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Lupin ( Lupinus angustifolius L.) proteins are potential sources of bioactive peptides (LBPs) that can inhibit dipeptidyl peptidase IV (DPP-IV) and angiotensin I-converting enzyme (ACE-I) activity. However, the capacity of different enzymes to release LBPs, the pharmacokinetic and bioactivities of the peptides released, and their binding affinities with the active sites of DPP-IV and ECA-I are topics scarcely addressed. Therefore, we used in silico hydrolysis (BIOPEP-UWM platform) with various enzymes to predict the release of LBPs. Among the bioactive peptides identified in lupin proteins (n = 4813), 2062 and 1558 had DPP-IV and ACE-I inhibitory activity, respectively. Ficin, bromelain, and papain released the highest proportion of ACE-I (n = 433, 411, and 379, respectively) and DPP-IV (n = 556, 544, and 596, respectively) inhibitory peptides. LBPs with favorable pharmacokinetics and gastrointestinal stability tightly interacted with the active sites of ACE-I (-5.6 to -8.9 kcal/mol) and DPP-IV (-5.4 to -7.6 kcal/mol). Papain generated the most bioavailable LBPs (n = 459) with ACE-I (n = 223) and DPP-IV (n = 412) inhibitory activity. These peptides were non-toxic and gastrointestinal digestion stable. Notably, papain-based hydrolysis released some LBPs (n = 270) that inhibited both ACE-I and DPP-IV. Plant protease-based hydrolysis is a promising approach for producing lupin hydrolysates with ACE-I and DPP-IV inhibitory activities.

As awareness of the impact of anthropogenic activities on climate change increases, the concepts of durability, resilience, and sustainability in concrete tend to be adopted more seriously in the concrete construction industry. In this sense, one of the concrete technologies that began in the 1980s and that significantly contributes to maximize the beneficial effect on all these concepts are the ultra-high-performance concretes, a very attractive technology because it presents ultra-high strength and durability performances far superior to those of conventional concretes, a performance that is leading to a permanent increased demand. However, the development of these concretes has been widely criticized due to their high ecological impact, which is mainly attributable to the high cement dosages required for their production (800-1000 kg/m 3 ). To address this criticism in a comprehensive manner and thereby reduce the embodied carbon attributable exclusively to the material, this research was oriented to determine the effect of an industrial by-product of vitrified clay, as a partial or total substitution for cement, silica fume, and limestone aggregate, on the compressive strength, flexural toughness, and embodied CO 2 . For the UHPC's evaluated in this work with a dosage of 2% by volume of steel micro-fibers, the results evidence the feasibility that the following substitutions by mass: 30% of the Portland cement, 100% of the silica fume, and 30% of the limestone aggregate and powder, do not detract the fresh stage, the compressive strength, the static modulus of elasticity, and the flexural strength, leading to significant reductions of the embodied CO 2 .

EMC1 is part of the endoplasmic reticulum (ER) membrane protein complex, whose functions include the insertion of transmembrane proteins into the ER membrane, ER-mitochondria contact, and lipid exchange. Here, we show that the Drosophila melanogaster EMC1 gene is expressed in the somatic musculature and the protein localizes to the sarcoplasmic reticulum (SR) network. Muscle-specific EMC1 RNAi led to severe motility defects and partial late pupae/early adulthood lethality, phenotypes that are rescued by co-expression with an EMC1 transgene. Motility impairment in EMC1-depleted flies was associated with aberrations in muscle morphology in embryos, larvae, and adults, including tortuous and misaligned fibers with reduced size and weakness. They were also associated with an altered SR network, cytosolic calcium overload, and mitochondrial dysfunction and dysmorphology that impaired membrane potential and oxidative phosphorylation capacity. Genes coding for ER stress sensors, mitochondrial biogenesis/dynamics, and other EMC components showed altered expression and were mostly rescued by the EMC1 transgene expression. In conclusion, EMC1 is required for the SR network's mitochondrial integrity and influences underlying programs involved in the regulation of muscle mass and shape. We believe our data can contribute to the biology of human diseases caused by EMC1 mutations.

Background/objectives: Given the importance of emotion recognition for communication purposes, and the impairment for such skill in CI users despite impressive language performances, the aim of the present study was to investigate the neural correlates of emotion recognition skills, apart from language, in adult unilateral CI (UCI) users during a music in noise (happy/sad) recognition task. Furthermore, asymmetry was investigated through electroencephalographic (EEG) rhythm, given the traditional concept of hemispheric lateralization for emotional processing, and the intrinsic asymmetry due to the clinical UCI condition., Methods: Twenty adult UCI users and eight normal hearing (NH) controls were recruited. EEG gamma and alpha band power was assessed as there is evidence of a relationship between gamma and emotional response and between alpha asymmetry and tendency to approach or withdraw from stimuli. The TAS-20 questionnaire (alexithymia) was completed by the participants., Results: The results showed no effect of background noise, while supporting that gamma activity related to emotion processing shows alterations in the UCI group compared to the NH group, and that these alterations are also modulated by the etiology of deafness. In particular, relative higher gamma activity in the CI side corresponds to positive processes, correlated with higher emotion recognition abilities, whereas gamma activity in the non-CI side may be related to positive processes inversely correlated with alexithymia and also inversely correlated with age; a correlation between TAS-20 scores and age was found only in the NH group., Conclusions: EEG gamma activity appears to be fundamental to the processing of the emotional aspect of music and also to the psychocognitive emotion-related component in adults with CI.

Genome-Wide Association Studies (GWASs) have identified a huge number of variants associated with different traits. However, their validation through in vitro and in vivo studies often lags well behind their identification. For variants associated with traits or diseases of biomedical interest, this gap delays the development of possible therapies. This issue also impacts beta-hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). The definitive cures for these diseases are currently bone marrow transplantation and gene therapy. However, limitations regarding their effective use restrict their worldwide application. Great efforts have been made to identify whether modulators of fetal hemoglobin (HbF) and, to a lesser extent, hemoglobin A2 (HbA 2 ) are possible therapeutic targets. Herein, we performed the post-GWAS in vivo validation of two genes, cyclin D3 ( CCND3 ) and nuclear factor I X ( NFIX ), previously associated with HbF and HbA 2 levels. The absence of Ccnd3 expression in vivo significantly increased g (HbF) and d (HbA 2 ) globin gene expression. Our data suggest that CCND3 is a possible therapeutic target in sickle cell disease. We also confirmed the association of Nfix with γ-globin gene expression and present data suggesting a possible role for Nfix in regulating Kruppel-like transcription factor 1 ( Klf1 ), a master regulator of hemoglobin switching. This study contributes to filling the gap between GWAS variant identification and target validation for beta-hemoglobinopathies.

Background and Objectives : The upper posterior teeth are typically regarded as being exclusively inferior to the maxillary sinus (MS). The expansion of the nasal fossa above the maxillary alveolar base (MAB) needs better investigation. The hypothesis was raised that the MAB in the upper premolar region, which is usually addressed by surgeons for the elevation of the antral floor, is not exclusively beneath the MS. Therefore, we aimed to document the possible upper relations of the MAB as antral, nasal, or both. Materials and Methods : A total of 145 CBCT scans were used to study four types of MAB: type 1-antral; type 2-antral with a palatal recess; type 3-antral and nasal; type 4-nasal. In type 2, the orthoradial width of the alveolar bone, the rectilinear width of the antral floor, and the maximum depth of the palatal recess were measured. For type 3, the MAB width and the straight widths of the antral and nasal segments of the MAB were measured. Results : Type 1 was found in 67.24%, type 2 in 13.45%, type 3 in 16.21%, and type 4 in 3.1% of the 290 MSs investigated. Palatal recesses were found in 11.72% of the MSs on the right side and 15.17% of the MSs on the left side. Types 1 and 2 exhibited strongly statistically significant bilateral symmetry (Pearson's Chi2 = 86.42, p < 0.001). Type 3 correlated equally with contralateral types 1 and 3. The bilateral symmetry for types 1-3 was stronger in the males (Pearson's Chi2 = 47.83, p < 0.001) than in the females (Pearson's Chi2 = 56.96, p < 0.001). There were no statistically significant associations between sex and the unilateral anatomical type. Conclusions : The MAB in the upper second premolar area should not be considered to be exclusively antral during surgeries or in anatomical teaching.

Glioblastoma is the most frequent and aggressive brain tumor in adults. This study aims to evaluate the expression and prognostic impact of CD99, a membrane glycoprotein involved in cellular migration and invasion. In a cohort of patients with glioblastoma treated with surgery, radiotherapy and temozolomide, we retrospectively analyzed tumor expression of CD99 by immunohistochemistry (IHC) and by quantitative real-time polymerase chain reaction (qRT-PCR) for both the wild type (CD99wt) and the truncated (CD99sh) isoforms. The impact on overall survival (OS) was assessed with the Kaplan-Meier method and log-rank test and by multivariable Cox regression. Forty-six patients with glioblastoma entered this study. Immunohistochemical expression of CD99 was present in 83%. Only the CD99wt isoform was detected by qRT-PCR and was significantly correlated with CD99 expression evaluated by IHC (rho = 0.309, p = 0.037). CD99 expression was not associated with OS, regardless of the assessment methodology used ( p = 0.61 for qRT-PCR and p = 0.73 for IHC). In an exploratory analysis of The Cancer Genome Atlas, casuistry of glioblastomas CD99 expression was not associated with OS nor with progression-free survival. This study confirms a high expression of CD99 in glioblastoma but does not show any significant impact on survival. Further preclinical studies are needed to define its role as a therapeutic target in glioblastoma.

