeren (affiliation 22), Guillaume Bayon-Vicente (affiliation 23), Fabrice Bureau, Claire Gourzonès and Joey Schyns (affiliation 28), Stéphanie Evrard (affiliation 42), Clara Ceyssens (affiliation 58), Jorn Hellemans (affiliation 77), Bram Slechten (affiliation 86) and the entire team of the laboratory of microbiology of UZA (affiliation 89) and of the UZA Federal testing platform COVID-19 (affiliation 85) for their boundless dedication.

Halophiles, the salt-loving organisms, have been investigated for at least a hundred years. They are found in all three domains of life, namely Archaea, Bacteria, and Eukarya, and occur in saline and hypersaline environments worldwide. They are already a valuable source of various biomolecules for biotechnological, pharmaceutical, cosmetological and industrial applications. In the present era of multidrug-resistant bacteria, cancer expansion, and extreme environmental pollution, the demand for new, effective compounds is higher and more urgent than ever before. Thus, the unique metabolism of halophilic microorganisms, their low nutritional requirements and their ability to adapt to harsh conditions (high salinity, high pressure and UV radiation, low oxygen concentration, hydrophobic conditions, extreme temperatures and pH, toxic compounds and heavy metals) make them promising candidates as a fruitful source of bioactive compounds. The main aim of this review is to highlight the nucleic acid sequencing experimental strategies used in halophile studies in concert with the presentation of recent examples of bioproducts and functions discovered in silico in the halophile’s genomes. We point out methodological gaps and solutions based on in silico methods that are helpful in the identification of valuable bioproducts synthesized by halophiles. We also show the potential of an increasing number of publicly available genomic and metagenomic data for halophilic organisms that can be analysed to identify such new bioproducts and their producers. Publication’s printing cost was co-financed by the European Union from the European Social Fund under the "InterDOC-STARt" project (POWR.03.02.00-00-I033/16-00).

Dynamic computer tomography (CT) is an emerging modality to analyze in-vivo joint kinematics at the bone level, but it requires manual bone segmentation and, in some instances, landmark identification. The objective of this study is to present an automated workflow for the assessment of three-dimensional in vivo joint kinematics from dynamic musculoskeletal CT images. The proposed method relies on a multi-atlas, multi-label segmentation and landmark propagation framework to extract bony structures and detect anatomical landmarks on the CT dataset. The segmented structures serve as regions of interest for the subsequent motion estimation across the dynamic sequence. The landmarks are propagated across the dynamic sequence for the construction of bone embedded reference frames from which kinematic parameters are estimated. We applied our workflow on dynamic CT images obtained from 15 healthy subjects on two different joints: thumb base (n = 5) and knee (n = 10). The proposed method resulted in segmentation accuracies of 0.90 ± 0.01 for the thumb dataset and 0.94 ± 0.02 for the knee as measured by the Dice score coefficient. In terms of motion estimation, mean differences in cardan angles between the automated algorithm and manual segmentation, and landmark identification performed by an expert were below 1°. Intraclass correlation (ICC) between cardan angles from the algorithm and results from expert manual landmarks ranged from 0.72 to 0.99 for all joints across all axes. The proposed automated method resulted in reproducible and reliable measurements, enabling the assessment of joint kinematics using 4DCT in clinical routine.

Simple Summary Liver cancer and tumours spreading from other organs to the liver are associated with high death rates. Current treatments include surgical removal of the tumour and chemotherapy. Unfortunately, patients are often re-diagnosed with liver nodules in the years after cessation of the treatment. Therefore, scientists are looking for alternative treatment strategies, and these include targeting the tumour environment. The tumour environment includes the cancer-associated fibroblasts, which could be an interesting target for therapy in combination with current strategies. In this review paper we summarize the current models to investigate the effect of the tumour on the cancer-associated fibroblasts. Not many studies focus on the cancer-associated fibroblasts in non-animal models and this should improve in order to better understand the role of the cancer-associated fibroblasts and to evaluate the potential of cancer-associated fibroblast-directed therapies. Abstract Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models.

