Facile discovery of surrogate cytokine agonists.

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice.

BACKGROUND AIMS: Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. APPROACH RESULTS: We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains. CONCLUSIONS: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

A simple and inexpensive method to monitor and minimize exposure from manipulation of cytotoxic drugs.

Pharmacy personnel that manipulate cytotoxic drugs are under continuous exposure risk. Therefore, training and strict adherence to recommended practices should always be promoted. The main objective of this study was to develop and apply a safe, effective and low-cost method for the training and assessment of the safe handling of cytotoxic drugs, using commercially available tonic water. To evaluate the potential of tonic water as a replacement marker for quinine hydrochloride, deliberate spills of 1 mL of four different tonic waters (one coloured and three non-coloured) were analysed under ultraviolet light (300-400 nm). The pigmented sample did not produce fluorescence under ultraviolet (UV) light. The three commercially available tonic waters that exhibited fluorescence were further analysed by UV/Vis spectrophotometry (300-500 nm). Afterwards, a protocol of simulated manipulation of cytotoxic drugs was developed and applied to 12 pharmacy technicians, that prepared 24 intravenous bags according to recommended routine procedures using tonic water. Participants responded to a brief questionnaire to evaluate the adequacy and applicability of the activity. Seven of the participants had spillages during manipulation, the majority of which recorded during manipulation with needles. All participants scored the tonic water manipulation simulation with 4 or 5 points for simplicity, efficiency and feasibility. The obtained results suggest that tonic water can be used to simulate the manipulation of cytotoxic drugs in training and assessment programs. By using this replacement marker for quinine hydrochloride, it is possible to perform a more cost-effective, yet equally effective, assessment.

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein.

BACKGROUND: Patients with antibody deficiency respond poorly to coronavirus disease 2019 (COVID-19) vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesized that immunoglobulin preparations will now contain neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies, which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralizing capacity of patient samples and immunoglobulin products was assessed using in vitro pseudovirus and live-virus neutralization assays, the latter investigating multiple batches against current circulating Omicron variants. We describe the clinical course of 9 patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titer increased from 2123 to 10 600 U/mL postinfusion, with corresponding increase in pseudovirus neutralization titers to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralization, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum >900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralizing anti-SARS-CoV-2 antibodies that are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity.

Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma.

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.

Characterization of education, technical practices and attitudes of Portuguese pharmacy technicians towards manipulation of cytotoxic drugs.

Pharmacy professionals that manipulate cytotoxic drugs need to undergo educational programs, adopt the most convenient practices, and use appropriate equipment to avoid, as far as possible, occupational exposure to cytotoxic drugs. The main goal of this work is to characterize the education, technical practices, and attitudes towards cytotoxic drugs, of Portuguese pharmacy technicians. A questionnaire comprising eleven questions deemed pertinent was elaborated and subsequently validated by a pilot test. The anonymous, web-based survey was conducted between December 2022 and January 2023, by graduated pharmacy technicians that had manipulated cytotoxic drugs between 2017 and 2022. A total of 77 pharmacy technicians responded to the survey. Although sixty-six pharmacy technicians (86%) had been trained before beginning to manipulate cytotoxic drugs, the promotion of regular post-admission training by the institutions is sparse - only assumed by 53% of the pharmacy technicians (n = 41). All participants reported using gloves and gown during manipulation and the use of double gloves was common (99%; n = 76). Compliances with the recommended limit time for uninterrupted manipulation activity (82%; n = 63) and systematic double-checking (86%; n = 66) were high, but the regular use of sterile gauze around syringe connection sites 58% (n = 45), was less frequent. None of the surveyed pharmacy technicians used closed-system transfer devices (CSTD) and 41 (53%) of those who used spikes did not thoughtfully use these devices. The implementation of regular training programs in manipulating cytotoxic drugs should be fostered, to promote the more judicious use of engineering controls and transversal adoption of the safest technical practices.

Airway inflammation and dysbiosis in antibody deficiency despite the presence of IgG.