The aim of this work was to develop sustainable patches for wound application, using the biopolymer starch, created using a low-cost 3D printing PAM device. The composition of a starch gel was optimized for PAM extrusion: corn starch 10% w / w , β-glucan water suspension (filler, 1% w / w ), glycerol (plasticizer, 29% w / w ), and water 60% w / w . The most suitable 3D printing parameters were optimized as well (nozzle size 0.8 mm, layer height 0.2 mm, infill 100%, volumetric flow rate 3.02 mm 3 /s, and print speed 15 mm/s). The suitable conditions for post-printing drying were set at 37 °C for 24 h. The obtained patch was homogenous but with low mechanical resistance. To solve this problem, the starch gel was extruded over an alginate support, which, after drying, becomes an integral part of the product, constituting the backing layer of the final formulation. This approach significantly improved the physicochemical and post-printing properties of the final bilayer patch, showing suitable mechanical properties such as elastic modulus (3.80 ± 0.82 MPa), strength (0.92 ± 0.08 MPa), and deformation at break (50 ± 1%). The obtained results suggest the possibility of low-cost production of patches for wound treatment by additive manufacturing technology.

Hazelnut shells, the main waste deriving from hazelnut processing, represent an interesting source of active molecules useful in pharmaceutics, although they have not yet been examined in depth. A hydrosoluble extract (hazelnut shell extract, HSE) was prepared by the maceration method using a hydroalcoholic solution and used as the active ingredient of patches (prepared by casting method) consisting of composites of highly deacetylated chitosan and green clay. In vitro studies showed that the formulation containing HSE is able to stimulate keratinocyte growth, which is useful for healing purposes, and to inhibit the growth of S. aureus (Log CFU/mL 0.95 vs. 8.85 of the control after 48 h); this bacterium is often responsible for wound infections and is difficult to treat by conventional antibiotics due to its antibiotic resistance. The produced patches showed suitable tensile properties that are necessary to withstand mechanical stress during both the removal from the packaging and application. The obtained results suggest that the developed patch could be a suitable product to treat wounds.

Essential oils are composed of terpenes, some of which have properties related to healing. Bursera schlechtendalii essential oil (BSEO) is used to heal superficial wounds. However, there have been no studies verifying this property. The objectives of this study were to evaluate the healing activity of BSEO in a murine model and to propose the roles of its chemical components in this process. Healing activity was evaluated by an incision model, histological analysis was performed, and tensile strength and antibacterial activity were measured. The chemical composition of BSEO was determined by gas chromatography coupled with mass spectrometry (GC-MS), and the mechanisms of action of each chemical component during the phases of the healing process were proposed. In addition, acute dermal toxicity was evaluated. BSEO showed better wound closure at the macroscopic, histological, and tensile strength levels compared to controls and had an antibacterial effect. The major compound in BSEO was α-phellandrene. However, most of the monoterpenes identified in BSEO were in agreement with information found in the literature, so the possibility of synergy between the chemical components and their different targets in the healing process was schematically proposed. BSEO was shown to be safe in the dermal toxicity evaluation.

Voltage-gated calcium channels (VGCCs) are targeted to treat pain conditions. Since the discovery of their relation to pain processing control, they are investigated to find new strategies for better pain control. This review provides an overview of naturally based and synthetic VGCC blockers, highlighting new evidence on the development of drugs focusing on the VGCC subtypes as well as mixed targets with pre-clinical and clinical analgesic effects.

In many countries, water quality monitoring is limited due to the high cost of logistics and professional equipment such as multiparametric probes. However, low-cost sensors integrated with the Internet of Things can enable real-time environmental monitoring networks, providing valuable water quality information to the public. To facilitate the widespread adoption of these sensors, it is crucial to identify which sensors can accurately measure key water quality parameters, their manufacturers, and their reliability in different environments. Although there is an increasing body of work utilizing low-cost water quality sensors, many questions remain unanswered. To address this issue, a systematic literature review was conducted to determine which low-cost sensors are being used for remote water quality monitoring. The results show that there are three primary vendors for the sensors used in the selected papers. Most sensors range in price from US$6.9 to US$169.00 but can cost up to US$500.00. While many papers suggest that low-cost sensors are suitable for water quality monitoring, few compare low-cost sensors to reference devices. Therefore, further research is necessary to determine the reliability and accuracy of low-cost sensors compared to professional devices.