Metabolomics has achieved great progress over the last 20 years, and it is currently considered a mature research field. As a result, the number of applications in toxicology, biomarker, and drug discovery has also increased. Toxicometabolomics has emerged as a powerful strategy to provide complementary information to study molecular-level toxic effects, which can be combined with a wide range of toxicological assessments and models. The zebrafish model has gained importance in recent decades as a bridging tool between in vitro assays and mammalian in vivo studies in the field of toxicology. Furthermore, as this vertebrate model is a low-cost system and features highly conserved metabolic pathways found in humans and mammalian models, it is a promising tool for toxicometabolomics. This short review aims to introduce zebrafish researchers interested in understanding the effects of chemical exposure using metabolomics to the challenges and possibilities of the field, with a special focus on toxicometabolomics-based mass spectrometry. The overall goal is to provide insights into analytical strategies to generate and identify high-quality metabolomic experiments focusing on quality management systems (QMS) and the importance of data reporting and sharing.

Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors. Yes

One of the most debilitating consequences of aging is the progressive decline in immune function, known as immunosenescence. This phenomenon is characterized by a shift in T-cell pheno-types, with a manifest decrease of naive T-cells—dealing with newly encountered antigens—and a concomitant accumulation of senescent and regulatory T-cells, leading to a greater risk of morbidity and mortality in older subjects. Additionally, with aging, several studies have unequivocally revealed an increase in the prevalence of onchocerciasis infection. Most lymphatic complications, skin and eye lesions due to onchocerciasis are more frequent among the elderly population. While the reasons for increased susceptibility to onchocerciasis with age are likely to be multi-factorial, age-associated immune dysfunction could play a key role in the onset and progression of the disease. On the other hand, there is a growing consensus that infection with onchocerciasis may evoke deleterious effects on the host’s immunity and exacerbate immune dysfunction. Indeed, Onchocerca volvulus has been reported to counteract the immune responses of the host through molecular mimicry by impairing T-cell activation and interfering with the processing of antigens. Moreover, reports indicate impaired cellular and humoral immune responses even to non-parasite antigens in onchocerciasis patients. This diminished protective response may intensify the immunosenescence outcomes, with a consequent vulnerability of those affected to additional diseases. Taken together, this review is aimed at contributing to a better understanding of the immunological and potential pathological mechanisms of onchocerciasis in the older population., SCOPUS: re.j, info:eu-repo/semantics/published

Periodontal disease encompasses gingivitis and periodontitis and is one of the most common chronic infections in the adult population. This study aimed to evaluate the influence of Spanish propolis extract (EEP) on the effect of the clinical and microbiological parameters as an adjuvant to scaling and root planning in patients undergoing supportive periodontal therapy (SPT). Forty chronic periodontitis patients were randomly assigned into two groups for the treatment. In the control group (n = 20), the sites were treated by scaling and root planing followed by gingival irrigation with physiological saline and in the test group (n = 20), the sites were treated by scaling and root planing followed by subgingival placement of EEP. At baseline (BL), bleeding on probing positive (BOP+) sites with probing pocket (PPD) ≥ 4 mm were defined as study sites. Plaque index, PPD, BOP, clinical attachment level (CAL), and subgingival plaque were evaluated at BL and 1 month later. The results showed a significant clinical improvement (p &lt, 0.05) in the PPD, CAL and BOP+ comparing them with BL and one month after the periodontal treatment and a significant reduction (p &lt, 0.05) for Tannerella forsythensis, Porphyromonas gingivalis, Prevotella intermedia and Treponema denticola in both groups. In addition, the improvement of clinical parameters was observed with subgingival use of EEP and also statistically significant differences between groups were observed (p &lt, 0.05) such as reductions of BOP+ % and reduced counts of T. forsythensis and P. gingivalis, considered as the “key pathogens” for the periodontal diseases. Our results suggest prophylactic and therapeutic potential for EEP against periodontal diseases, improving clinical parameters, reducing gingival bleeding and decreasing bacterial counts of T. forsythensis and P. gingivalis. The subgingival use of EEP represents a promising modality as an adjuvant in periodontal therapy to avoid microbial resistance and other adverse effects.

Pandemics impose an immense psychological burden on healthcare workers due to a combination of workplace stressors and personal fears. Nurses and auxiliary nursing care technicians (ANCTs) are on the front line of this pandemic and form the largest group in healthcare practice. The aim of this study is to determine the symptoms of depression and/or anxiety among nurses and ANCTs during the periods known as the first wave (March–June) and second wave (September–November) of theCOVID-19 pandemic in Spain. An observational cross-sectional study was carried out using an anonymous, self-administered questionnaire among nurses and ANCTs practising in Spain. During the first period, 68.3% and 49.6% of the subjects presented anxiety and depression, respectively, decreasing in the second period (49.5% for anxiety and 35.1% for depression). There were statistically significant differences between the different categories and periods (p &lt, 0.001). The COVID-19 pandemic has negatively influenced mental health in nurses and ANCTs. Mental health should be monitored and coping strategies promoted to improve the health, productivity and efficiency of these professionals.

