Staphylococcus aureus small colony variants: A potentially underestimated microbiological challenge in peritoneal dialysis.

INTRODUCTION: Peritonitis remains the major infectious complication in the setting of peritoneal dialysis (PD). Despite known only moderate pathogenicity, the most frequently detected pathogens in PD-related peritonitis are surprisingly coagulase-negative staphylococci. However, this could be explained, at least in part, by Staphylococcus aureus small colony variants (SCVs) induced by PD fluids (PDFs) and misidentified by routinely used microbiological methods. MATERIAL AND METHODS: Bacteria were exposed to commonly used PDFs in various regimens designed to simulate daily use as closely as possible. Wild-type isolates and SCVs were subsequently used to determine minimum inhibitory concentrations (MICs), in vitro biofilm formation capacities, and auxotrophies. Underlying genetic alterations were investigated using whole-genome sequencing, and various microbial identification methods were tested to determine their performance for wild-types and SCVs. RESULTS: Stable SCVs could be isolated most successfully after exposure to glucose-containing PDFs alone. The reading of MICs was significantly affected by the reduced growth of SCVs, resulting in lower MIC values in 44% of all tests. Nonsynonymous mutations were found in all but one SCV, while only two isolates showed typical auxotrophic responses. While MALDI-TOF, PCR and Pastorex Staph-Plus correctly identified all S. aureus SCVs, API-Staph and VITEK-2 yielded identification rates of only 40% and 10%, respectively. CONCLUSIONS: Overall, the present study has shown that commercially available PDFs induce S. aureus SCVs in vitro, which are difficult to identify and test for antimicrobial susceptibility and can potentially lead to recurrent or persistent infections. Thus, they represent a potentially underappreciated challenge not only for microbiologists, but also for clinicians.

Rituximab treatment in pediatric-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

What is in a smile: The role of evaluation goal and response labels in facial muscle responses to prejudiced groups.

Based on the assumption that valence is permanently linked to facial responses, we expected that the corrugator muscle is contracted faster in response to overweight persons than to slim persons, whereas we expected faster contractions of the zygomaticus muscle in response to slim persons rather than to overweight persons. To detect such differences, we conducted experiments with different versions of a facial stimulus-response compatibility task that required participants to respond with the two facial muscles to photos of overweight or slim persons. Contrary to the assumption that valence is permanently linked to facial responses, in Experiments 1 and 2, social categories (overweight vs. slim persons) did not influence the response latencies assessed by electromyography. Whereas in Experiments 1 and 2, neutral labels were used for the muscle responses, in Experiment 3, affective response labels (smile vs. frown) were used. In Experiment 3, faster responses with the corrugator to overweight than to slim persons and with the zygomaticus to slim than to overweight persons were obtained. The influence of task and response label is consistent with the theory of event coding that suggests a more flexible link between valence and action.

Differences in oxazolidinone resistance mechanisms and small colony variants emergence of Staphylococcus aureus induced in an in vitro resistance development model.

Invasive Staphylococcus aureus infections are associated with a high burden of disease, case fatality rate and healthcare costs. Oxazolidinones such as linezolid and tedizolid are considered potential treatment choices for conditions involving methicillin resistance or penicillin allergies. Additionally, they are being investigated as potential inhibitors of toxins in toxin-mediated diseases. In this study, linezolid and tedizolid were evaluated in an in vitro resistance development model for induction of resistance in S. aureus. Whole genome sequencing was conducted to elucidate resistance mechanisms through the identification of causal mutations. After inducing resistance to both linezolid and tedizolid, several partially novel single nucleotide variants (SNVs) were detected in the rplC gene, which encodes the 50S ribosome protein L3 in S. aureus. These SNVs were found to decrease the binding affinity, potentially serving as the underlying cause for oxazolidinone resistance. Furthermore, in opposite to linezolid we were able to induce phenotypically small colony variants of S. aureus after induction of resistance with tedizolid for the first time in literature. In summary, even if different antibiotic concentrations were required and SNVs were detected, the principal capacity of S. aureus to develop resistance to oxazolidinones seems to differ between linezolid and tedizolid in-vivo but not in vitro. Stepwise induction of resistance seems to be a time and cost-effective tool for assessing resistance evolution. Inducted-resistant strains should be examined and documented for epidemiological reasons, if MICs start to rise or oxazolidinone-resistant S. aureus outbreaks become more frequent.

Natural Language Processing: Chances and Challenges in Dentistry.