We aimed to identify HLA-DRB1 , -DQA1 , and -DQB1 alleles/haplotypes associated with European, African, or Native American genomic ancestry (GA) in admixed Brazilian patients with type 1 diabetes (T1D). This exploratory nationwide study enrolled 1599 participants. GA percentage was inferred using a panel of 46 ancestry informative marker-insertion/deletion. Receiver operating characteristic curve analysis (ROC) was applied to identify HLA class II alleles related to European, African, or Native American GA, and showed significant ( p < 0.05) accuracy for identifying HLA risk alleles related to European GA: for DRB1*03:01 , the area under the curve was (AUC) 0.533; for DRB1*04:01 AUC = 0.558, for DRB1*04:02 AUC = 0.545. A better accuracy for identifying African GA was observed for the risk allele DRB1*09:01 AUC = 0.679 and for the protective alleles DRB1*03:02 AUC = 0.649, DRB1*11:02 AUC = 0.636, and DRB1*15:03 AUC = 0.690. Higher percentage of European GA was observed in patients with risk haplotypes ( p < 0.05). African GA percentage was higher in patients with protective haplotypes ( p < 0.05). Risk alleles and haplotypes were related to European GA and protective alleles/haplotypes to African GA. Future studies with other ancestry markers are warranted to fill the gap in knowledge regarding the genetic origin of T1D in highly admixed populations such as that found in Brazil.

Analysis of neural encoding and plasticity processes frequently relies on studying spatial patterns of activity-induced immediate early genes' expression, such as c-fos . Quantitatively analyzing the numbers of cells expressing the Fos protein or c-fos mRNA is a major challenge owing to large human bias, subjectivity and variability in baseline and activity-induced expression. Here, we describe a novel open-source ImageJ/Fiji tool, called 'Quanty-cFOS', with an easy-to-use, streamlined pipeline for the automated or semi-automated counting of cells positive for the Fos protein and/or c-fos mRNA on images derived from tissue sections. The algorithms compute the intensity cutoff for positive cells on a user-specified number of images and apply this on all the images to process. This allows for the overcoming of variations in the data and the deriving of cell counts registered to specific brain areas in a highly time-efficient and reliable manner. We validated the tool using data from brain sections in response to somatosensory stimuli in a user-interactive manner. Here, we demonstrate the application of the tool in a step-by-step manner, with video tutorials, making it easy for novice users to implement. Quanty-cFOS facilitates a rapid, accurate and unbiased spatial mapping of neural activity and can also be easily extended to count other types of labelled cells.

Green propolis may represent a promising therapeutic alternative against dental anaerobic pathogens because of its antimicrobial action. This study aimed to evaluate the antimicrobial and antibiofilm actions of Brazilian green propolis aqueous extract (BGP-AqExt) against dental anaerobic bacteria. The minimum inhibitory concentration (MIC) and minimum microbicide concentration (MMC) of the extract were determined against the standard strains (ATCC) of Fusobacterium nucleatum , Parvimonas micra , Prevotella intermedia, Porphyromonas gingivalis and Porphyromonas endodontalis . BGP-AqExt was chemically characterized by high-performance liquid chromatography with diode-array detection (HPLC-DAD) analysis. Antibiofilm action was measured by MTT and crystal violet tests. The data were statistically analyzed by ANOVA and Tukey (5%) tests. The extract had antimicrobial action against all tested anaerobic bacteria, with an MIC value of 55 mg/mL for all bacteria, an MMC of 27.5 mg/mL for F. nucleatum and P. micra and 55 mg/mL for P. intermedia . Chemically, BGP-AqExt is composed of quercetin, gallic acid, caffeic and p-coumaric acid, drupani, kaempferol and Artepillin C. Significant reductions in biomass and metabolic action of biofilms were found after BGP-AqExt application. Therefore, BGP-AqExt has an antimicrobial and antibiofilm effect against dental anaerobic bacteria.

Objective: To identify factors associated with mortality in indigenous populations diagnosed with tuberculosis in Peru, 2015-2019., Methods: We conducted a nested case-control study in a retrospective cohort using the registry of indigenous peoples of the National Health Strategy for TB Prevention and Control of the Ministry of Health of Peru. A descriptive analysis was performed, and then bivariate and multivariate logistic regression was used to evaluate associations between the variables and the outcome (alive-deceased). The results are shown as OR with their respective 95% confidence intervals., Results: The mortality rate of the total indigenous population of Peru was 1.75 deaths per 100,000 indigenous people diagnosed with TB. The community of Kukama Kukamiria-Yagua reported 505 (28.48%) individuals, followed by the Shipibo-Konibo community with 385. The final logistic model showed that indigenous males (OR = 1.93; 95% CI: 1.001-3.7) with a history of HIV prior to TB (OR = 16.7; 95% CI: 4.7-58.7), and indigenous people in old age (OR = 2.95; 95% CI: 1.5-5.7) were factors associated with a greater chance of dying from TB., Conclusions: It is important to reorient health services among indigenous populations, especially those related to improving a timely diagnosis and early treatment of TB/HIV co-infection, to ensure comprehensive care for this population considering that they are vulnerable groups.