Recently, the International Association for the Study of Pain (IASP) released clinical criteria and a grading system for nociplastic pain affecting the musculoskeletal system. These criteria replaced the 2014 clinical criteria for predominant central sensitization (CS) pain and accounted for clinicians’ need to identify (early) and correctly classify patients having chronic pain according to the pain phenotype. Still, clinicians and researchers can become confused by the multitude of terms and the variety of clinical criteria available. Therefore, this paper aims at (1) providing an overview of what preceded the IASP criteria for nociplastic pain (‘the past’); (2) explaining the new IASP criteria for nociplastic pain in comparison with the 2014 clinical criteria for predominant CS pain (‘the present’); and (3) highlighting key areas for future implementation and research work in this area (‘the future’). It is explained that the 2021 IASP clinical criteria for nociplastic pain are in line with the 2014 clinical criteria for predominant CS pain but are more robust, comprehensive, better developed and hold more potential. Therefore, the 2021 IASP clinical criteria for nociplastic pain are important steps towards precision pain medicine, yet studies examining the clinimetric and psychometric properties of the criteria are urgently needed.

During the preparation of [68Ga]Ga-NOTA-sdAb at high activity, degradation of the tracers was observed, impacting the radiochemical purity (RCP). Increasing starting activities in radiolabelings is often paired with increased degradation of the tracer due to the formation of free radical species, a process known as radiolysis. Radical scavengers and antioxidants can act as radioprotectant due to their fast interaction with formed radicals and can therefore reduce the degree of radiolysis. This study aims to optimize a formulation to prevent radiolysis during the labeling of NOTA derivatized single domain antibody (sdAbs) with 68Ga. Gentisic acid, ascorbic acid, ethanol and polyvinylpyrrolidone were tested individually or in combination to find an optimal mix able to prevent radiolysis without adversely influencing the radiochemical purity (RCP) or the functionality of the tracer. RCP and degree of radiolysis were assessed via thin layer chromatography and size exclusion chromatography for up to three hours after radiolabeling. Individually, the radioprotectants showed insufficient efficacy in reducing radiolysis when using high activities of 68Ga, while being limited in amount due to negative impact on radiolabeling of the tracer. A combination of 20% ethanol (VEtOH/VBuffer%) and 5 mg ascorbic acid proved successful in preventing radiolysis during labeling with starting activities up to 1–1.2 GBq of 68Ga, and is able to keep the tracer stable for up to at least 3 h after labeling at room temperature. The prevention of radiolysis by the combination of ethanol and ascorbic acid potentially allows radiolabeling compatibility of NOTA-sdAbs with all currently available 68Ge/68Ga generators. Additionally, a design is proposed to allow the incorporation of the radioprotectant in an ongoing diagnostic kit development for 68Ga labeling of NOTA-sdAbs.

Colistin; Phramacokinetic; Technique of nebulization Colistina; Farmacocinètica; Tècnica de nebulització Colistina; Farmacocinético; Técnica de nebulización Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis. This research received no external funding.

The use of probiotics in reproductive-related dysbiosis is an area of continuous progress due to the growing interest from clinicians and patients suffering from recurrent reproductive microbiota disorders. An imbalance in the natural colonization sites related to reproductive health-vaginal, cervicovaginal, endometrial, and pregnancy-related altered microbiota-could play a decisive role in reproductive outcomes. Oral and vaginal administrations are in continuous discussion regarding the clinical effects pursued, but the oral route is used and studied more often despite the need for further transference to the colonization site. The aim of the present review was to retrieve the standardized protocols of vaginal probiotics commonly used for investigating their microbiota modulation capacities. Most of the studies selected focused on treating bacterial vaginosis (BV) as the most common dysbiosis; a few studies focused on vulvovaginal candidiasis (VVC) and on pretreatment during in vitro fertilization (IVF). Vaginal probiotic doses administered were similar to oral probiotics protocols, ranging from ≥107 CFU/day to 2.5 × 1010 CFU/day, but were highly variable regarding the treatment duration timing. Moderate vaginal microbiota modulation was achieved; the relative abundance of abnormal microbiota decreased and Lactobacillus species increased. Yes

Neonatal hypoxia-ischemia (HI) is a brain injury caused by oxygen deprivation to the brain due to birth asphyxia or reduced cerebral blood perfusion, and it often leads to lifelong limiting sequelae such as cerebral palsy, seizures, or mental retardation. HI remains one of the leading causes of neonatal mortality and morbidity worldwide, and current therapies are limited. Hypothermia has been successful in reducing mortality and some disabilities, but it is only applied to a subset of newborns that meet strict inclusion criteria. Given the unpredictable nature of the obstetric complications that contribute to neonatal HI, prophylactic treatments that prevent, rather than rescue, HI brain injury are emerging as a therapeutic alternative. Nutraceuticals are natural compounds present in the diet or used as dietary supplements that have antioxidant, anti-inflammatory, or antiapoptotic properties. This review summarizes the preclinical in vivo studies, mostly conducted on rodent models, that have investigated the neuroprotective properties of nutraceuticals in preventing and reducing HI-induced brain damage and cognitive impairments. The natural products reviewed include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate). These nutraceuticals were administered before the damage occurred, either to the mothers as a dietary supplement during pregnancy and/or lactation or to the pups prior to HI induction. To date, very few of these nutritional interventions have been investigated in humans, but we refer to those that have been successful in reducing ischemic stroke in adults. Overall, there is a robust body of preclinical evidence that supports the neuroprotective properties of nutraceuticals, and these may represent a safe and inexpensive nutritional strategy for the prevention of neonatal HI encephalopathy. Yes

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment., Instituto de Salud Carlos III PI17/00989, European Regional Development Fund "A way to build Europe", Ramon y Cajal - Ministry of Economy and Competitiveness RYC-2015-18382, Ministry of Education, Culture and Sport FPU14/05461, University of Granada

Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass of cell plasma membrane proteins enabling the exchange of molecules and ions between the extracellular environment and the cytosol. A plethora of human pathologies are associated with the altered expression or dysfunction of cell plasma membrane transport proteins, making them interesting therapeutic drug targets. However, the search for therapeutics is challenging, since many drug candidates targeting cell plasma membrane proteins fail in (pre)clinical testing due to inadequate selectivity, specificity, potency or stability. These latter characteristics are met by nanobodies, which potentially renders them eligible therapeutics targeting cell plasma membrane proteins. Therefore, a therapeutic nanobody-based strategy seems a valid approach to target and modulate the activity of cell plasma membrane transport proteins. This review paper focuses on methodologies to generate cell plasma membrane transport protein-targeting nanobodies, and the advantages and pitfalls while generating these small antibody-derivatives, and discusses several therapeutic nanobodies directed towards transmembrane proteins, including channels and pores, adenosine triphosphate-powered pumps and porters.

Given the widespread use of bisphenols and parabens in consumer products, the assessment of their intake is crucial and represents the first step towards the assessment of the potential risks that these compounds may pose to human health. In the present study, a total of 98 samples of food items commonly consumed by the Spanish population were collected from different national supermarkets and grocery stores for the determination of parabens and bisphenols. Our analysis demonstrated that 56 of the 98 food samples contained detectable levels of parabens with limits of quantification (LOQ) between 0.4 and 0.9 ng g&minus, 1. The total concentration of parabens (sum of four parabens: &sum, parabens) ranged from below the LOQ to 281.7 ng g&minus, 1, with a mean value of 73.86 ng g⁻1. A total of 52% of the samples showed detectable concentrations of bisphenols. Bisphenol A (BPA) was the most frequently detected bisphenol in the food samples analysed, followed by bisphenol S (BPS) and bisphenol E (BPE). Bisphenol AF (BPAF), bisphenol B (BPB) and bisphenol P (BPP) were not found in any of the analysed samples. LOQ for these bisphenols were between 0.4 and 4.0 ng g&minus, 1.

Obesogenic endocrine-disrupting chemicals, such as bisphenol A (BPA) and its analogue bisphenol S (BPS), seem to play an important role in the development of obesity, although contradictory results have been reported. The aim of the present study was to conduct a gender analysis of the factors associated with exposure to dietary bisphenols in 585 Spanish adolescents. Dietary BPA and BPS exposure was assessed using a food frequency questionnaire. Foods and macronutrients accounting for more than 95% of energy intake were selected for analysis. Stepwise regression was used to estimate the foods that most contributed to dietary bisphenol exposure in the sample. Gender-related factors associated with greater dietary bisphenol exposure were evaluated using multivariate logistic regression models. Canned tuna was the main dietary source of BPA and BPS in both adolescent boys and girls. Overweight/obese girls showed a higher risk of high dietary exposure to BPA (odds ratio (OR): 3.38, 95% confidence interval (CI): 1.25–9.07) and total bisphenols (OR: 2.81, 95% CI: 1.03–7.67) in comparison with girls with a BMI lower than 25 kg/m2 . Present results indicate a positive association of dietary exposure to both total bisphenols and BPA with being overweight/obese in adolescent girls., GP/EFSA/ENCO/380 2018/03/G04: OBEMIRISK: Knowledge platform for assessing the risk of bisphenol on gut microbiota and its role in obesogenic phenotypes: looking for biomarkers’ framework, Plan Estatal de I + D + I 2013–2016, FEDER-ISCIII PI17/01758, FEDER-Consejería de Salud y Familias, Junta de Andalucía PE-0250–2019, FEDER-Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades/ Proyecto P18-RT-4247, Fundación Mapfre MAPFRE2018

Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system. Yes

Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its intro-duction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of down-stream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal., SCOPUS: ar.j, info:eu-repo/semantics/published

Despite the proven clinical value of spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS), factors related to a successful SCS outcome are not yet clearly understood. This study aimed to predict responders for high frequency SCS at 10 kHz (HF-10). Data before implantation and the last available data was extracted for 119 FBSS patients treated with HF-10 SCS. Correlations, logistic regression, linear discriminant analysis, classification and regression trees, random forest, bagging, and boosting were applied. Based on feature selection, trial pain relief, predominant pain location, and the number of previous surgeries were relevant factors for predicting pain relief. To predict responders with 50% pain relief, 58.33% accuracy was obtained with boosting, random forest and bagging. For predicting responders with 30% pain relief, 70.83% accuracy was obtained using logistic regression, linear discriminant analysis, boosting, and classification trees. For predicting pain medication decrease, accuracies above 80% were obtained using logistic regression and linear discriminant analysis. Several machine learning techniques were able to predict responders to HF-10 SCS with an acceptable accuracy. However, none of the techniques revealed a high accuracy. The inconsistent results regarding predictive factors in literature, combined with acceptable accuracy of the currently obtained models, might suggest that routinely collected baseline parameters from clinical practice are not sufficient to consistently predict the SCS response with a high accuracy in the long-term.

Immune checkpoints, such as programmed death-ligand 1 (PD-L1), limit T-cell function and tumor cells use this ligand to escape the anti-tumor immune response. Treatments with monoclonal antibodies blocking these checkpoints have shown long-lasting responses, but only in a subset of patients. This study aims to develop a Nanobody (Nb)-based probe in order to assess human PD-L1 (hPD-L1) expression using positron emission tomography imaging, and to compare the influence of two different radiolabeling strategies, since the Nb has a lysine in its complementarity determining region (CDR), which may impact its affinity upon functionalization. The Nb has been conjugated with the NOTA chelator site-specifically via the Sortase-A enzyme or randomly on its lysines. [68Ga]Ga-NOTA-(hPD-L1) Nbs were obtained in &gt, 95% radiochemical purity. In vivo tumor targeting studies at 1 h 20 post-injection revealed specific tumor uptake of 1.89 &plusmn, 0.40%IA/g for the site-specific conjugate, 1.77 &plusmn, 0.29%IA/g for the random conjugate, no nonspecific organ targeting, and excretion via the kidneys and bladder. Both strategies allowed for easily obtaining 68Ga-labeled hPD-L1 Nbs in high yields. The two conjugates were stable and showed excellent in vivo targeting. Moreover, we proved that the random lysine-conjugation is a valid strategy for clinical translation of the hPD-L1 Nb, despite the lysine present in the CDR.

Mothers who underwent bariatric surgery (BS) before pregnancy have worrisome eating habits, but little is known about the eating habits of their offspring. EFFECTOR is a cross-sectional, long-term follow-up study of 4&ndash, 11-year-old children born from mothers that underwent bariatric surgery before pregnancy (n = 36), mothers with overweight/obesity (OW/OB) in a control group (n = 71), and mothers with a normal weight (NW) in a second control group (n = 35). Data on anthropometry and on eating habits obtained through a Food Frequency Questionnaire were collected prospectively. The children&rsquo, s body mass index (BMI) scores significantly correlated with maternal pre-pregnancy BMI. The prevalence of overweight and obesity was the highest in children of the BS group (38.9% vs. 15.5% for children of the OW/OB group and 5.7% for those of the NW group, p = 0.004). Meal-skipping behavior was comparable between the groups. There was no difference in fruit and vegetable consumption. The BS group consumed more low-calorie sweetened beverages compared to the NW group (p = 0.01) but less fruit juice compared to the NW and OW/OB groups (p = 0.01). Our results may indicate a sugar-avoiding behavior in children of the BS group, fitting dietary maternal habits in a strategy to prevent dumping syndrome. In conclusion, maternal pre-pregnancy bariatric surgery does not alter unhealthy eating behaviors and the risk of development of overweight during childhood in their children.

The enormity of the public health burden of onchocerciasis motivated the creation of various large-scale control programs that have depended principally on mass treatment of endemic communities with ivermectin for the elimination of the disease. Parasitological evaluation of Onchocerca species in the West Region of Cameroon indicates significant progress in the interruption of parasite transmission in some communities under ivermectin treatment. However, to verify the complete elimination of onchocerciasis, entomological assessment through O-150 PCR poolscreen of black flies is mandatory. Thus, in the present study, we assessed transmission of Onchocerca species using an O-150 PCR technique to screen pools of black flies&mdash, in seven onchocerciasis endemic communities (Makouopsap, Bankambe, Lemgo, Tsesse, Ndionzou, Kouffen, and Bayon) in Cameroon. Two thousand black flies were assessed&mdash, in each community&mdash, for the presence of Onchocerca species DNA. Our results show that the frequency of infective flies was 0.6% in Makouopsap and 0.0% in the other communities. On the other hand, the frequency of infected flies was 0.8% in Makouopsap, 0.2% in Bankambe, 0.1% in Bayon, and 0.0% in Lemgo, Tsesse, Ndionzou, and Kouffen. These results provide entomologic evidence for continuous transmission of Onchocerca species in Makouopsap, risk of active transmission in Bankambe, and Bayon, and a suppressed transmission in the four other studied communities.

The authors would like to acknowledge the support given by the Institute of Water Research of University of Granada and the disposition of Municipal Water Company of Granada (EMASAGRA S.A.) for financial support to carry out the research., In wastewater treatment plants, most microbial characterization has focused on bacterial, archaeal, and fungal populations. Due to the difficult isolation, quantification, and identification of viruses, only a limited number of virome studies associated with wastewater treatment plants have been carried out. However, the virus populations play an important role in the microbial dynamics in wastewater treatment systems and the biosafety of effluents. In this work, the viral members present in influent wastewater, mixed liquor (aerobic bioreactor), excess sludge, and effluent water of a conventional activated sludge system for the treatment of urban wastewater were identified. Viral members were observed by transmission electron microscopy and studied through next-generation sequencing studies. The results showed the dominance of bacteriophages in the viral community in all samples, with the dominant viral phylotype classified as Escherichia coli O157 typing phage 7. Moreover, different human viruses, such as Cynomolgus cytomegalovirus and Gammaherpesvirus, were also detected., Institute of Water Research of University of Granada

This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases. The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases. This review was funded by the Spanish Ministerio de Ciencia, Innovación y Universidades /FEDER/UE RTI2018-098645-B-100, FEDER I+D+i-USE US-1265062 and US-1264806, the Swedish Brain Foundation and Brain Tumour Research Campaign (BTRC), and Brain Tumour Research (BTR). M.A.B. was funded by the Spanish Ministerio de Economia y Competitividad (Programa Ramón y Cajal: RYC-2017-21804).

Additive manufacturing technologies have been widely used in the medical field. More specifically, fused filament fabrication (FFF) 3D-printing technology has been thoroughly investigated to produce drug delivery systems. Recently, few researchers have explored the possibility of directly 3D printing such systems without the need for producing a filament which is usually the feedstock material for the printer. This was possible via direct feeding of a mixture consisting of the carrier polymer and the required drug. However, as this direct feeding approach shows limited homogenizing abilities, it is vital to investigate the effect of the pre-mixing step on the quality of the 3D printed products. Our study investigates the two commonly used mixing approaches&mdash, solvent casting and powder mixing. For this purpose, polycaprolactone (PCL) was used as the main polymer under investigation and gentamicin sulfate (GS) was selected as a reference. The produced systems&rsquo, efficacy was investigated for bacterial and biofilm prevention. Our data show that the solvent casting approach offers improved drug distribution within the polymeric matrix, as was observed from micro-computed topography and scanning electron microscopy visualization. Moreover, this approach shows a higher drug release rate and thus improved antibacterial efficacy. However, there were no differences among the tested approaches in terms of thermal and mechanical properties.

