Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells.

Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.

Inherent tolerance of Colletotrichum gloeosporioides to fludioxonil.

Colletotrichum spp. cause devastating diseases in agricultural crops, including fruit crops. They can differ in host plant and plant organ specificity and even in fungicide sensitivity. In strawberry, members of the C. gloeosporioides species complex (referred to as C. gloeosporioides) primarily cause crown rot and those of the C. acutatum species complex (referred to as C. acutatum) primarily cause fruit rot. Fludioxonil is registered for use (in combination with cyprodinil; Switch 62.5WG in the US) in strawberry against anthracnose disease caused by Colletotrichum spp. In this study we examined the sensitivity of C. gloeosporioides (C. fructicola and C. siamense) and C. acutatum (C. nymphaeae and C. fioriniae) isolates from different hosts and different geographical locations in the US to fludioxonil and examined possible mechanisms of inherent fungicide tolerance. The dose response to fludioxonil of C. gloeosporioides isolates (including 4 isolates of C. theobromicola) revealed about 70% inhibition of mycelial growth at 1 mg/L that was maintained at 10 mg/L and 100 mg/L and lead to minimum inhibitory concentration (MIC) values >100 mg/L. In contrast, mycelial growth of C. acutatum isolates was completely inhibited at 1 mg/L. C. gloeosporioides isolates were also significantly less sensitive to iprodione. An investigation into possible mechanisms of C. gloeosporioides isolates tolerance to fludioxonil and iprodione revealed no evidence of OS-1 gene involvement. Isolates of both species complexes were equally sensitive to salt stress based on mycelial growth inhibition on potato dextrose agar amended with 2%, 4%, and 6% NaCl. In addition, orthologous amino acid alterations in OS-1 previously linked to fludioxonil resistance in Botrytis cinerea were not found in C. gloeosporioides or C. acutatum isolates. This study also showed limited in vitro inhibitory activity of cyprodinil against isolates of both species complexes (MIC values >100 mg/L) and unveils a potential weakness of the fludioxonil+cyprodinil premixture marketed as Switch 62.5WG against C. gloeosporioides species complexes.

Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling.

Controlling the adipo-osteogenic lineage decision of trabecular human bone marrow stromal cells (hBMSCs) in favor of osteogenesis represents a promising approach for osteoporosis therapy and prevention. Previously, Fibroblast Growth Factor 1 (FGF1) and its subfamily member FGF2 were scored as leading candidates to exercise control over skeletal precursor commitment and lineage decision albeit literature results are highly inconsistent. We show here that FGF1 and 2 strongly prevent the osteogenic commitment and differentiation of hBMSCs. Mineralization of extracellular matrix (ECM) and mRNA expression of osteogenic marker genes Alkaline Phosphatase (ALP), Collagen 1A1 (COL1A1), and Integrin-Binding Sialoprotein (IBSP) were significantly reduced. Furthermore, master regulators of osteogenic commitment like Runt-Related Transcription Factor 2 (RUNX2) and Bone Morphogenetic Protein 4 (BMP4) were downregulated. When administered under adipogenic culture conditions, canonical FGFs did not support osteogenic marker expression. Moreover despite the presence of osteogenic differentiation factors, FGFs even disabled the pro-osteogenic lineage decision of pre-differentiated adipocytic cells. In contrast to FGF Receptor 2 (FGFR2), FGFR1 was stably expressed throughout osteogenic and adipogenic differentiation and FGF addition. Moreover, FGFR1 and Extracellular Signal-Regulated Kinases 1 and 2 (ERK1/2) were found to be responsible for underlying signal transduction using respective inhibitors. Taken together, we present new findings indicating that canonical FGFR-ERK1/2 signaling entrapped hBMSCs in a pre-committed state and arrested further maturation of committed precursors. Our results might aid in unraveling and controlling check points relevant for ageing-associated aberrant adipogenesis with consequences for the treatment of degenerative diseases such as osteoporosis and for skeletal tissue engineering strategies. J. Cell. Biochem. 118: 263-275, 2017. © 2016 Wiley Periodicals, Inc.