BACKGROUND: Patients with antibody deficiency suffer chronic respiratory symptoms, recurrent exacerbations, and progressive airways disease despite systemic replacement of IgG. Little is known about the respiratory tract biology of these patients. OBJECTIVE: We sought to measure immunoglobulin levels, inflammatory cytokines, and mediators of tissue damage in serum and sputum from patients with antibody deficiency and healthy controls; to analyze the respiratory microbiome in the same cohorts. METHODS: We obtained paired sputum and serum samples from 31 immunocompetent subjects and 67 antibody-deficient patients, the latter divided on computed tomography scan appearance into "abnormal airways" (bronchiectasis or airway thickening) or "normal airways." We measured inflammatory cytokines, immunoglobulin levels, neutrophil elastase, matrix-metalloproteinase-9, urea, albumin, and total protein levels using standard assays. We used V3-V4 region 16S sequencing for microbiome analysis. RESULTS: Immunodeficient patients had markedly reduced IgA in sputum but higher concentrations of IgG compared with healthy controls. Inflammatory cytokines and tissue damage markers were higher in immunodeficient patients, who also exhibited dysbiosis with overrepresentation of pathogenic taxa and significantly reduced alpha diversity compared with immunocompetent individuals. These differences were seen regardless of airway morphology. Sputum matrix-metalloproteinase-9 and elastase correlated inversely with alpha diversity in the antibody-deficient group, as did sputum IgG, which correlated positively with several inflammatory markers, even after correction for albumin levels. CONCLUSIONS: Patients with antibody deficiency, even with normal lung imaging, exhibit inflammation and dysbiosis in their airways despite higher levels of IgG compared with healthy controls.

Electrochemical Chemically Based Sensors and Emerging Enzymatic Biosensors for Antidepressant Drug Detection: A Review.

Major depressive disorder is a widespread condition with antidepressants as the main pharmacological treatment. However, some patients experience concerning adverse reactions or have an inadequate response to treatment. Analytical chromatographic techniques, among other techniques, are valuable tools for investigating medication complications, including those associated with antidepressants. Nevertheless, there is a growing need to address the limitations associated with these techniques. In recent years, electrochemical (bio)sensors have garnered significant attention due to their lower cost, portability, and precision. Electrochemical (bio)sensors can be used for various applications related to depression, such as monitoring the levels of antidepressants in biological and in environmental samples. They can provide accurate and rapid results, which could facilitate personalized treatment and improve patient outcomes. This state-of-the-art literature review aims to explore the latest advancements in the electrochemical detection of antidepressants. The review focuses on two types of electrochemical sensors: Chemically modified sensors and enzyme-based biosensors. The referred papers are carefully categorized according to their respective sensor type. The review examines the differences between the two sensing methods, highlights their unique features and limitations, and provides an in-depth analysis of each sensor.

Chromatographic Methods Developed for the Quantification of Quercetin Extracted from Natural Sources: Systematic Review of Published Studies from 2018 to 2022.

Quercetin (QUE) is the most widely used flavonoid for therapeutic purposes. To improve the available knowledge about the properties of some natural products, determining the amount of QUE is crucial. The main objective of this systematic review is to identify the analytical methods validated for detecting and quantifying QUE in different matrices and characterize their sensitivity. A search was conducted until 30 June 2023 in the PubMed database for experimental studies that addressed the validation of chromatographic analytical methods to detect and quantify QUE from consumable natural products. Only studies published between 2018 and 2022, written in English, were included. The risk of bias was assessed by emphasizing methods of comparison according to previously published studies. Descriptive statistics were used to depict the obtained results. The studies were analyzed based on the type of QUE source, chromatographic method, and validation parameters. A total of 17 studies were included in this review. Plants were the most commonly analyzed source of QUE. Among the detection methods, spectrophotometry proved to be the most widely used, surpassing mass spectrometry (MS). After analyzing the bias, all the included studies mentioned/presented, totally or partially, at least four of the eight parameters.

Meaningful learning: motivations of older adults in serious games.

Social sustainability is the generation of significant behaviors through balanced levels of education, learning and awareness so that the population has a good standard of living, achieves self-improvement and supports society. This can be achieved with various strategies, one of which is learning through games, which has gained popularity in recent years due to positive results. This is effectively achieved through serious gaming, which is growing steadily, mostly in education and healthcare. This type of strategy has been typically used in young populations with a transparent interaction with technological processes that facilitate its application. However, one cannot neglect other populations such as the elderly, who may experience a technology gap and may not perceive this type of initiative in the best light. The purpose of this article is to identify the different motivations that can encourage older adults to use serious games to encourage learning processes through technology. For this purpose, different previous research on gaming experiences with older adults has been identified, from which it was possible to categorize a series of factors that motivate this population. Subsequently, we represented these factors by means of a model of motivation for the elderly and, to be able to use it, we have defined a set of heuristics based on this model. Finally, we used the heuristics by means of a questionnaire to evaluate the design of serious gaming for older adults, obtaining positive results for the use of these elements to guide the design and construction of serious games for learning in older adults.

Bowel Histology of CVID Patients Reveals Distinct Patterns of Mucosal Inflammation.

Diarrhea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Different pathologies in patients' bowel biopsies have been described and links with infections have been demonstrated. The aim of this study was to analyze the bowel histology of CVID patients in the Royal-Free-Hospital (RFH) London CVID cohort. Ninety-five bowel histology samples from 44 adult CVID patients were reviewed and grouped by histological patterns. Reasons for endoscopy and possible causative infections were recorded. Lymphocyte phenotyping results were compared between patients with different histological features. There was no distinctive feature that occurred in most diarrhea patients. Out of 44 patients (95 biopsies), 38 lacked plasma cells. In 14 of 21 patients with nodular lymphoid hyperplasia (NLH), this was the only visible pathology. In two patients, an infection with Giardia lamblia was associated with NLH. An IBD-like picture was seen in two patients. A coeliac-like picture was found in six patients, four of these had norovirus. NLH as well as inflammation often occurred as single features. There was no difference in blood lymphocyte phenotyping results comparing groups of histological features. We suggest that bowel histology in CVID patients with abdominal symptoms falls into three major histological patterns: (i) a coeliac-like histology, (ii) IBD-like changes, and (iii) NLH. Most patients, but remarkably not all, lacked plasma cells. CVID patients with diarrhea may have an altered bowel histology due to poorly understood and likely diverse immune-mediated mechanisms, occasionally driven by infections.

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study.

BACKGROUND: Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. OBJECTIVES: COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. METHODS: Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. RESULTS: A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. CONCLUSION: SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

Phenotypic antimicrobial resistance (AMR) of avian pathogenic Escherichia coli (APEC) from broiler breeder flocks between 2009 and 2018.

Colibacillosis is one of the most important diseases in poultry production. The use of antimicrobials remains a therapeutic cornerstone for avian pathogenic E. coli (APEC), thereby contributing to the development of antimicrobial resistance (AMR). The aim of this study was to characterize AMR in broiler breeder flocks reared under commercial conditions. Data covering 10 years, from 2009 to 2018, were used to evaluate the phenotypic AMR of 264 APEC isolates obtained from 158 broiler breeder flocks of a large company in Portugal. The APEC isolates were tested against eleven antimicrobials by the Kirby-Bauer disc diffusion test. The annual proportion of AMR was calculated by dividing the number of APEC isolates with phenotypic resistance by the total number of APEC isolated that year. Similarly, the overall AMR of the whole period was calculated. The relationship of antimicrobial resistance with time (years) was investigated with a generalized linear model using logistic regression. The overall AMR of the 10-year period was: amoxicillin 78%, ampicillin 73.5%, tetracycline 63.3%, doxycycline 56.4%, apramycin 34.5%, neomycin 68.2%, enrofloxacin 32.6%, flumequine 39.4%, co-trimoxazole 47.7%, florfenicol 46.6% and lincospectin 66.3%. Over time, a significant decrease in AMR was observed for amoxicillin and ampicillin, neomycin, flumequine, co-trimoxazole, florfenicol and lincospectin. Multidrug resistance (MDR) decreased from 100% in 2009 to 48% in 2018. Only seven (2.7%) APEC strains were fully susceptible to all tested antimicrobials. The decrease over time of AMR in APEC likely reflects the efficacy of manifold improvements in broiler breeder production systems. A further reduction in AMR is still desirable. RESEARCH HIGHLIGHTSDecreasing trend of antimicrobial resistance in avian pathogenic E. coli over time.Over 50% of isolates still resistant to amoxicillin, tetracycline and doxycycline.Multidrug resistance decreased from 100% in 2009 to 48% in 2018.Further reduction of antimicrobial resistance in broiler breeders desirable.

Mixed Assessment of Virtual Serious Games Applied in Architectural and Urban Design Education.

The creation and usage of serious games on virtual reality (VR) and/or interactive platforms for the teaching of architecture, construction, urban planning, and other derived areas, such as security and risk prevention, require design processes, studies, and research that lead to further consolidation expansion. In that sense, this paper presents two main aims developed: the improvement of a virtual navigation system through the results of previous user studies and mixed research (quantitative and qualitative) improved based on the user perception for educational and professional uses. The VR system used is based on Unreal Engine programming of the HTC Vive sensor. This study is related to the GAME4City 3.0 and a broader project focused on gamified visualization and its educational uses in architectural and urban projects. The results reflect great interest, good usability, and high motivation for further usage for all types of users. However, an apparent resistance to deepen its use continues to be perceived in academia. Based on the research results, weak points of educational gamified systems have been identified, and the main differences and needs in user profiles' function. With these data, progress regarding implementing this kind of system at the teaching and professional levels must be pursued.

Potentialities and limitations of computer-aided design and manufacturing technology in the nonextraction treatment of Class I malocclusion.

INTRODUCTION: Computer-aided design and manufacturing (CAD-CAM) systems have assisted orthodontists to position brackets virtually. The purpose of this study was to evaluate if a CAD-CAM system could predict the orthodontic treatment outcome of patients with Angle Class I malocclusion with mild crowding or spacing and with no need for orthodontic extraction. METHODS: Using the American Board of Orthodontics Cast-Radiograph Evaluation (ABO-CRE) and color map superimposition, the treated occlusion was compared with the virtual final occlusion of 24 young adults with Class I occlusion. Using eXceed software (eXceed, Witten, Germany), we created the final occlusion prediction for each patient (virtual set up group). A digital model of the final occlusion of each patient was created (treated occlusion group). ABO-CRE score was used to compare groups. In addition, a color map was created for all subjects to access the mean and range values between the virtual set up model and treated occlusion model of each patient. Random and systematic errors were calculated. In addition, chi-square and t test were used. RESULTS: Comparisons between virtual set up occlusion and treated occlusion showed statistically significant differences in 3 out of 7 measurements: interproximal contact score was larger for treated than virtual occlusion (0.45 mm and 0.04 mm, respectively), and the treated occlusion showed larger values than the virtual occlusion for occlusal contacts (14.13 mm and 7.62 mm, respectively) and overjet (7.37 mm and 0.66 mm, respectively). Although the treated occlusion showed a larger score than the virtual occlusion (50.41 mm and 34.58 mm, respectively), there is no significant difference between both. Root angulation decreased (from 1.95 ± 1.29 to 0.65 ± 0.71) because of the treatment. CONCLUSIONS: ABO-CRE overall score presents no difference between groups. In addition, CAD-CAM setup occlusion closely predicts the final teeth alignment and leveling with interarch relationships showing less ABO-CRE score deduction.

Absence of Persistent Hepatitis E Virus Infection in Antibody-Deficient Patients Is Associated With Transfer of Antigen-Neutralizing Antibodies From Immunoglobulin Products.

Background: Persistent hepatitis E virus (HEV) infection is described in a number of immunosuppressive conditions. We aimed to determine the risk of persistent HEV infection in patients with primary or secondary antibody deficiency. Methods: Two hundred forty-five antibody-deficient patients receiving regular immunoglobulin replacement therapy were tested for HEV RNA and anti-HEV immunoglobulin G (IgG). Immunoglobulin products and plasma specimens obtained from 9 antibody-deficient patients before and after intravenous immunoglobulin (IVIG) therapy, 5 recently treated patients with persistent HEV infection, and 5 healthy patients recovered from acute HEV infection were analyzed for anti-HEV IgG and for antibody reacting with HEV antigen. Results: No antibody-deficient patient had detectable plasma HEV RNA. Anti-HEV IgG was detected in 38.8% of patients. All 10 immunoglobulin products tested contained anti-HEV capable of neutralizing HEV antigen. Plasma samples collected following IVIG infusion therapy demonstrated a higher anti-HEV IgG level and neutralizing activity, compared with samples collected before IVIG therapy. Neutralizing activity was similar to that in healthy patients with recent acute HEV infection. Conclusion: The risk of persistent HEV infection in patients with antibody deficiency appears extremely low. This may be due to passive seroprotection afforded by the ubiquitous presence of anti-HEV in immunoglobulin replacement products.

Chronic Granulomatous Disorder-Associated Colitis Can Be Accurately Evaluated with MRI Scans and Fecal Calprotectin Level.

PURPOSE: Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. METHODS: We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. RESULTS: MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p < 0.0001; for CDMI R2 0.83, p = 0.0006; for MaRIA R2 0.89, p = 0.0002). MRI was better tolerated and generally preferred, quicker, and visualized the entire large bowel whereas colonoscopy did not reach the terminal ileum in 3 participants. Elevated FCP accurately differentiated patients with colitis from those without, and log(calprotectin) correlated well with disease activity (R2 0.71, p = 0.009). Serum interleukin (IL)-12 concentration correlated with colitis activity but IL-1ß and TNF did not. Harvey-Bradshaw index did not correlate with colitis activity. CONCLUSIONS: MRI and fecal calprotectin are useful methods for monitoring CGD colitis and should reduce the need for colonoscopy in these patients. IL-12 may represent an appropriate target for treatment.

Flow experience and the mobilization of attentional resources.

The present study attempts to better identify the neurophysiological changes occurring during flow experience and how this can be related to the mobilization of attentional resources. Self-reports of flow (using a flow feelings scale) and attention (using thought probes), autonomic activity (heart rate, heart rate variability, and breathing rate), and cerebral oxygenation (using near-infrared spectroscopy) in two regions of the frontoparietal attention network (right lateral frontal cortex and right inferior parietal lobe) were measured during the practice of two simple video games (Tetris and Pong) played at different difficulty conditions (easy, optimal, hard, or self-selected). Our results indicated that an optimal level of difficulty, compared with an easy or hard level of difficulty led to greater flow feelings and a higher concentration of oxygenated hemoglobin in the regions of the frontoparietal network. The self-selected, named autonomy condition did not lead to more flow feelings than the optimal condition; however, the autonomy condition led to greater sympathetic activity (reduced heart rate variability and greater breathing rate) and higher activation of the frontoparietal regions. Our study suggests that flow feelings are highly connected to the mobilization of attentional resources, and all the more in a condition that promotes individuals' choice and autonomy.

Photobiomodulation and bacterial cellulose membrane in the treatment of third-degree burns in rats.

Burns are injuries caused mainly by thermal trauma, which can progress to unsatisfactory results healing. This study aimed to evaluate the biomaterial (bacterial cellulose membrane) and photobiomodulation, exclusively and associated, in the treatment of third degree burns in rats. Forty male Wistar rats (±280 g) were randomly divided into four groups, with 10 animals each: control group (CG); bacterial cellulose membrane group (MG); laser group (LG) and bacterial cellulose membrane and laser group (MG + L). The burn was caused with a 1 cm2 aluminum plate heated to 150 °C and pressed on the animal's back for 10 s. The treatments were started immediately after induction of injury. For to laser irradiation (660 nm, 100 mW, 25 J/cm2 and energy of 1 J) on five distinct application points were used, on alternate days, a total of five sessions. After ten days of treatment the animals were euthanized for collected samples. One-way ANOVA and Tukey's tests (P < 0.05) were used. Histological analysis revealed differences regarding the healing process phase in each experimental group. MG showed the proliferative phase. The LG demonstrated greater amount of blood vessels and immune expression of VEGF. However, when the treatments were combined, the number of vessels and the immune expression of VEGF factor was lower than LG. Thus, it was concluded that both treatments proposed (biomaterial and LLLT) are good alternatives for third degree burns when applied isolated because they stimulate the healing process by acting on the modulation of the inflammatory phase and promote stimulation of angiogenesis.