Obesity is a growing health threat worldwide. Administration of probiotics in obesity has also parallelly increased but without any protocolization. We conducted a systematic review exploring the administration pattern of probiotic strains and effective doses for obesity-related disorders according to their capacity of positively modulating key biomarkers and microbiota dysbiosis. Manuscripts targeting probiotic strains and doses administered for obesity-related disorders in clinical studies were sought. MEDLINE, Scopus, Web of Science, and Cochrane Library databases were searched using keywords during the last fifteen years up to April 2020. Two independent reviewers screened titles, abstracts, and then full-text papers against inclusion criteria according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. From 549 interventional reports identified, we filtered 171 eligible studies, from which 24 full-text assays were used for calculating intervention total doses (ITD) of specific species and strains administered. Nine of these reports were excluded in the second-step because no specific data on gut microbiota modulation was found. Six clinical trials (CT) and 9 animal clinical studies were retained for analysis of complete outcome prioritized (body mass index (BMI), adiposity parameters, glucose, and plasma lipid biomarkers, and gut hormones). Lactobacillus spp. administered were double compared to Bifidobacterium spp.; Lactobacillus as single or multispecies formulations whereas most Bifidobacteria only through multispecies supplementations. Differential factors were estimated from obese populations' vs. obesity-induced animals: ITD ratio of 2 × 106 CFU and patterns of administrations of 11.3 weeks to 5.5 weeks, respectively. Estimation of overall probiotics impact from selected CT was performed through a random-effects model to pool effect sizes. Comparisons showed a positive association between the probiotics group vs. placebo on the reduction of BMI, total cholesterol, leptin, and adiponectin. Moreover, negative estimation appeared for glucose (FPG) and CRP. While clinical trials including data for positive modulatory microbiota capacities suggested that high doses of common single and multispecies of Lactobacillus and Bifidobacterium ameliorated key obesity-related parameters, the major limitation was the high variability between studies and lack of standardized protocols. Efforts in solving this problem and searching for next-generation probiotics for obesity-related diseases would highly improve the rational use of probiotics. Yes

Despite the large number of polymeric nanodelivery systems that have been recently developed, there is still room for improvement in terms of therapeutic efficiency. Most reported nanodevices for controlled release are based on drug encapsulation, which can lead to undesired drug leakage with a consequent reduction in efficacy and an increase in systemic toxicity. Herein, we present a strategy for covalent drug conjugation to the nanodevice to overcome this drawback. In particular, we characterize and evaluate an effective therapeutic polymeric PEGylated nanosystem for controlled pH-sensitive drug release on a breast cancer (MDA-MB-231) and two lung cancer (A549 and H520) cell lines. A significant reduction in the required drug dose to reach its half maximal inhibitory concentration (IC50 value) was achieved by conjugation of the drug to the nanoparticles, which leads to an improvement in the therapeutic index by increasing the efficiency. The genotoxic effect of this nanodevice in cancer cells was confirmed by nucleus histone H2AX specific immunostaining. In summary, we successfully characterized and validated a pH responsive therapeutic polymeric nanodevice in vitro for controlled anticancer drug release., Spanish Ministry of Economy and Competitiveness (MINECO) BIO2016-80519, Health Institute Carlos III (ISCIII) DTS18/00121, Andalusian Regional Government PAIDI-TC-PVT-PSETC-2.0

In spite of the enormous potential of CRISPR/Cas in basic and applied science, the levels of undesired genomic modifications cells still remain mostly unknown and controversial. Nowadays, the efficiency and specificity of the cuts generated by CRISPR/Cas is the main concern. However, there are also other potential drawbacks when DNA donors are used for gene repair or gene knock-ins. These GE strategies should take into account not only the specificity of the nucleases, but also the fidelity of the DNA donor to carry out their function. The current methods to quantify the fidelity of DNA donor are costly and lack sensitivity to detect illegitimate DNA donor integrations. In this work, we have engineered two reporter cell lines (K562_SEWAS84 and K562GWP) that efficiently quantify both the on-target and the illegitimate DNA donor integrations in a WAS-locus targeting setting. K562_SEWAS84 cells allow the detection of both HDR-and HITI-based donor integration, while K562GWP cells only report HDR-based GE. To the best of our knowledge, these are the first reporter systems that allow the use of gRNAs targeting a relevant locus to measure efficacy and specificity of DNA donor-based GE strategies. By using these models, we have found that the specificity of HDR is independent of the delivery method and that the insertion of the target sequence into the DNA donor enhances efficiency but do not affect specificity. Finally, we have also shown that the higher the number of the target sites is, the higher the specificity and efficacy of GE will be., Spanish ISCIII Health Research Fund, European Union (EU) PI15/02015 PI18/00337 PI18/00330, CECEyU of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) 2016000073391-TRA 2016000073332-TRA PI-57069 CARTPI-0001-201 PAIDI-Bio326 PI-0014-2016, CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) 2016000073391-TRA 2016000073332-TRA PI-57069 CARTPI-0001-201 PAIDI-Bio326 PI-0014-2016, Nicolas Monardes regional Ministry of Health contract 0006/2018, Fundacion Poco Frecuente, Spanish Government FPU17/04327 FPU17/02268, ISCIII through a PFIS fellowship FI19/00163, SMSI PEJ-2018-001760-A