Contribution of intracellular ATP to cisplatin resistance of tumor cells.

Decreased cellular accumulation of cisplatin is a frequently observed mechanism of resistance to the drug. Beside passive diffusion, several cellular proteins using ATP hydrolysis as an energy source are assumed to be involved in cisplatin transport in and out of the cell. This investigation aimed at clarifying the contribution of intracellular ATP as an indicator of energy-dependent transport to cisplatin resistance using the A2780 human ovarian adenocarcinoma cell line and its cisplatin-resistant variant A2780cis. Depletion of intracellular ATP with oligomycin significantly decreased cellular platinum accumulation (measured by flameless atomic absorption spectrometry) in sensitive but not in resistant cells, and did not affect cisplatin efflux in both cell lines. Inhibition of Na(+),K(+)-ATPase with ouabain reduced platinum accumulation in A2780 cells but to a lesser extent compared with oligomycin. Western blot analysis revealed lower expression of Na(+),K(+)-ATPase α(1) subunit in resistant cells compared with sensitive counterparts. The basal intracellular ATP level (determined using a bioluminescence-based assay) was significantly higher in A2780cis cells than in A2780 cells. Our results highlight the importance of ATP-dependent transport, among other processes mediated by Na(+),K(+)-ATPase, for cisplatin influx in sensitive cells. Cellular platinum accumulation in resistant cells is reduced and less dependent on energy sources, which may partly result from Na(+),K(+)-ATPase downregulation. Our data suggest the involvement of other ATP-dependent processes beside those regulated by Na(+),K(+)-ATPase. Higher basal ATP level in cisplatin-resistant cells, which appears to be a consequence of enhanced mitochondrial ATP production, may represent a survival mechanism established during development of resistance.

Loneliness Trajectories, Associated Factors and Subsequent Health in Children and Young People During the COVID-19 Pandemic: A National Matched Cohort Study.

Purpose: Loneliness is common amongst children and young people (CYP) and is an independent risk factor for poor health. This study aimed to i) determine whether subgroups of CYP with different loneliness trajectories (during the second year of the pandemic) exist; ii) examine associations with socio-demographic characteristics and subsequent health; and iii) understand whether associations between loneliness and subsequent health were modified by SARS-CoV-2 infection. Methods: A total of 5851 CYP (N=3260 SARS-CoV-2 positive and 2591 SARS-CoV-2 negative) provided data on loneliness (via the validated 3-item version of the UCLA Loneliness Scale for Children) at least twice in a 12-month period post PCR index-testing (conducted October 2020-March 2021). Latent class growth analyses were used to identify distinct classes of loneliness trajectories. Multinomial logistic regression was used to identify socio-demographic characteristics associated with class membership. Logistic regression models assessed the odds of reporting impairing symptoms 12-months post index-test. Results: Four distinct loneliness trajectories were identified: three mostly stable (low, medium, high) and one low-increasing trajectory. Being older, female, living in more deprived areas and testing negative were associated with greater odds of being in the highest vs lowest loneliness trajectory; eg OR for female vs male: 5.6 (95% CI:4.1,7.8); OR for 15-17 vs 11-14 years: 4.5 (95% CI:3.4,6.0). Following higher loneliness trajectories was associated with higher odds of experiencing impairing symptoms 12-months post index-test: ORadjusted (compared to lowest loneliness trajectory) were 15.9 (95% CI:11.9,21.3) (high loneliness), 6.5 (5.3,7.9) (medium loneliness) and 2.3 (1.9,2.8) (low-increasing loneliness). There was no evidence that this association was modified by PCR index-test result. Conclusion: About 5.3% of CYP were classified into a group experiencing (chronically) high loneliness. Being female, older and from more deprived areas were risk factors of belonging to this group. Results suggest that even small increases from low loneliness levels may be associated with worse health outcomes.