INTRODUCTION: Natural language processing (NLP) is an intersection between Computer Science and Linguistic which aims to enable machines to process and understand human language. We here summarized applications and limitations of NLP in dentistry. DATA AND SOURCES: Narrative review. FINDINGS: NLP has evolved increasingly fast. For the dental domain, relevant NLP applications are text classification (e.g., symptom classification) and natural language generation and understanding (e.g., clinical chatbots assisting professionals in office work and patient communication). Analyzing large quantities of text will allow understanding diseases and their trajectories and support a more precise and personalized care. Speech recognition systems may serve as virtual assistants and facilitate automated documentation. However, to date, NLP has rarely been applied in dentistry. Existing research focuses mainly on rule-based solutions for narrow tasks. Technologies such as Recurrent Neural Networks and Transformers have been shown to surpass the language processing capabilities of such rule-based solutions in many fields, but are data-hungry (i.e., rely on large amounts of training data), which limits their application in the dental domain at present. Technologies such as federated or transfer learning or data sharing concepts may allow to overcome this limitation, while challenges in terms of explainability, reproducibility, generalizability and evaluation of NLP in dentistry remain to be resolved for enabling approval of such technologies in medical devices and services. CONCLUSIONS: NLP will become a cornerstone of a number of applications in dentistry. The community is called to action to improve the current limitations and foster reliable, high-quality dental NLP. CLINICAL SIGNIFICANCE: NLP for text classification (e.g., dental symptom classification) and language generation and understanding (e.g., clinical chatbots, speech recognition) will support administrative tasks in dentistry, provide deeper insights for clinicians and support research and education.

Corrigendum to 'Modeling mixoplankton along the biogeochemical gradient of the Southern North Sea' Ecological Modelling 458 (2021) 0304-3800/109690.

[This corrects the article DOI: 10.1016/j.ecolmodel.2021.109690.].

Early treatment response to piperacillin/tazobactam in patients with bloodstream infections caused by non-ESBL ampicillin/sulbactam-resistant Escherichia coli: a binational cohort study.

PURPOSE: This study aimed to compare treatment outcomes for bloodstream infections (BSI) caused by a piperacillin/tazobactam (PIP/TAZ)-susceptible E. coli among three patient groups: BSI caused by ampicillin/sulbactam (AMP/SLB)-resistant isolates treated with PIP/TAZ, BSI caused by AMP/SLB-sensitive isolates treated with PIP/TAZ, and BSI caused by AMP/SLB-resistant isolates treated with another monotherapy. METHODS: This retrospective study was conducted in two academic centres in Europe. Adult patients with E. coli BSI were screened from 2014 to 2020. Inclusion criteria were non-ESBL BSI and initial monotherapy for ≥ 72 h. To reduce the expected bias between the patient groups, propensity score matching was performed. The primary outcome was early treatment response after 72 h and required absence of SOFA score increase in ICU/IMC patients, as well as resolution of fever, leukocytosis, and bacteraemia. RESULTS: Of the 1707 patients screened, 315 (18.5%) were included in the final analysis. Urinary tract infection was the most common source of BSI (54.9%). Monotherapies other than PIP/TAZ were cephalosporins (48.6%), carbapenems (34.3%), and quinolones (17.1%). Enhanced early treatment response rate was detected (p = 0.04) in patients with BSI caused by AMP/SLB-resistant isolates treated with another monotherapy (74.3%) compared to those treated with PIP/TAZ (57.1%), and was mainly driven by the use of cephalosporins and quinolones (p ≤ 0.03). Clinical success, 28-day mortality, and rate of relapsing BSI did not significantly differ between the groups. CONCLUSIONS: Our study suggests that initial use of PIP/TAZ may be associated with reduced early treatment response in E. coli BSI caused by AMP/SLB-resistant isolates compared to alternative monotherapies.

Early Detection of Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is increasingly common. Screening for pancreatic cancer is not well established but might increase the chance of detection in early stages. SUMMARY: We conducted a literature search to summarize current recommendations and to give an overview of patient groups that may benefit from screening. In the general population, screening is not recommended because the low prevalence of PDAC renders any diagnostic tests non-predictive and because there is no direct evidence that links early diagnosis to improved survival. To date, novel approaches like liquid biopsies and molecular markers are not yet able to improve screening in unselected individuals but offer promising potential. Screening efficiency increases considerably with increasing pretest probability. Therefore, the best way to improve early diagnosis is identifying high-risk individuals. KEY MESSAGES: There are well-defined populations with distinct genetic alterations with an increased risk for pancreatic cancer. Those may be screened with common diagnostic methods. In addition, new-onset diabetes is increasingly recognized as an early symptom, especially in elderly patients with weight loss.

Impact of Noisy Labels on Dental Deep Learning-Calculus Detection on Bitewing Radiographs.

Supervised deep learning requires labelled data. On medical images, data is often labelled inconsistently (e.g., too large) with varying accuracies. We aimed to assess the impact of such label noise on dental calculus detection on bitewing radiographs. On 2584 bitewings calculus was accurately labeled using bounding boxes (BBs) and artificially increased and decreased stepwise, resulting in 30 consistently and 9 inconsistently noisy datasets. An object detection network (YOLOv5) was trained on each dataset and evaluated on noisy and accurate test data. Training on accurately labeled data yielded an mAP50: 0.77 (SD: 0.01). When trained on consistently too small BBs model performance significantly decreased on accurate and noisy test data. Model performance trained on consistently too large BBs decreased immediately on accurate test data (e.g., 200% BBs: mAP50: 0.24; SD: 0.05; p < 0.05), but only after drastically increasing BBs on noisy test data (e.g., 70,000%: mAP50: 0.75; SD: 0.01; p < 0.05). Models trained on inconsistent BB sizes showed a significant decrease of performance when deviating 20% or more from the original when tested on noisy data (mAP50: 0.74; SD: 0.02; p < 0.05), or 30% or more when tested on accurate data (mAP50: 0.76; SD: 0.01; p < 0.05). In conclusion, accurate predictions need accurate labeled data in the training process. Testing on noisy data may disguise the effects of noisy training data. Researchers should be aware of the relevance of accurately annotated data, especially when testing model performances.

Federated vs Local vs Central Deep Learning of Tooth Segmentation on Panoramic Radiographs.

OBJECTIVE: Federated Learning (FL) enables collaborative training of artificial intelligence (AI) models from multiple data sources without directly sharing data. Due to the large amount of sensitive data in dentistry, FL may be particularly relevant for oral and dental research and applications. This study, for the first time, employed FL for a dental task, automated tooth segmentation on panoramic radiographs. METHODS: We employed a dataset of 4,177 panoramic radiographs collected from nine different centers (n = 143 to n = 1881 per center) across the globe and used FL to train a machine learning model for tooth segmentation. FL performance was compared against Local Learning (LL), i.e., training models on isolated data from each center (assuming data sharing not to be an option). Further, the performance gap to Central Learning (CL), i.e., training on centrally pooled data (based on data sharing agreements) was quantified. Generalizability of models was evaluated on a pooled test dataset from all centers. RESULTS: For 8 out of 9 centers, FL outperformed LL with statistical significance (p<0.05); only the center providing the largest amount of data FL did not have such an advantage. For generalizability, FL outperformed LL across all centers. CL surpassed both FL and LL for performance and generalizability. CONCLUSION: If data pooling (for CL) is not feasible, FL is shown to be a useful alternative to train performant and, more importantly, generalizable deep learning models in dentistry, where data protection barriers are high. CLINICAL SIGNIFICANCE: This study proves the validity and utility of FL in the field of dentistry, which encourages researchers to adopt this method to improve the generalizability of dental AI models and ease their transition to the clinical environment.

Humoral Immune Response Following SARS-CoV-2 mRNA Vaccination and Infection in Pediatric-Onset Multiple Sclerosis.

OBJECTIVE: Currently, there are no data available on SARS-CoV-2 vaccine responses in pediatric-onset multiple sclerosis (POMS), and little is known about the course of SARS-CoV-2 infection in this age group. We therefore investigated humoral immune responses after COVID-19 vaccination and/or infection in POMS. METHODS: We retrospectively analyzed seroconversion rates and SARS-CoV-2-specific antibody levels in 30 POMS and one pediatric CIS patient treated with no disease-modifying therapy (no DMT), immunomodulatory DMT (IM-DMT), or immunosuppressive DMT (IS-DMT) from two Austrian MS centers. RESULTS: The median age at MS onset was 15.39 years (interquartile range [IQR]: 1.97). The median age at the first COVID-19 vaccination was 17.43 years (IQR: 2.76). After two vaccine doses, seroconversion (≥0.8 BAU/ml) was reached in 25 of 28 patients (89.3%). All patients with no DMT or IM-DMT generated robust immune responses to vaccination (seroconversion: no DMT: 6/6, IM-DMT: 7/7 [100%]; median titers: no DMT: 2075 BAU [IQR: 1268.50], IM-DMT: 2500 BAU [IQR: 0]). In the IS-DMT group, seroconversion was achieved in 12 of 14 patients (80%), and median titers were 50.8 BAU (IQR 254.63). Titers were significantly higher in no DMT versus IS-DMT (P = 0.012) and in IM-DMT versus IS-DMT (P = 0.001). Infection with SARS-CoV-2 occurred in 11 of 31 patients, and symptoms were mild in all cases. One relapse occurred after infection, but no relapses were documented after vaccination. CONCLUSIONS: Generally, mRNA vaccinations were well tolerated in POMS patients with and without DMT. Immune response was significantly reduced in patients treated with IS-DMT. No unexpected adverse events or relapses related to vaccinations were observed.

[Acute soft Tissue Infection with impending Loss of Finger in amniotic Band Syndrome of a 22-years-old Patient with palmoplantar Keratoderma congenital Alopecia Syndrome Type II]. / Akute Weichteilinfektion mit drohendem Fingerverlust bei Schnürfurchensyndrom einer 22-jährigen Patientin mit palmoplantarem Keratoderm-kongenitalem Alopezie-Syndrom Typ II.

We report on the treatment of a 22-year-old female patient with an acute soft tissue infection in the area of an amniotic band due to palmoplantar keratoderma congenital alopecia syndrome (PPKCA) type II, a very rare genodermatosis with less than 20 cases described in literature. An acute soft tissue infection distal from the pre-existing constriction ring with hyperkeratosis on the right small finger led to a decompensation of the venous and lymphatic drain with imminent loss of the finger. Due to urgent surgical treatment with decompression and debridement of the dorsal soft tissue infection, microsurgical circular resection of the constriction ring and primary wound closure the finger could be preserved. After soft tissue consolidation and hand therapy, the patient achieved free movement of the small finger with subjective freedom of symptoms and good aesthetic results.

The accelerated waning of immunity and reduced effect of booster in patients treated with bDMARD and tsDMARD after SARS-CoV-2 mRNA vaccination.

Objectives: This study aimed to assess the duration of humoral responses after two doses of SARS-CoV-2 mRNA vaccines in patients with inflammatory joint diseases and IBD and booster vaccination compared with healthy controls. It also aimed to analyze factors influencing the quantity and quality of the immune response. Methods: We enrolled 41 patients with rheumatoid arthritis (RA), 35 with seronegative spondyloarthritis (SpA), and 41 suffering from inflammatory bowel disease (IBD), excluding those receiving B-cell-depleting therapies. We assessed total anti-SARS-CoV-2 spike antibodies (Abs) and neutralizing Ab titers 6 months after two and then after three doses of mRNA vaccines compared with healthy controls. We analyzed the influence of therapies on the humoral response. Results: Patients receiving biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) showed reduced anti-SARS-CoV-2 S Abs and neutralizing Ab titers compared with HC or patients receiving conventional synthetic (cs)DMARDs 6 months after the first two vaccination doses. Anti-SARS-CoV-2 S titers of patients with b/tsDMARDs declined more rapidly, leading to a significant reduction in the duration of vaccination-induced immunity after two doses of SARS-CoV-2 mRNA vaccines. While 23% of HC and 19% of patients receiving csDMARDs were without detectable neutralizing Abs 6 months after the first two vaccination doses, this number was 62% in patients receiving b/tsDMARDs and 52% in patients receiving a combination of csDMARDs and b/tsDMARDs. Booster vaccination led to increased anti-SARS-CoV-2 S Abs in all HC and patients. However, anti-SARS-CoV-2 S Abs after booster vaccination was diminished in patients receiving b/tsDMARDs, either alone or in combination with csDMARDs compared to HC. Conclusion: Patients receiving b/tsDMARDs have significantly reduced Abs and neutralizing Ab titers 6 months after mRNA vaccination against SARS-CoV-2. This was due to a faster decline in Ab levels, indicating a significantly reduced duration of vaccination-induced immunity compared with HC or patients receiving csDMARDs. In addition, they display a reduced response to a booster vaccination, warranting earlier booster vaccination strategies in patients under b/tsDMARD therapy, according to their specific Ab levels.

Effects of a seat-integrated mobilization system on long-haul truck drivers motion activity, muscle stiffness and discomfort during a 4.5-h simulated driving task.

OBJECTIVE: The aim of this study is to evaluate the effects of a seat-integrated mobilization system on motion activity, muscle stiffness and discomfort during prolonged driving. METHOD: During a 4.5-h driving task, motion activity, muscle stiffness and discomfort (measured subjectively and objectively) of long-haul truck drivers were determined and compared intra-individually in a test condition with mobilization (seat-integrated stimulation) and a control condition under standardized conditions in a simulated driving study (N = 16). RESULTS: In the experimental condition, participants showed a significantly increased motion activity and a reduced muscle stiffness compared to the control condition. Furthermore, discomfort occurred significantly more frequently in the control condition. CONCLUSION: The mobilization system increased motion activity and reduced discomfort as well as muscle stiffness. Therefore, it provides considerable potential to counteract negative effects of prolonged sitting and to promote truck driver's health.

Reactogenicity and immunogenicity of the second COVID-19 vaccination in patients with inborn errors of immunity or mannan-binding lectin deficiency.

Background: Patients with inborn errors of immunity (IEI) are at increased risk for severe courses of SARS-CoV-2 infection. COVID-19 vaccination provides effective protection in healthy individuals. However, it remains unclear whether vaccination is efficient and safe in patients with constitutional dysfunctions of the immune system. Thus, we analyzed the humoral response, adverse reactions and assessed the disease activity of the underlying disease after COVID-19 vaccination in a cohort of patients suffering from IEIs or mannan-binding lectin deficiency (MBLdef). Methods: Vaccination response was assessed after basic immunization using the Elecsys anti-SARS-CoV-2 S immunoassay and via Vero E6 cell based assay to detect neutralization capabilities. Phenotyping of lymphocytes was performed by flow cytometry. Patient charts were reviewed for disease activity, autoimmune phenomena as well as immunization status and reactogenicity of the vaccination. Activity of the underlying disease was assessed using a patient global numeric rating scale (NRS). Results: Our cohort included 11 individuals with common variable immunodeficiency (CVID), one patient with warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) syndrome, two patients with X-linked agammaglobulinemia (XLA), one patient with Muckle Wells syndrome, two patients with cryopyrin-associated periodic syndrome, one patient with Interferon-gamma (IFN-gamma) receptor defect, one patient with selective deficiency in pneumococcal antibody response combined with a low MBL level and seven patients with severe MBL deficiency. COVID-19 vaccination was generally well tolerated with little to no triggering of autoimmune phenomena. 20 out of 26 patients developed an adequate humoral vaccine response. 9 out of 11 patients developed a T cell response comparable to healthy control subjects. Tested immunoglobulin replacement therapy (IgRT) preparations contained Anti-SARS-CoV-2 S antibodies implicating additional protection through IgRT. Summary: In summary the data support the efficacy and safety of a COVID-19 vaccination in patients with IEIs/MBLdef. We recommend evaluation of the humoral immune response and testing for virus neutralization after vaccination in this cohort.

Emulating Clinical Diagnostic Reasoning for Jaw Cysts with Machine Learning.

The detection and classification of cystic lesions of the jaw is of high clinical relevance and represents a topic of interest in medical artificial intelligence research. The human clinical diagnostic reasoning process uses contextual information, including the spatial relation of the detected lesion to other anatomical structures, to establish a preliminary classification. Here, we aimed to emulate clinical diagnostic reasoning step by step by using a combined object detection and image segmentation approach on panoramic radiographs (OPGs). We used a multicenter training dataset of 855 OPGs (all positives) and an evaluation set of 384 OPGs (240 negatives). We further compared our models to an international human control group of ten dental professionals from seven countries. The object detection model achieved an average precision of 0.42 (intersection over union (IoU): 0.50, maximal detections: 100) and an average recall of 0.394 (IoU: 0.50-0.95, maximal detections: 100). The classification model achieved a sensitivity of 0.84 for odontogenic cysts and 0.56 for non-odontogenic cysts as well as a specificity of 0.59 for odontogenic cysts and 0.84 for non-odontogenic cysts (IoU: 0.30). The human control group achieved a sensitivity of 0.70 for odontogenic cysts, 0.44 for non-odontogenic cysts, and 0.56 for OPGs without cysts as well as a specificity of 0.62 for odontogenic cysts, 0.95 for non-odontogenic cysts, and 0.76 for OPGs without cysts. Taken together, our results show that a combined object detection and image segmentation approach is feasible in emulating the human clinical diagnostic reasoning process in classifying cystic lesions of the jaw.

Immune Response after mRNA COVID-19 Vaccination in Lung Transplant Recipients: A 6-Month Follow-Up.

BACKGROUND AND OBJECTIVE: This prospective cohort study analyzed the immune response to COVID-19 mRNA vaccines in lung transplant recipients (LuTRs) compared to healthy controls (HCs) at a 6-month follow-up. METHODS: After the first two doses of either BNT162b2 or mRNA-1273, SARS-CoV-2 antibodies were measured in LuTRs (n = 57) and sex- and age-matched HCs (n = 57). Antibody kinetics during a 6-month follow-up and the effect of a third vaccine dose were evaluated. Humoral responses were assessed using the Elecsys® Anti-SARS-CoV-2 S immunoassay. In 16 LuTRs, SARS-CoV-2-specific T cell responses were quantified using IFN-γ ELISpot assays. RESULTS: Seroconversion rates were 94% and 100% after the first and second vaccine dose, respectively, in HCs, while only 19% and 56% of LuTRs developed antibodies. Furthermore, 22 of 24 LuTRs who received the third vaccine dose showed seroconversion (five of seven primary non-responders and 17 of 17 primary responders). A T cell response against SARS-CoV-2-spike S1 and/or S2 was detected in 100% (16/16) of HCs and 50% (8/16) of LuTRs. CONCLUSIONS: The data suggest that LuTRs have reduced humoral and cellular immune responses after two doses of COVID-19 mRNA vaccination when compared to HCs. A third dose may be of substantial benefit.

Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF.

Enhancer RNAs (eRNAs) are long non-coding RNAs that originate from enhancers. Although eRNA transcription is a canonical feature of activated enhancers, the molecular features required for eRNA function and the mechanism of how eRNAs impinge on target gene transcription have not been established. Thus, using eRNA-dependent RNA polymerase II (Pol II) pause release as a model, we here investigate the requirement of sequence, structure and length of eRNAs for their ability to stimulate Pol II pause release by detaching NELF from paused Pol II. We find eRNAs not to exert their function through common structural or sequence motifs. Instead, eRNAs that exhibit a length >200 nucleotides and that contain unpaired guanosines make multiple, allosteric contacts with NELF subunits -A and -E to trigger efficient NELF release. By revealing the molecular determinants of eRNA function, our study establishes eRNAs as an important player in Pol II pause release, and it provides new insight into the regulation of metazoan transcription.

Experiences of Discrimination and Everyday Racism Among Children and Adolescents With an Immigrant Background - Results of a Systematic Literature Review on the Impact of Discrimination on the Developmental Outcomes of Minors Worldwide.

Experiences of discrimination such as everyday racism can negatively affect the mental and physical health of children and adolescents with an immigrant background and impair their integration process in the host societies. Although experiences of racism are part of the everyday life of many minors affected by the process of "Othering" (e.g., those with an immigrant background), an overview of empirical findings is missing for this age group worldwide. A systematic review was conducted to identify and analyze international research on the impact of discrimination on the developmental outcomes and integration of immigrant children and adolescents. Three scientific databases were systematically searched up to June 11, 2021. A total of k = 4,769 identified publications were reviewed based on inclusion and exclusion criteria in terms of the PICOS format by independent reviewers. Thirty-four primary studies published between 1998 and 2021 met all inclusion criteria. The samples examined were mainly migrant youth (k = 30), with only k = 2 studies assessing refugee youth and k = 1 study assessing both migrant and refugee youth. The majority of included studies assessed perceived discrimination, with only k = 1 study directly assessing experiences of racism. The association between discrimination or racism and developmental outcomes was assessed by the included studies within the three main topics of (a) mental and physical health-related outcomes (k = 30, e.g., self-esteem, depressive symptoms), (b) school-related outcomes (k = 6, e.g., academic achievement), and (c) other developmental outcomes (k = 13, e.g., misconduct or delinquency). Data collection procedures were implemented, and findings on minors' developmental outcomes and integration process who experience discrimination and racism were summarized and discussed. The current review suggests experienced (racial) discrimination as a negative predictor of children and adolescents' (mental) health-related outcomes, while no clear results could be found for the association between discrimination and school-related outcomes. A need for more empirical research focusing on the path and (possibly) indirect link between discrimination and children and adolescents' school-related outcomes as well as resulting school recommendations and the chosen career path was derived. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=260291], identifier [CRD42021260291].