Human microbiota seems to play a key role in endocrine and reproductive systems. Fortunately, microbiota reproductive dysbiosis start to be treated by probiotics using typical species from genus Lactobacillus. This work presents the compiled and analysed results from the most up-to-date information from clinical trials regarding microbiota, fertility, probiotics and oral route administration, reviewing open access scientific documents. These studies analyse the clinical impact of probiotics administered on several endocrine disorders’ manifestations in women: mastitis; vaginal dysbiosis; pregnancy complication disorders; and polycystic ovary syndrome. In all cases, the clinical modulation achieved by probiotics was evaluated positively through the improvement of specific disease outcomes with the exception of the pregnancy disorders studies, where the sample sizes results were statistically insufficient. High amounts of studies were discarded because no data were provided on specific probiotic strains, doses, impact on the individual autochthon microbiota, or data regarding specific hormonal values modifications and endocrine regulation effects. However, most of the selected studies with probiotics contained no protocolised administration. Therefore, we consider that intervention studies with probiotics might allocate the focus, not only in obtaining a final outcome, but in how to personalise the administration according to the disorder to be palliated. Yes

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR, PROPESP/UFPA, National Council for Scientific and Technological Development (CNPq)

Due to the great therapeutic interest that involves the translation of mesenchymal stromal cells (MSCs) into clinical practice, they have been widely studied as innovative drugs, in order to treat multiple pathologies. MSC-based cell therapy involves the administration of MSCs either locally or systemically into the receptor body where they can traffic and migrate towards the affected tissue and participate in the process of healing. The therapeutic effects of MSCs compromise of different mechanisms such as the functional integration of differentiated MSCs into diseased host tissue after transplantation, their paracrine support, and their impact on the regulation of both the innate and the acquired immune system. Here, we establish and provide recent advances about the principal mechanisms of action through which MSCs can perform their activity and effect as a therapeutic tool. The purpose of this review is to examine and discuss the MSCs capacity of migration, their paracrine effect, as well as MSC-mediated modifications on immune cell responses. Yes

(1) Background: Little is known about the interlinkages between dietary and plasma non-enzymatic antioxidant capacity (D-NEAC and P-NEAC, respectively) and the body&rsquo, s antioxidant and inflammation response. Our aim was to explore these associations in 210 participants from two Spanish European Prospective Investigation into Cancer and Nutrition (EPIC) centers. (2) Methods: D-NEAC was estimated using published NEAC values in food. P-NEAC and total polyphenols (TP) were quantified by FRAP (ferric-reducing antioxidant power), TRAP (total radical-trapping antioxidant parameter), TEAC-ABTS (trolox equivalent antioxidant capacity - Azino Bis Thiazoline Sulfonic), ORAC (oxygen radical absorbance capacity) and Folin&ndash, Ciocalteu assays. Nutrient antioxidants (carotenes, &alpha, tocopherol, ascorbic acid, retinol, uric acid, Q9 and Q10 coenzymes) and inflammation markers (IL-6, IL-8, CRP, TNF-&alpha, PAI-I, resistin and adiponectin) were also analyzed. Spearman correlation and linear regression analyses were performed in association analyses. Analyses were stratified by covariates and groups were defined using cluster analysis. (3) Results: P-FRAP was correlated with D-NEAC, and significantly associated with P-NEAC in multivariate adjusted models. P-FRAP levels were also significantly associated with plasma antioxidants (log2 scale: TP &beta, = 0.26, ascorbic acid &beta, = 0.03, retinol &beta, = 0.08, &alpha, tocopherol &beta, = 0.05, carotenes &beta, = 0.02, Q10 &beta, = 0.06, uric acid &beta, = 0.25), though not with inflammation-related biomarkers. Different profiles of individuals with varying levels of P-NEAC and biomarkers were found. (4) Conclusions: P-NEAC levels were to some extent associated with D-NEAC and plasma antioxidants, yet not associated with inflammation response.