Two self-sampling strategies for HPV primary cervical cancer screening compared with clinician-collected sampling: an economic evaluation.

OBJECTIVE: To compare the costs and effects of three sampling strategies for human papillomavirus (HPV) primary screening. DESIGN: Cost-consequence analysis from a health system perspective using a deterministic decision tree model. SETTING: England. PARTICIPANTS: A cohort of 10 000 women aged 25-65 years eligible for the National Health Service Cervical Screening Programme (NHSCSP). METHODS: The model was based on the NHSCSP HPV primary screening pathway and adapted for self-sampling. It used a 3-year cycle: routine screening (year 1) and recall screening (years 2/3). Parameter inputs were informed using published studies, NHSCSP reports and input from experts and manufacturers. Costs were from 2020/2021, British pound sterling (£). INTERVENTIONS: Three sampling strategies were implemented: (1) routine clinician-collected cervical sample, (2) self-collected first-void (FV) urine, (3) self-collected vaginal swab. The hypothetical self-sampling strategies involved mailing women a sampling kit. MAIN OUTCOME MEASURES: Primary outcomes: overall costs (for all screening steps to colposcopy), number of complete screens and cost per complete screen. SECONDARY OUTCOMES: number of women screened, number of women lost to follow-up, cost per colposcopy and total screening costs for a plausible range of uptake scenarios. RESULTS: In the base case, the average cost per complete screen was £56.81 for clinician-collected cervical sampling, £38.57 for FV urine self-sampling and £40.37 for vaginal self-sampling. In deterministic sensitivity analysis, the variables most affecting the average cost per screen were the cost of sample collection for clinician-collected sampling and the cost of laboratory HPV testing for the self-sampling strategies. Scaled to consider routine screening in England, if uptake in non-attenders increased by 15% and 50% of current screeners converted to self-sampling, the NHSCSP would save £19.2 million (FV urine) or £16.5 million (vaginal) per year. CONCLUSION: Self-sampling could provide a less costly alternative to clinician-collected sampling for routine HPV primary screening and offers opportunities to expand the reach of cervical screening to under-screened women.

An ontology of mechanisms of action in behaviour change interventions.

Background: Behaviour change interventions influence behaviour through causal processes called "mechanisms of action" (MoAs). Reports of such interventions and their evaluations often use inconsistent or ambiguous terminology, creating problems for searching, evidence synthesis and theory development. This inconsistency includes the reporting of MoAs. An ontology can help address these challenges by serving as a classification system that labels and defines MoAs and their relationships. The aim of this study was to develop an ontology of MoAs of behaviour change interventions. Methods: To develop the MoA Ontology, we (1) defined the ontology's scope; (2) identified, labelled and defined the ontology's entities; (3) refined the ontology by annotating (i.e., coding) MoAs in intervention reports; (4) refined the ontology via stakeholder review of the ontology's comprehensiveness and clarity; (5) tested whether researchers could reliably apply the ontology to annotate MoAs in intervention evaluation reports; (6) refined the relationships between entities; (7) reviewed the alignment of the MoA Ontology with other relevant ontologies, (8) reviewed the ontology's alignment with the Theories and Techniques Tool; and (9) published a machine-readable version of the ontology. Results: An MoA was defined as "a process that is causally active in the relationship between a behaviour change intervention scenario and its outcome behaviour". We created an initial MoA Ontology with 261 entities through Steps 2-5. Inter-rater reliability for annotating study reports using these entities was α=0.68 ("acceptable") for researchers familiar with the ontology and α=0.47 for researchers unfamiliar with it. As a result of additional revisions (Steps 6-8), 23 further entities were added to the ontology resulting in 284 entities organised in seven hierarchical levels. Conclusions: The MoA Ontology extensively captures MoAs of behaviour change interventions. The ontology can serve as a controlled vocabulary for MoAs to consistently describe and synthesise evidence about MoAs across diverse sources.

Within-person associations between psychological and contextual factors and lapse incidence in smokers attempting to quit: A systematic review and meta-analysis of ecological momentary assessment studies.

AIMS: When attempting to stop smoking, discrete smoking events ('lapses') are strongly associated with a return to regular smoking ('relapse'). No study has yet pooled the psychological and contextual antecedents of lapse incidence, captured in ecological momentary assessment (EMA) studies. This systematic review and meta-analysis aimed to synthesize within-person psychological and contextual predictor-lapse associations in smokers attempting to quit. METHODS: We searched Ovid MEDLINE, Embase, PsycINFO and Web of Science. A narrative synthesis and multi-level, random-effects meta-analyses were conducted, focusing on studies of adult, non-clinical populations attempting to stop smoking, with no restrictions on setting. Outcomes were the association between a psychological (e.g. stress, cravings) or contextual (e.g. cigarette availability) antecedent and smoking lapse incidence; definitions of 'lapse' and 'relapse'; the theoretical underpinning of EMA study designs; and the proportion of studies with pre-registered study protocols/analysis plans and open data. RESULTS: We included 61 studies, with 19 studies contributing ≥ 1 effect size(s) to the meta-analyses. We found positive relationships between lapse incidence and 'environmental and social cues' [k = 12, odds ratio (OR) = 4.53, 95% confidence interval (CI) = 2.02, 10.16, P = 0.001] and 'cravings' (k = 10, OR = 1.71, 95% CI = 1.34, 2.18, P < 0.001). 'Negative feeling states' was not significantly associated with lapse incidence (k = 16, OR = 1.10, 95% CI = 0.98, 1.24, P = 0.12). In the narrative synthesis, negative relationships with lapse incidence were found for 'behavioural regulation', 'motivation not to smoke' and 'beliefs about capabilities'; positive relationships with lapse incidence were found for 'positive feeling states' and 'positive outcome expectancies'. Although lapse definitions were comparable, relapse definitions varied widely across studies. Few studies explicitly drew upon psychological theory to inform EMA study designs. One of the included studies drew upon Open Science principles. CONCLUSIONS: In smokers attempting to stop, environmental and social cues and cravings appear to be key within-person antecedents of smoking lapse incidence. Due to low study quality, the confidence in these estimates is reduced.

Correlates of and changes in aerobic physical activity and strength training before and after the onset of COVID-19 pandemic in the UK: findings from the HEBECO study.

OBJECTIVES: Understanding changes in moderate to vigorous aerobic physical activity (MVPA) and muscle-strengthening activity (MSA) at the start of the COVID-19 pandemic and their correlates (socio-demographics, health characteristics, living and exercise conditions and pre-pandemic MVPA/MSA) can inform interventions. DESIGN: A cross-sectional analysis of retrospective and concurrent data on MVPA/MSA. SETTING: An online survey in the UK. PARTICIPANTS: 2657 adults (weighted n=2442, 53.6% women) participating in the baseline survey (29 April 2020-14 June 2020) of the HEalth BEhaviours during the COVID-19 pandemic (HEBECO) study. PRIMARY AND SECONDARY OUTCOME MEASURES: Meeting WHO-recommended levels for MVPA/MSA/both (vs meeting neither) during the first lockdown and changes in MVPA/MSA from before to since the COVID-19 pandemic following stratification for pre-pandemic MVPA/MSA. RESULTS: A third of adults maintained (30.4%), decreased (36.2%) or increased (33.4%) MVPA. For MSA, the percentages were 61.6%, 18.2% and 20.2%, respectively. MVPA increased or decreased by an average of 150 min/week and 219 min/week, respectively, and MSA by 2 days/week. Meeting both MSA+MVPA recommendations since COVID-19 (vs meeting neither) was positively associated with meeting MVPA+MSA before COVID-19 (adjusted OR (aOR)=16.11, 95% CI 11.24 to 23.07) and education: post-16 years of age (aOR=1.57, 95% CI 1.14 to 2.17), and negatively associated with having obesity (aOR=0.49, 95% CI 0.33 to 0.73), older age (65+ years vs ≤34 years; aOR=0.53, 95% CI 0.32 to 0.87) and annual household income of <50 000 GBP (aOR=0.65, 95% CI 0.46 to 0.91). The odds for decreasing MVPA were lower for white ethnicity (aOR=0.62, 95% CI 0.44 to 0.86), education: post-16 years of age (aOR=0.73, 95% CI 0.58 to 0.91) and access to garden/balcony (aOR=0.75, 95% CI 0.60 to 0.94), and were higher for those living in total isolation (aOR=3.81, 95% CI 2.33 to 6.23), with deteriorated psychological well-being (aOR=1.40, 95% CI 1.15 to 1.71) and conditions limiting physical activity (aOR=1.74, 95% CI 1.27 to 2.39). The odds for decreasing MSA were higher for having overweight (aOR=1.88, 95% CI 1.39 to 2.55), obesity (aOR=23.38, 95% CI 2.23 to 5.14) and being employed (aOR=1.81, 95% CI 1.34 to 2.46). CONCLUSION: Aerobic and strength training were differently impacted during the first UK lockdown, with poorer outcomes associated with older age, lower education and higher body mass index. Targeted interventions may be required to avoid pandemic-related inequities in physical activity.

UK Adults' Exercise Locations, Use of Digital Programs, and Associations with Physical Activity During the COVID-19 Pandemic: Longitudinal Analysis of Data From the Health Behaviours During the COVID-19 Pandemic Study.

BACKGROUND: Digital physical activity (PA) program use has been associated with higher PA guideline adherence during COVID-19 pandemic confinements. However, little is known longitudinally about exercise locations (inside vs outside the home environment), digital program use, and their associations with moderate-to-vigorous PA (MVPA) and muscle-strengthening activities (MSAs) during the pandemic. OBJECTIVE: The aims of this study were to assess the relationship between exercise location and use of digital programs with PA guideline adherence during the COVID-19 pandemic, describe how individuals exercised inside and outside of their home environments, and explore which sociodemographic and contextual factors were associated with exercise locations and digital PA program use. METHODS: Active UK adults (N=1938) who participated in the 1-month follow-up survey of the Health Behaviours During the COVID-19 Pandemic (HEBECO) study (FU1, June-July 2020) and at least one more follow-up survey (FU2, August-September; FU3, November-December 2020) reported exercise locations and types of exercises inside and outside their homes, including digital programs (online/app-based fitness classes/programs), MVPA, and MSA. Generalized linear mixed models were used to assess associations of exercise location and digital PA program use with PA guideline adherence (MVPA, MSA, full [combined] adherence), and predictors of exercise location and digital program use. RESULTS: As the pandemic progressed, active UK adults were less likely to exercise inside or to use digital PA programs compared with periods of initial confinement: 61% (95% CI 58%-63%; weighted n=1024), 50% (95% CI 48%-53%; weighted n=786), and 49% (95% CI 46%-51%; weighted n=723) performed any exercise inside their homes at FU1, FU2, and FU3, respectively. At FU1, FU2, and FU3, 22% (95% CI 21%-25%; weighted n=385), 17% (95% CI 15%-19%; weighted n=265), and 16% (95% CI 14%-18%; weighted n=241) used digital PA programs, respectively. Most participants who exercised inside already owned indoor equipment, used digital PA programs, or had their own workout routines, whereas MVPA and gentle walking were the most common exercise types performed outside the home. Being female, nonwhite, having a condition limiting PA, indoor exercising space, a lower BMI, and living in total isolation were associated with increased odds of exercising inside the home or garden compared with outside exercise only. Digital PA program users were more likely to be younger, female, highly educated, have indoor space to exercise, and a lower BMI. While exercising inside was positively associated with MSA and exercising outside was positively associated with MVPA guideline adherence, both inside (vs outside only) and outside (vs inside only) activities contributed to full PA guideline adherence (odds ratio [OR] 5.05, 95% CI 3.17-8.03 and OR 1.89, 95% CI 1.10-3.23, respectively). Digital PA program use was associated with a higher odds of MSA (OR 3.97-8.71) and full PA (OR 2.24-3.95), but not with MVPA guideline adherence. CONCLUSIONS: During the COVID-19 pandemic, full PA guideline adherence was associated with exercising inside and outside of one's home environment and using digital PA programs. More research is needed to understand the reach, long-term adherence, and differences between digital PA solutions.

Hexoprenaline Compared with Atosiban as Tocolytic Treatment for Preterm Labor.

Introduction Preterm birth is defined as a live birth before 37 weeks of gestation and is associated with increased neonatal morbidity and mortality. The aim of this study is to compare the efficacy of hexoprenaline and atosiban for short- and long-term tocolysis and their effects on neonatal and maternal outcomes. Methods This retrospective cohort study included women with threatened preterm labor between 24 + 0 and 34 + 0 weeks of gestation without premature rupture of membranes. The tocolytic efficacy of hexoprenaline and atosiban was compared in women receiving one of the two medications for short- and long-term tocolysis. Continuous variables were compared using t-test or Mann-Whitney U test, as appropriate. Comparison of categorical variables between the two groups was done with χ 2 test after Pearson's and Fisher's exact test. Results 761 women were enrolled in this study; 387 women received atosiban and 374 women received hexoprenaline as their primary tocolytic agent. Atosiban showed a higher efficacy as a primary tocolytic agent (p = 0.000) within 48 hours. As regards long-term tocolysis, there were no differences between the treatment groups (p = 0.466). Maternal side effects such as tachycardia (p = 0.018) or palpitations (p = 0.000) occurred more frequently after the administration of hexoprenaline, while there were no differences between the two drugs administered with regard to any other maternal or neonatal outcome parameter. Conclusion Our retrospective study shows a significantly higher efficacy of atosiban in the first 48 hours, especially when administered at an early gestational age. There were no significant differences in terms of neonatal outcome but significantly more maternal adverse effects during the administration of hexoprenaline.

Understanding health behaviours in context: A systematic review and meta-analysis of ecological momentary assessment studies of five key health behaviours.

Ecological Momentary Assessment (EMA) involves repeated, real-time sampling of health behaviours in context. We present the state-of-knowledge in EMA research focused on five key health behaviours (physical activity and sedentary behaviour, dietary behaviour, alcohol consumption, tobacco smoking, sexual health), summarising theoretical (e.g., psychological and contextual predictors) and methodological aspects (e.g., study characteristics, EMA adherence). We searched Ovid MEDLINE, Embase, PsycINFO and Web of Science until February 2021. We included studies focused on any of the aforementioned health behaviours in adult, non-clinical populations that assessed ≥1 psychological/contextual predictor and reported a predictor-behaviour association. A narrative synthesis and random-effects meta-analyses of EMA adherence were conducted. We included 633 studies. The median study duration was 14 days. The most frequently assessed predictors were 'negative feeling states' (21%) and 'motivation and goals' (16.5%). The pooled percentage of EMA adherence was high at 81.4% (95% CI = 80.0%, 82.8%, k = 348) and did not differ by target behaviour but was somewhat higher in student (vs. general population) samples, when EMAs were delivered via mobile phones/smartphones (vs. handheld devices), and when event contingent (vs. fixed) sampling was used. This review showcases how the EMA method has been applied to improve understanding and prediction of health behaviours in context.

The process-inducing activity of transmembrane agrin requires follistatin-like domains.

Clustering or overexpression of the transmembrane form of the extracellular matrix proteoglycan agrin in neurons results in the formation of numerous highly motile filopodia-like processes extending from axons and dendrites. Here we show that similar processes can be induced by overexpression of transmembrane-agrin in several non-neuronal cell lines. Mapping of the process-inducing activity in neurons and non-neuronal cells demonstrates that the cytoplasmic part of transmembrane agrin is dispensable and that the extracellular region is necessary for process formation. Site-directed mutagenesis reveals an essential role for the loop between beta-sheets 3 and 4 within the Kazal subdomain of the seventh follistatin-like domain of TM-agrin. An aspartic acid residue within this loop is critical for process formation. The seventh follistatin-like domain could be functionally replaced by the first and sixth but not by the eighth follistatin-like domain, demonstrating a functional redundancy among some follistatin-like domains of agrin. Moreover, a critical distance of the seventh follistatin-like domain to the plasma membrane appears to be required for process formation. These results demonstrate that different regions within the agrin protein are responsible for synapse formation at the neuromuscular junction and for process formation in central nervous system neurons and suggest a role for agrin's follistatin-like domains in the developing central nervous system.

Arts in Education: A Systematic Review of Competency Outcomes in Quasi-Experimental and Experimental Studies.

Arts education in schools frequently experiences the pressure of being validated by demonstrating quantitative impact on academic outcomes. The quantitative evidence to date has been characterized by the application of largely correlational designs and frequently applies a narrow focus on instrumental outcomes such as academically relevant competencies. The present review aims to summarize quantitative evidence from quasi-experimental and experimental studies with pre-test post-test designs on the effects of school-based arts education on a broader range of competency outcomes, including intra- and interindividual competencies. A systematic literature search was conducted to identify relevant evaluation studies. Twenty-four articles reporting on 26 evaluation studies were eligible for inclusion, and their results were reviewed in terms of art domains and outcome categories. Whilst there is some evidence of beneficial effects on some competencies, for example of music education on arithmetic abilities, speech segmentation and processing speed, the evidence across arts domains and for different outcomes is limited due to small sample sizes, small number of studies, and a large range of effect sizes. The review highlights that sufficiently powered (quasi-)experimental studies with pre-test post-test designs evaluating arts education are sparse and that the "gold standard" of experimental research comes at the expense of a number of other study characteristics such as sample size, intervention and follow-up length. By summarizing the limitations of the current (quasi-)experimental research, the application of experimental designs is critically assessed and a combination with qualitative methods in mixed-method designs and choice of relevant outcomes discussed.

Systematic review of ecological momentary assessment (EMA) studies of five public health-related behaviours: review protocol.

INTRODUCTION: Ecological momentary assessment (EMA) involves repeated, real-time assessments of phenomena (eg, cognitions, emotions, behaviours) over a period of time in naturalistic settings. EMA is increasingly used to study both within-person and between-person processes. We will review EMA studies investigating key health behaviours and synthesise: (1) study characteristics (eg, frequency of assessments, adherence, incentives), (2) associations between psychological predictors and behaviours and (3) moderators of adherence to EMA protocols. METHODS AND ANALYSIS: This review will focus on EMA studies conducted across five public health behaviours in adult, non-clinical populations: movement behaviour (including physical activity and sedentary behaviour), dietary behaviour, alcohol consumption, tobacco smoking and preventive sexual health behaviours. Studies need to have assessed at least one psychological or contextual predictor of these behaviours. Studies reporting exclusively on physiological outcomes (eg, cortisol) or those not conducted under free-living conditions will be excluded. We will search OVID MEDLINE, Embase, PsycINFO and Web of Science using terms relevant to EMA and the selected health behaviours. Reference lists of existing systematic reviews of EMA studies will be hand searched. Identified articles will be screened by two reviewers. This review is expected to provide a comprehensive summary of EMA studies assessing psychological or contextual predictors of five public health behaviours. ETHICS AND DISSEMINATION: The results will be disseminated through peer-reviewed publications and presentations. Data from included studies will be made available to other researchers. No ethics are required. PROSPERO REGISTRATION NUMBER: CRD42020168314.

A 3D In Vitro Model for Burn Wounds: Monitoring of Regeneration on the Epidermal Level.

Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and a limited predictiveness. Here, we present a three-dimensional burn model, based on an open-source model, to monitor wound healing on the epidermal level. Skin equivalents were burned, using a preheated metal cylinder. The healing process was monitored regarding histomorphology, metabolic changes, inflammatory response and reepithelialization for 14 days. During this time, the wound size decreased from 25% to 5% of the model area and the inflammatory response (IL-1ß, IL-6 and IL-8) showed a comparable course to wounding and healing in vivo. Additionally, the topical application of 5% dexpanthenol enhanced tissue morphology and the number of proliferative keratinocytes in the newly formed epidermis, but did not influence the overall reepithelialization rate. In summary, the model showed a comparable healing process to in vivo, and thus, offers the opportunity to better understand the physiology of thermal burn wound healing on the keratinocyte level.

Technical Note: ADAM PETer - An anthropomorphic, deformable and multimodality pelvis phantom with positron emission tomography extension for radiotherapy.

OBJECTIVE: To develop an anthropomorphic, deformable and multimodal pelvis phantom with positron emission tomography extension for radiotherapy (ADAM PETer). METHODS: The design of ADAM PETer was based on our previous pelvis phantom (ADAM) and extended for compatibility with PET and use in 3T magnetic resonance imaging (MRI). The formerly manually manufactured silicon organ surrogates were replaced by three-dimensional (3D) printed organ shells. Two intraprostatic lesions, four iliac lymph node metastases and two pelvic bone metastases were added to simulate prostate cancer as multifocal and metastatic disease. Radiological properties [computed tomography (CT) and 3T MRI] of cortical bone, bone marrow and adipose tissue were simulated by heavy gypsum, a mixture of Vaseline and K2 HPO4 and peanut oil, respectively. For soft tissues, agarose gels with varying concentrations of agarose, gadolinium (Gd) and sodium fluoride (NaF) were developed. The agarose gels were doped with patient-specific activity concentrations of a Fluorine-18 labelled compound and then filled into the 3D printed organ shells of prostate lesions, lymph node and bone metastases. The phantom was imaged at a dual energy CT and a 3T PET/MRI scanner. RESULTS: The compositions of the soft tissue surrogates are the following (given as mass fractions of agarose[w%]/NaF[w%]/Gd[w%]): Muscle (4/1/0.027), prostate (1.35/4.2/0.011), prostate lesions (2.25/4.2/0.0085), lymph node and bone metastases (1.4/4.2/0.025). In all imaging modalities, the phantom simulates human contrast. Intraprostatic lesions appear hypointense as compared to the surrounding normal prostate tissue in T2-weighted MRI. The PET signal of all tumors can be localized as focal spots at their respective site. Activity concentrations of 12.0 kBq/mL (prostate lesion), 12.4 kBq/mL (lymph nodes) and 39.5 kBq/mL (bone metastases) were measured. CONCLUSION: The ADAM PETer pelvis phantom can be used as multimodal, anthropomorphic model for CT, 3T-MRI and PET measurements. It will be central to simulate and optimize the technical workflow for the integration of PET/MRI-based radiation treatment planning of prostate cancer patients.

Humoral protection to SARS-CoV2 declines faster in patients on TNF alpha blocking therapies.

BACKGROUND: The persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID. METHODS: 23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls. RESULTS: While anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected. CONCLUSION: Although the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations.

Joint Imaging Platform for Federated Clinical Data Analytics.

PURPOSE: Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles. METHODS: The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions. RESULTS: The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform. CONCLUSION: The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level.

Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na+,K+-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na+,K+-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.