Krüppel-like factor 1 (KLF1) plays a crucial role in erythropoiesis. In-depth studies conducted on mice and humans have highlighted its importance in erythroid lineage commitment, terminal erythropoiesis progression and the switching of globin genes from γ to β. The role of KLF1 in haemoglobin switching is exerted by the direct activation of β-globin gene and by the silencing of γ-globin through activation of BCL11A, an important γ-globin gene repressor. The link between KLF1 and γ-globin silencing identifies this transcription factor as a possible therapeutic target for β-hemoglobinopathies. Moreover, several mutations have been identified in the human genes that are responsible for various benign phenotypes and erythroid disorders. The study of the phenotype associated with each mutation has greatly contributed to the current understanding of the complex role of KLF1 in erythropoiesis. This review will focus on some of the principal functions of KLF1 on erythroid cell commitment and differentiation, spanning from primitive to definitive erythropoiesis. The fundamental role of KLF1 in haemoglobin switching will be also highlighted. Finally, an overview of the principal human mutations and relative phenotypes and disorders will be described.

This paper explains the mathematical foundations of a method for modelling semi-rigid unions. The unions are modelled using rotational rather than linear springs. A nonlinear second-order analysis is required, which includes both the effects of the flexibility of the connections as well as the geometrical nonlinearity of the elements. The first task in the implementation of a 2D Beam element with semi-rigid unions in a nonlinear finite element method (FEM) is to define the vector of internal forces and the tangent stiffness matrix. After defining the formula for this vector and matrix in the context of a semi-rigid steel frame, an iterative adjustment of the springs is proposed. This setting allows a moment-rotation relationship for some given load parameters, dimensions, and unions. Modelling semi-rigid connections is performed using Frye and Morris' polynomial model. The polynomial model has been used for type-4 semi-rigid joints (end plates without column stiffeners), which are typically semi-rigid with moderate structural complexity and intermediate stiffness characteristics. For each step in a non-linear analysis required to adjust the matrix of tangent stiffness, an additional adjustment of the springs with their own iterative process subsumed in the overall process is required. Loops are used in the proposed computational technique. Other types of connections, dimensions, and other parameters can be used with this method. Several examples are shown in a correlated analysis to demonstrate the efficacy of the design process for semi-rigid joints, and this is the work's application content. It is demonstrated that using the mathematical method presented in this paper, semi-rigid connections may be implemented in the designs while the stiffness of the connection is verified.

Delirium and psychomotor agitation are relevant clinical conditions that may develop during COVID-19 infection, especially in intensive care unit (ICU) settings. The psychopharmacological management of these conditions is receiving increasing interest in psychiatry, considering hyperkinetic delirium as one of the most common neuropsychiatries acute consequences in COVID-19 recovery patients. However, there are no actual internationally validated guidelines about this topic, due to the relatively newly introduced clinical condition; in addition, a standardized psychopharmacologic treatment of these cases is a complex goal to achieve due to the risk of both drug-drug interactions and the vulnerable conditions of those patients. The aim of this systematic review and case series is to evaluate and gather the scientific evidence on pharmacologic handling during delirium in COVID-19 patients to provide practical recommendations on the optimal management of psychotropic medication in these kinds of patients. The electronic databases PubMed, Embase and Web of Science were reviewed to identify studies, in accordance with the PRISMA guidelines. At the end of the selection process, a total of 21 studies ( n = 2063) were included. We also collected a case series of acute psychomotor agitation in COVID-19 patients hospitalized in ICU. Our results showed how the symptom-based choice of the psychotropic medication is crucial, and even most of the psychotropic drug classes showed good safety, one must not underestimate the possible drug interactions and also the possible decrease in vital functions which need to be strictly monitored especially during treatment with some kinds of molecules. We believe that the evidence-based recommendations highlighted in the present research will enhance the current knowledge and could provide better management of these patients.

During the 2020 first wave of the COVID-19 pandemic, general practitioners (GPs) represented the first line of primary care and were highly exposed to the pandemic risks, with a consequent risk of developing a wide range of mental health symptoms. However, scant data are still available on factors associated with a worse outcome. The aim of the present study was to investigate mental health symptoms in 139 GPs in the aftermath of the first COVID-19 national lockdown in Italy, detecting groups of subjects with different depressive, anxiety, and post-traumatic stress symptom severity. The impact of the mental health symptoms on quality of life and individual functioning were also evaluated. A cluster analysis identified three groups with mild (44.6%), moderate (35.3%), and severe psychopathological burden (20.1%). Higher symptom severity was related to younger age, fewer years in service as GPs, working in a high incidence area for the pandemic, having a relative at risk of medical complications due to COVID-19, besides more severe global functioning impairment, burnout, and secondary traumatic stress. The present findings showed that GPs, forced to perform their professional activity in extremely stressful conditions during the COVID-19 pandemic, were at high risk of developing mental health problems and a worse quality of life.

The adult autism subthreshold spectrum model appears to be a useful tool for detecting possible vulnerability factors in order to develop mental disorders in the contest of work-related stress. The aim of the present study is to analyze the relationship between autism, mood, and post-traumatic spectrum in a cohort of subjects complaining of work-related stress before the COVID-19 pandemic. The authors carried out a retrospective investigation of both medical records and self-assessment tools of a sample of subjects evaluated at the Occupational Health Department of a University hospital in central Italy. Data showed significant correlations between the AdAS spectrum, TALS-SR, and MOODS total and domain scores. A multiple linear regression evidenced that both the AdAS spectrum and TAL-SR significantly predict the MOODS scores. In particular, mediation analysis showed both a direct and indirect, mediated by TALS-SR, effect of the AdAS Spectrum on the MOODS-SR. These results corroborate the role of autistic traits in influencing the traumatic impact of work-related stress and the development of mood spectrum symptoms.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline ( n = 37), at 8 weeks of treatment ( n = 32), progressive disease (PD; n = 36) and 3 months after PD ( n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients ( p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

Multiple myeloma (MM) accounts for 10-15% of all hematologic malignancies, as well as 20% of deaths related to hematologic malignant tumors, predominantly affecting bone and bone marrow. Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG-PET/CT) is an important method to assess the tumor burden of these patients. It is often challenging to classify the extent of disease involvement in the PET scans for many of these patients because both focal and diffuse bone lesions may coexist, with varying degrees of FDG uptake. Different metrics involving volumetric parameters and texture features have been proposed to objectively assess these images. Here, we review some metabolic parameters that can be extracted from FDG-PET/CT images of MM patients, including technical aspects and predicting MM outcome impact. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are volumetric parameters known to be independent predictors of MM outcome. However, they have not been adopted in clinical practice due to the lack of measuring standards. CT-based segmentation allows automated, and therefore reproducible, calculation of bone metabolic metrics in patients with MM, such as maximum, mean and standard deviation of the standardized uptake values (SUV) for the entire skeleton. Intensity of bone involvement (IBI) is a new parameter that also takes advantage of this approach with promising results. Other indirect parameters obtained from FDG-PET/CT images, such as visceral adipose tissue glucose uptake and subcutaneous adipose tissue radiodensity, may also be useful to evaluate the prognosis of MM patients. Furthermore, the use and quantification of new radiotracers can address different metabolic aspects of MM and may have important prognostic implications.

The implementation of health technology assessment (HTA) in emerging countries depends on the characteristics of the health care system and the needs of public health care. The objective of this survey was to investigate experts' expectations for the development of HTA in Brazil and to derive measures to strengthen the impact of HTA in Brazil on health care decisions. Based on a scoping literature review, a questionnaire was developed proposing eight theses for seven domains of HTA: (i) capacity building, (ii) public involvement, (iii) role of cost-effectiveness analysis (CEA), (iv) institutional framework, (v) scope of HTA studies, (vi) methodology of HTA, and (vii) HTA as the basis for jurisdiction. Thirty experts responded in full to the survey and agreed to five of the eight theses proposed. Experts suggested several measures to promote HTA within the scope of each domain, thus addressing capacity building related to HTA, availability, and reliability of population data, and legal endowment of the HTA system. Finally, HTA processes in Brazil should also address public health issues (e.g., appraisal of interventions directed at chronic diseases).

During the production of pharmaceutical glass tubes, a machine-vision based inspection system can be utilized to perform the high-quality check required by the process. The necessity to improve detection accuracy, and increase production speed determines the need for fast solutions for defects detection. Solutions proposed in literature cannot be efficiently exploited due to specific factors that characterize the production process. In this work, we have derived an algorithm that does not change the detection quality compared to state-of-the-art proposals, but does determine a drastic reduction in the processing time. The algorithm utilizes an adaptive threshold based on the Sigma Rule to detect blobs, and applies a threshold to the variation of luminous intensity along a row to detect air lines. These solutions limit the detection effects due to the tube's curvature, and rotation and vibration of the tube, which characterize glass tube production. The algorithm has been compared with state-of-the-art solutions. The results demonstrate that, with the algorithm proposed, the processing time of the detection phase is reduced by 86%, with an increase in throughput of 268%, achieving greater accuracy in detection. Performance is further improved by adopting Region of Interest reduction techniques. Moreover, we have developed a tuning procedure to determine the algorithm's parameters in the production batch change. We assessed the performance of the algorithm in a real environment using the "certification" functionality of the machine. Furthermore, we observed that out of 1000 discarded tubes, nine should not have been discarded and a further seven should have been discarded.

In the search for increased productivity and efficiency in the industrial sector, a new industrial revolution, called Industry 4.0, was promoted. In the electric sector, power plants seek to adapt these new concepts to optimize electric power generation processes, as well as to reduce operating costs and unscheduled downtime intervals. In these plants, PID control strategies are commonly used in water cooling systems, which use fans to perform the thermal exchange between water and the ambient air. However, as the nonlinearities of these systems affect the performance of the drivers, sometimes a greater number of fans than necessary are activated to ensure water temperature control which, consequently, increases energy expenditure. In this work, our objective is to develop digital twins for a water cooling system with auxiliary equipment, in terms of the decision making of the operator, to determine the correct number of fans. This model was developed based on the algorithm of automatic extraction of fuzzy rules, derived from the SCADA of a power plant located in the capital of Paraíba, Brazil. The digital twins can update the fuzzy rules in the case of new events, such as steady-state operation, starting and stopping ramps, and instability. The results from experimental tests using data from 11 h of plant operations demonstrate the robustness of the proposed digital twin model. Furthermore, in all scenarios, the average percentage error was less than 5% and the average absolute temperature error was below 3 °C.

The porosity of mortars with recycled ceramic aggregates (10, 20, 30, 50, and 100% as a replacement of natural aggregate) was evaluated and analyzed using three different techniques. The results of gas adsorption (N 2 ), Scanning Electron Microscopy (SEM) image analysis and open porosity allowed establishing the relationship between the recycled aggregate content and the porosity of these mortars, as well as the relationship between porosity and the physical and mechanical properties of the mortars: absorption, density, compressive strength, modulus of elasticity, and drying shrinkage. Using the R 2 coefficient and the equation typology as criteria, additional data such as Brunauer, Emmett, and Teller (BET) surface area (N 2 adsorption) established significant correlations with the mentioned properties; with SEM image analysis, no explanatory relationships could be established; and with open porosity, revealing relationships were established (R 2 > 0.9). With the three techniques, it was confirmed that the increase in porosity is related to the increase in the amount of ceramic aggregate; in particular with gas adsorption (N 2 ) and open porosity. It was concluded that the open porosity technique can explain the behavior of these recycled mortars with more reliable data, in a simple and direct way, linked to its establishment with a more representative sample of the mortar matrix.

Severe illnesses in children and adolescents/young adults (AYAs) may represent a complex burden for patients and their caregivers, including a wide range of mental disorders, particularly post-traumatic stress disorder (PTSD). Few events are as potentially traumatizing as having a son or a daughter diagnosed with a severe, life-threatening, or disabling disease. The presence of PTSD symptoms in caregivers may compromise their efficacy as caregivers and negatively affect the child's well-being. This systematic review aims at outlining potential risk and protective factors for the development of PTSD symptoms in caregivers of children and AYAs affected by severe acute or chronic illnesses. Thirty-one studies on caregivers of children and AYAs affected by severe, acute, or chronic diseases were included. Socio-demographic and socio-economic characteristics, illness-related distress, psychiatric symptoms, support, and coping styles were found as potential risk/protective factors across studies. It is crucial to consider risk factors affecting caregivers of severely ill young patients, in order to plan focused interventions aimed at preventing an adverse clinical outcome in caregivers and at enhancing caregivers' coping skills, in order to ultimately improve their quality of life.

The novel coronavirus disease 2019 (COVID-19) is a global pandemic spreading worldwide, and Italy represented the first European country involved. Healthcare workers (HCWs) facing COVID-19 pandemic represented an at-risk population for new psychosocial COVID-19 strain and consequent mental health symptoms. The aim of the present study was to identify the possible impact of working contextual and personal variables (age, gender, working position, years of experience, proximity to infected patients) on professional quality of life, represented by compassion satisfaction (CS), burnout, and secondary traumatization (ST), in HCWs facing COVID-19 emergency. Further, two multivariable linear regression analyses were fitted to explore the association of mental health selected outcomes, anxiety and depression, with some personal and working characteristics that are COVID-19-related. A sample of 265 HCWs of a major university hospital in central Italy was consecutively recruited at the outpatient service of the Occupational Health Department during the acute phase of COVID-19 pandemic. HCWs were assessed by Professional Quality of Life-5 (ProQOL-5), the Nine-Item Patient Health Questionnaire (PHQ-9), and the Seven-Item Generalized Anxiety Disorder scale (GAD-7) to evaluate, respectively, CS, burnout, ST, and symptoms of depression and anxiety. Females showed higher ST than males, while frontline staff and healthcare assistants reported higher CS rather than second-line staff and physicians, respectively. Burnout and ST, besides some work or personal variables, were associated to depressive or anxiety scores. The COVID-19 pandemic represents a new working challenge for HCWs and intervention strategies to prevent burnout and ST to reduce the risk of adverse mental health outcomes are needed.

Caregivers of severely ill individuals often struggle to adjust to new responsibilities and roles while experiencing negative psychological outcomes that include depression, anxiety and Post-Traumatic Stress Disorder (PTSD). This systematic review aims to outline potential risk and protective factors for the development of PTSD in caregivers of adult subjects affected by severe somatic, potentially life-threatening illnesses. Twenty-nine studies on caregivers of adult patients affected by severe, acute, or chronic somatic diseases have been included. Eligibility criteria included: full-text publications reporting primary, empirical data; PTSD in caregivers of adult subjects affected by severe physical illnesses; risk and/or protective factors related to PTSD; and English language. Specific sociodemographic and socioeconomic characteristics, besides the illness-related distress, familiar relationships, exposure characteristics, coping style, and support, were identified as relevant risk/protective factors for PTSD. The review limitations are the small number of studies; studies on different types of diseases; studies with same samples. It is crucial to consider factors affecting caregivers of severely ill adult patients in order to plan effective intervention strategies aimed at reducing the risk of an adverse mental health outcome and at enhancing the psychological endurance of this population.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX , DIPK2A , NELFB , and TEF . However, when primary AMs (PALM + NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.

The role of local electron-vibration and electron-electron interactions on the thermoelectric properties of molecular junctions is theoretically analyzed focusing on devices based on fullerene molecules. A self-consistent adiabatic approach is used in order to obtain a non-perturbative treatment of the electron coupling to low frequency vibrational modes, such as those of the molecule center of mass between metallic leads. The approach also incorporates the effects of strong electron-electron interactions between molecular degrees of freedom within the Coulomb blockade regime. The analysis is based on a one-level model which takes into account the relevant transport level of fullerene and its alignment to the chemical potential of the leads. We demonstrate that only the combined effect of local electron-vibration and electron-electron interactions is able to predict the correct behavior of both the charge conductance and the Seebeck coefficient in very good agreement with available experimental data.

Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and immune cells can reciprocally influence each other, with EMT cells promoting immune exclusion and deviation and immune cells promoting, under certain circumstances, the induction of EMT in tumor cells. This cross-talk between EMT tumor cells and immune cells can occur both between EMT tumor cells and cells of either the native or adaptive immune system. In this article, we review this evidence and the functional consequences of it. We also discuss some recent evidence showing that tumor cells and cells of the immune system respond to similar stimuli, activate the expression of partially overlapping gene sets, and acquire, at least in part, identical functionalities such as migration and invasion. The possible significance of these symmetrical changes in the cross-talk between EMT tumor cells and immune cells is addressed. Eventually, we also discuss possible therapeutic opportunities that may derive from disrupting this cross-talk.

Background : Over the past decades, problematic internet use (PIU) has dramatically increased, especially among young people. PIU has been recently associated with autism spectrum disorder (ASD) and autistic traits. Subjects with PIU report an increased suicidal risk and the same has been demonstrated among patients with ASD. The aim of this study was to investigate putative PIU rates among students and explore the correlation between autistic traits and suicide risk. Methods : A sample of 178 high achieving university students was assessed by means of the Adult Autism Subthreshold Spectrum (AdAS Spectrum), Autism Quotient questionnaire (AQ). Suicide risk was investigated by some specific items of the Trauma and Loss Spectrum-Self Report (TALS-SR) and putative PIU was identified on the basis of a specific AdAS Spectrum item. Results : 27.5% subjects reporting putative PIU. This subgroup showed higher scores in all domains of AdAS Spectrum and AQ compared with others. Students with putative PIU showed a significant correlation between suicide risk and the non-verbal communication domain of the AdAS Spectrum and the Social skills domain of the AQ. Conclusions : We found that students with PIU show higher levels of autistic traits compared to those without PIU. A significant correlation was found between autistic traits and suicide risk.

Despite the low mortality rates, well-differentiated thyroid carcinomas (WDTC) frequently relapse. BRAF and TERT mutations have been extensively related to prognosis in thyroid cancer. In this study, the methylation levels of selected CpGs (5-cytosine-phosphate-guanine-3) comprising a classifier, previously reported by our group, were assessed in combination with BRAF and TERT mutations. We evaluated 121 WDTC, three poorly-differentiated/anaplastic thyroid carcinomas (PDTC/ATC), 22 benign thyroid lesions (BTL), and 13 non-neoplastic thyroid (NT) tissues. BRAF (V600E) and TERT promoter (C228T and C250T) mutations were tested by pyrosequencing and Sanger sequencing, respectively. Three CpGs mapped in PFKFB2 , ATP6V0C , and CXXC5 were evaluated by bisulfite pyrosequencing. ATP6V0C hypermethylation and PFKFB2 hypomethylation were detected in poor-prognosis (PDTC/ATC and relapsed WDTC) compared with good-prognosis (no relapsed WDTC) and non-malignant cases (NT/BTL). CXXC5 was hypomethylated in both poor and good-prognosis cases. Shorter disease-free survival was observed in WDTC patients presenting lower PFKFB2 methylation levels ( p = 0.004). No association was observed on comparing BRAF (60.7%) and TERT (3.4%) mutations and prognosis. Lower PFKFB2 methylation levels was an independent factor of high relapse risk (Hazard Ratio = 3.2; CI 95% = 1.1⁻9.5). PFKFB2 promoter methylation analysis has potential applicability to better stratify WDTC patients according to the recurrence risk, independently of BRAF and TERT mutations.

The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-D-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% ± 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels.