7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.

Radiopalmar ganglion cysts: prevalence, morphology, and clinical significance in wrist MRI.

OBJECTIVES: To assess radiopalmar ganglion cysts' (RPG) prevalence, morphology, and clinical significance in consecutive patients. MATERIALS AND METHODS: In this retrospective single-center study, two radiologists assessed the presence of RPG and morphologic features on wrist MRI. Radiopalmar complaints and scapholunate ligament (SLL) tears were evaluated. RESULTS: A total of 1053 wrists in 909 patients (mean age 43.4 ± 15.5 years, 602 females) were evaluated. All 308 RPG (Group 1; 308 patients, 29.2%) originated from the palmar capsule; 49 were unilocular, 95 oligolocular, and 164 multilocular; 745 wrists had no RPG (Group 2; 601 patients). One hundred and twenty-six RPG showed internal debris. The mean diameter was 8.5 ± 5.6 mm (cranio-caudal) (1.0-32.9 mm), 8.0 ± 4.1 mm (medio-lateral) (1.0-31.9 mm), and 3.7 ± 2.3 mm (dorso-palmar) (0.4-16.0 mm). 168 RPG showed direct contact with the radial vascular bundle, 24 with the flexor carpi radialis tendon, and 123 with the flexor pollicis longus tendon. In Group 1, significantly more patients showed partial (82/308) [group 2: 45/745, p < 0.001] or complete SLL tears (22/308) [group 2: 20/745, p < 0.001]. Of the patients with RPG, 15.3% presented with radiopalmar complaints. Only the dorso-palmar RPG diameter was positively correlated with radiopalmar complaints (for readers 1 and 2: rs = 0.66/0.61, p < 0.001, respectively), and the best dorso-palmar diameter cut-off value for the probability of having radiopalmar complaints was defined at 3 mm (area under the curve (AUC) 0.74). Other morphologic features were not eligible to discriminate symptomatic patients (AUC range 0.53-0.61). CONCLUSION: This study found RPG in 29% of patients, most of them asymptomatic. However, a dorso-palmar cyst diameter > 3 mm may be clinically significant. CLINICAL RELEVANCE STATEMENT: Radiopalmar ganglion cysts, observed in 29% of wrist MR examinations, are mostly asymptomatic, but those with a larger dorso-palmar diameter may be associated with radiopalmar complaints. KEY POINTS: Radiopalmar ganglion cysts are found in 29% of patients undergoing wrist MRI. Most patients with evidence of radiopalmar ganglion cysts do not show radiopalmar symptoms (85%). A dorso-palmar cyst diameter > 3 mm may be associated with radiopalmar complaints.

Alcohol does not influence trust in others or oxytocin, but increases positive affect and risk-taking: a randomized, controlled, within-subject trial.

BACKGROUND: Alcohol consumption to facilitate social interaction is an important drinking motive. Here, we tested whether alcohol influences trust in others via modulation of oxytocin and/or androgens. We also aimed at confirming previously shown alcohol effects on positive affect and risk-taking, because of their role in facilitating social interaction. METHODS: This randomized, controlled, within-subject, parallel group, alcohol-challenge experiment investigated the effects of alcohol (versus water, both mixed with orange juice) on perceived trustworthiness via salivary oxytocin (primary and secondary endpoint) as well as testosterone, dihydrotestosterone, positive affect, and risk-taking (additional endpoints). We compared 56 male participants in the alcohol condition (1.07 ± 0.18 per mille blood alcohol concentration) with 20 in the control condition. RESULTS: The group (alcohol versus control condition) × time (before [versus during] versus after drinking) interactions were not significantly associated with perceived trustworthiness (η2 < 0.001) or oxytocin (η2 = 0.003). Bayes factors provided also substantial evidence for the absence of these effects (BF01 = 3.65; BF01 = 7.53). The group × time interactions were related to dihydrotestosterone (η2 = 0.018 with an increase in the control condition) as well as positive affect and risk-taking (η2 = 0.027 and 0.007 with increases in the alcohol condition), but not significantly to testosterone. DISCUSSION: The results do not verify alcohol effects on perceived trustworthiness or oxytocin in male individuals. However, they indicate that alcohol (versus control) might inhibit an increase in dihydrotestosterone and confirm that alcohol amplifies positive affect and risk-taking. This provides novel mechanistic insight into social facilitation as an alcohol-drinking motive.

Static spacers play a crucial role in the treatment of complex periprosthetic joint infections of the knee.

PURPOSE: To determine the superior spacer design, a growing number of studies are comparing treatment results between patients having been treated with articulating and static knee spacers in the setting of two-stage revision for periprosthetic joint infection (PJI). In contrast, the primary objective of this study was to compare preoperative characteristics between patients from both spacer groups and examine whether significant differences were present prior to spacer implantation. METHODS: This retrospective, single-centre, cohort study examined the preoperative situation of 80 consecutive knee PJIs between 2017 and 2020. All patients underwent two-stage revision, with 35 (44%) receiving an articulating and 45 (56%) a static spacer. RESULTS: No significant differences were observed in terms of patient gender (p = 0.083), age (p = 0.666), comorbidity (p = 0.1) and preoperative clinical function (p = 0.246). Static spacers were significantly more often used in the presence of a periarticular fistula (p = 0.033), infection of a revision implant (p < 0.001), higher degree of bone loss (p < 0.001) and infection caused by a difficult-to-treat pathogen (p = 0.038). Complication and revision rates were similar for both spacer types during the interim period, while patients with articulating spacers demonstrated a superior clinical function (p < 0.001) during the interim period and after reimplantation. CONCLUSION: Static spacers are being utilised in significantly more complex and unfavourable preoperative scenarios. Therefore, a preoperative selection bias may be at least partially accountable for any disparities observed in postoperative outcomes. To achieve the best possible results, surgeons should know and respect the distinct indications of static and articulating spacers and consequently understand and use them as complementary surgical options. LEVEL OF EVIDENCE: Level III.

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.

OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). METHODS: RNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

When attitudes and beliefs get in the way of shared decision-making: A mediation analysis of participation preference.

INTRODUCTION: Certain sociodemographic characteristics (e.g., older age) have previously been identified as barriers to patients' participation preference in shared decision-making (SDM). We aim to demonstrate that this relationship is mediated by the perceived power imbalance that manifests itself in patients' negative attitudes and beliefs about their role in decision-making. METHODS: We recruited a large sample (N = 434) of outpatients with a range of urological diagnoses (42.2% urooncological). Before the medical consultation at a university hospital, patients completed the Patients' Attitudes and Beliefs Scale and the Autonomy Preference Index. We evaluated attitudes as a mediator between sociodemographic factors and participation preference in a path model. RESULTS: We replicated associations between relevant sociodemographic factors and participation preference. Importantly, attitudes and beliefs about one's own role as a patient mediated this relationship. The mediation path model explained a substantial proportion of the variance in participation preference (27.8%). Participation preferences and attitudes did not differ for oncological and nononcological patients. CONCLUSION: Patients' attitudes and beliefs about their role determine whether they are willing to participate in medical decision-making. Thus, inviting patients to participate in SDM should encompass an assessment of their attitudes and beliefs. Importantly, negative attitudes may be accessible to change. Unlike stable sociodemographic characteristics, such values are promising targets for interventions to foster more active participation in SDM. PATIENT OR PUBLIC CONTRIBUTION: This study was part of a larger project on implementing SDM in urological practice. Several stakeholders were involved in the design, planning and conduction of this study, for example, three authors are practising urologists, and three are psychologists with experience in patient care. In addition, the survey was piloted with patients, and their feedback was integrated into the questionnaire. The data presented in this study is based on patients' responses. Results may help to empower our patients.

Getting specific: participation preference in urooncological decision-making.

BACKGROUND: Shared decision-making is the gold standard for good clinical practice, and thus, psychometric instruments have been established to assess patients' generic preference for participation (e.g., the Autonomy Preference Index, API). However, patients' preferences may vary depending on the specific disease and with respect to the specific decision context. With a modified preference index (API-Uro), we assessed patients' specific participation preference in preference-sensitive decisions pertaining to urological cancer treatments and compared this with their generic participation preference. METHODS: In Study 1, we recruited (N = 469) urological outpatients (43.1% urooncological) at a large university hospital. Participation preference was assessed with generic measures (API and API case vignettes) and with the disease-specific API-Uro (urooncological case vignettes describing medical decisions of variable difficulty). A polychoric exploratory factor analysis was used to establish factorial validity and reduce items. In Study 2, we collected data from N = 204 bladder cancer patients in a multicenter study to validate the factorial structure with confirmatory factor analysis. Differences between the participation preference for different decision contexts were analyzed. RESULTS: Study 1: Scores on the specific urooncological case vignettes (API-Uro) correlated with the generic measure (r = .44) but also provided incremental information. Among the disease-specific vignettes of the API-Uro, there were two factors with good internal consistency (α ≥ .8): treatment versus diagnostic decisions. Patients desired more participation for treatment decisions (77.8%) than for diagnostic decisions (22%), χ2(1) = 245.1, p ≤ .001. Study 2: Replicated the correlation of the API-Uro with the API (r = .39) and its factorial structure (SRMR = .08; CFI = .974). Bladder cancer patients also desired more participation for treatment decisions (57.4%) than for diagnostic decisions (13.3%), χ²(1) =84, p ≤ .001. CONCLUSIONS: The desire to participate varies between treatment versus diagnostic decisions among urological patients. This underscores the importance of assessing participation preference for specific contexts. Overall, the new API-Uro has good psychometric properties and is well suited to assess patients' preferences. In routine care, measures of participation preference for specific decision contexts may provide incremental, allowing clinicians to better address their patients' individual needs.

Enhanced antibiotic release from bone cement spacers utilizing dual antibiotic loading with elevated vancomycin concentrations in two-stage revision for periprosthetic joint infection.

PURPOSE: Antibiotic loaded bone cement spacers provide high local antibiotic concentrations, preserve bone stock, and reduce soft tissue contractions. The objective of this in-vitro study was to compare antibiotic release from spacers, aiming to discover the most optimal preparation and identify modifiable factors that can further enhance antibiotic release. METHODS: Six distinct spacer preparation were created using three different bone cements and manual incorporation of antibiotics. During a six-week period, the release of antibiotics from each spacer was measured individually at ten predetermined time points using a chemiluminescent immunoassay. RESULTS: Manually adding 4 g of vancomycin to every 40 g of "Palacos R + G" yielded the most favorable release profile. Throughout all preparations, antibiotic release consistently and significantly decreased over the six-week period. When incorporating a higher concentration of vancomycin, a significantly higher cumulative release of vancomycin was observed, with varying effects on the release of gentamicin. The choice of bone cement had a significant impact on antibiotic release. CONCLUSION: To enhance antibiotic release from spacers, surgeons should manually incorporate high antibiotic concentrations into the most appropriate bone cement and keep the interim period as short as possible. Specifically, we suggest manual incorporation of 4 g of vancomycin to every 40 g of gentamicin premixed "Palacos R + G" to create bone cement spacers.

Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a disease characterized by increased susceptibility to infections, hypogammaglobulinemia, and immune dysregulation. Although CVID is thought to be a disorder of the peripheral B-cell compartment, in 25% of patients, early B-cell development in the bone marrow is impaired. Because poor B-cell reconstitution after hematopoietic stem cell transplantation has been observed, we hypothesized that in some patients the bone marrow environment is not permissive to B-cell development. Studying the differentiation dynamics of bone marrow-derived CD34+ cells into immature B cells in vitro allowed us to distinguish patients with B-cell intrinsic defects and patients with a nonpermissive bone marrow environment. In the former, immature B cells did not develop and in the latter CD34+ cells differentiated into immature cells in vitro, but less efficiently in vivo. In a further group of patients, the uncommitted precursors were unable to support the constant development of B cells in vitro, indicating a possible low frequency or exhaustion of the precursor population. Hematopoietic stem cell transplantation would result in normal B-cell repopulation in case of intrinsic B-cell defect, but in defective B-cell repopulation in a nonpermissive environment. Our study points to the importance of the bone marrow niche in the pathogenesis of CVID.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

A Smarter Way to Use Your Smartphone: An Intervention to Limit Smartphone-Related Distractions Reduces Hyperactivity but Not Inattention Symptoms.

INTRODUCTION: Smartphones are often helpful in our everyday lives. Yet, they also tend to interrupt us during other activities. It has been argued that such distractions contribute to attention-deficit/hyperactivity disorder-like symptoms. However, since there are mostly correlational studies, the causal nature of this relationship is unclear. Our aim was to test whether reducing smartphone-related distractions might have a beneficial effect on inattention and hyperactive symptoms. METHODS: We conducted a 1-week field experiment with 37 healthy undergraduates and quasi-randomly assigned them to an intervention or control group (CG). The intervention group was given theory-based specific instructions that aimed at reducing smartphone-related distractions, whereas the CG received no intervention. The outcomes of interest were inattention level, hyperactive symptoms, and working memory accuracy. RESULTS: Compared to those in the control condition, participants who limited their smartphone use showed considerable reductions in hyperactive symptoms after 1 week - particularly those who displayed high problematic smartphone use. However, there were no group differences regarding inattention symptoms and working memory accuracy. DISCUSSION: The results give a first hint that strategically reducing smartphone-related distractions via specific but simple use modifications can mitigate hyperactive symptoms. Especially people with problematic smartphone use seem to profit from such an intervention. Remaining questions and directions are discussed.

Mechanical strength of antibiotic-loaded PMMA spacers in two-stage revision surgery.

BACKGROUND: Antibiotic-loaded polymethylmethacrylate (PMMA) bone cement spacers provide high local antibiotic concentrations and patient mobility during the interim period of two-stage revision for periprosthetic joint infection (PJI). This study compares mechanical characteristics of six dual antibiotic-loaded bone cement (dALBC) preparations made from three different PMMA bone cements. The study`s main objective was to determine the effect of time and antibiotic concentration on mechanical strength of dALBCs frequently used for spacer fabrication in the setting of two-stage revision for PJI. METHODS: A total of 84 dual antibiotic-loaded bone cement specimens made of either Copal spacem, Copal G + V or Palacos R + G were fabricated. Each specimen contained 0.5 g of gentamicin and either 2 g (low concentration) or 4 g (high concentration) of vancomycin powder per 40 g bone cement. The bending strength was determined at two different timepoints, 24 h and six weeks after spacer fabrication, using the four-point bending test. RESULTS: Preparations made from Copal G + V showed the highest bending strength after incubation for 24 h with a mean of 57.6 ± 1.2 MPa (low concentration) and 50.4 ± 4.4 MPa (high concentration). After incubation for six weeks the bending strength had decreased in all six preparations and Palacos R + G showed the highest bending strength in the high concentration group (39.4 ± 1.6 MPa). All low concentration preparations showed superior mechanical strength compared to their high concentration (4 g of vancomycin) counterpart. This difference was statistically significant for Copal spacem and Copal G + V (both p < 0.001), but not for Palacos R + G (p = 0.09). CONCLUSIONS: This study suggests that mechanical strength of antibiotic-loaded PMMA bone cement critically decreases even over the short time period of six weeks, which is the recommended interim period in the setting of two-stage revision. This potentially results in an increased risk for PMMA spacer fracture at the end of the interim period and especially in patients with prolonged interim periods. Finally, we conclude that intraoperative addition of 4 g of vancomycin powder per 40 g of gentamicin-premixed Palacos R + G (Group D) is mechanically the preparation of choice if a dual antibiotic-loaded bone cement spacer with high antibiotic concentrations and good stability is warranted. In any case the written and signed informed consent including the off-label use of custom-made antibiotic-loaded PMMA bone cement spacers must be obtained before surgery.

Quality of life, infection control, and complication rates using a novel custom-made articulating hip spacer during two-stage revision for periprosthetic joint infection.

INTRODUCTION: Two-stage revision remains the gold standard treatment for most chronically infected and complex total hip arthroplasty infections. To improve patient outcome and reduce complication rates, we have developed a novel custom-made articulating hip spacer technique and present our short-term results. MATERIALS AND METHODS: Between November 2017 and November 2019, 27 patients (mean age 70 years) underwent two-stage revision for periprosthetic joint infection of the hip using the articulating spacer design described here. We retrospectively analyzed spacer-related complications as well as rates for complication, infection control, and implant survivorship after final reimplantation. Furthermore, we prospectively collected patient-reported health-related quality of life (HRQoL) scores prior to spacer implantation, with the spacer and after reimplantation of the new prosthesis. RESULTS: An additional round of spacer exchange was performed in two patients (8.3%), persistent wound discharge was the reason in both cases. We had one (4.2%) spacer-related mechanical complication, a dislocation that was treated with closed reduction. After reimplantation, infection control was achieved in 96% with an implant survivorship of 92% after a mean follow-up time of 19 (range 7-32, SD 7.2) months. While the scores for VR-12 MCS, VAS hip pain and patient-reported overall satisfaction significantly improved after first stage surgery, the scores for WOMAC, UCLA and VR-12 PCS significantly improved after second stage surgery. CONCLUSIONS: Our two-stage approach for periprosthetic joint infection shows high infection eradication and implant survivorship rates at short-term follow-up. Spacer-related complication rates were low, and we achieved high patient satisfaction rates and low pain levels already during the spacer period. To further simplify comparison between different spacer designs, we propose a new hip spacer classification system.

Effects of affective content and motivational context on neural gain functions during naturalistic scene perception.

Visual scene processing is modulated by semantic, motivational, and emotional factors, in addition to physical scene statistics. An open question is to what extent those factors affect low-level visual processing. One index of low-level visual processing is the contrast response function (CRF), representing the change in neural or psychophysical gain with increasing stimulus contrast. Here we aimed to (a) establish the use of an electrophysiological technique for assessing CRFs with complex emotional scenes and (b) examine the effects of motivational context and emotional content on CRFs elicited by naturalistic stimuli, including faces and complex scenes (humans, animals). Motivational context varied by expectancy of threat (a noxious noise) versus safety. CRFs were measured in 18 participants by means of sweep steady-state visual evoked potentials. Results showed a facilitation in visuocortical sensitivity (contrast gain) under threat, compared with safe conditions, across all stimulus categories. Facial stimuli prompted heightened neural response gain, compared with scenes. Within the scenes, response gain was smaller for scenes high in emotional arousal, compared with low-arousing scenes, consistent with interference effects of emotional content. These findings support the notion that motivational context alters the contrast sensitivity of cortical tissue, differing from changes in response gain (activation) when visual cues themselves carry motivational/affective relevance.

Patients' perspective on shared decision-making in urology: a prospective study at a university hospital.

PURPOSE: This study aims to determine the degree of shared decision-making (SDM) from urological patients' perspective and to identify possible predictors. METHODS: Overall, 469 urological patients of a university outpatient clinic were recruited for this prospective study. Before a medical consultation, clinical and sociodemographic information, and patients' emotional distress were assessed by questionnaires. After the consultation, patients completed the SDM-Questionnaire-9 (SDM-Q-9). The SDM-Q-9 scores of relevant subgroups were compared. Logistic regression was used to identify patients at risk for experiencing low involvement (SDM-Q-9 total score ≤ 66) in SDM. RESULTS: Data from 372 patients were available for statistical analyses. The SDM-Q-9 mean total score was 77.8 ± 20.6. The majority of patients (n = 271, 73%) experienced a high degree of involvement (SDM-Q-9 total score > 66). The mean score per SDM-Q-9 item was in the upper range (3.9 ± 1.4 out of 5). The most poorly rated item was "My doctor wanted to know how I want to be involved in decision-making" (3.5 ± 1.6). Immigration status (OR 3.7, p = 0.049), and nonscheduled hospital registration (OR 2.1, p = 0.047) were significant predictors for less perceived involvement. Comorbidity, oncological status, and emotional distress did not significantly predict perceived participation. CONCLUSION: In a university hospital setting, most urological patients feel adequately involved in SDM. Nevertheless, urologists should routinely ask for patients' participation preference. Patients without a scheduled appointment and patients who immigrated may need more support to feel involved in SDM.

Automatic facial coding versus electromyography of mimicked, passive, and inhibited facial response to emotional faces.

Decoding someone's facial expressions provides insights into his or her emotional experience. Recently, Automatic Facial Coding (AFC) software has been developed to provide measurements of emotional facial expressions. Previous studies provided first evidence for the sensitivity of such systems to detect facial responses in study participants. In the present experiment, we set out to generalise these results to affective responses as they can occur in variable social interactions. Thus, we presented facial expressions (happy, neutral, angry) and instructed participants (N = 64) to either actively mimic, to look at them passively (n = 21), or to inhibit their own facial reaction (n = 22). A video stream for AFC and an electromyogram (EMG) of the zygomaticus and corrugator muscles were registered continuously. In the mimicking condition, both AFC and EMG differentiated well between facial expressions in response to the different emotional pictures. In the passive viewing and in the inhibition condition AFC did not detect changes in facial expressions whereas EMG was still highly sensitive. Although only EMG is sensitive when participants intend to conceal their facial reactions, these data extend previous findings that Automatic Facial Coding is a promising tool for the detection of intense facial reaction.

The thioredoxin-1 and glutathione/glutaredoxin-1 systems redundantly fuel murine B-cell development and responses.

Antioxidant systems maintain cellular redox homeostasis. The thioredoxin-1 (Trx1) and the glutathione (GSH)/glutaredoxin-1 (Grx1) systems are key players in preserving cytosolic redox balance. In fact, T lymphocytes critically rely on reducing equivalents from the Trx1 system for DNA biosynthesis during metabolic reprogramming upon activation. We here show that the Trx1 system is also indispensable for development and functionality of marginal zone (MZ) B cells and B1 cells in mice. In contrast, development of conventional B cells, follicular B-cell homeostasis, germinal center reactions, and antibody responses are redundantly sustained by both antioxidant pathways. Proliferating B2 cells lacking Txnrd1 have increased glutathione (GSH) levels and upregulated cytosolic Grx1, which is barely detectable in expanding thymocytes. These results suggest that the redox capacity driving proliferation is more robust and flexible in B cells than in T cells, which may have profound implications for the therapy of B and T-cell neoplasms.

Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis.

Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and by 12/15-lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the Alox15 gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxidative mechanisms may compensate for the loss of Alox15, we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturbation of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with Gpx4 ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vitamin E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. Gpx4-deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythropoietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to Gpx4 loss in hematopoietic cells thus causes ineffective erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation.