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The Effect of Virtual Reality-Based Social Cognitive Training for Autistic Adults:Protocol for STEPS (Social Cognitive Training Enhancing Pro-Functional Skills) Randomized Clinical Trial
No full textBACKGROUND: Autistic adults constitute a growing and largely overlooked population with limited clinical and research resources. Social cognitive impairments are key deficits faced by this population, significantly impacting social interactions, educational and vocational functioning, and quality of life. Interventions targeting social cognition in autistic adults have shown promising results. Recent studies investigating the effect of virtual reality (VR)-based interventions for autistic adults have provided preliminary evidence supporting the feasibility and effectiveness of using this innovative technology. These studies indicate that VR interventions can enhance functional and social skills and improve specific neurocognitive and social cognitive functions. However, large-scale randomized clinical trials are urgently needed to fully assess the effectiveness of VR-based interventions for autistic adults.OBJECTIVE: This protocol aims to provide a comprehensive description of the design and methodology of the STEPS (Social Cognitive Training Enhancing Pro-Functional Skills) trial.METHODS: STEPS is a clinical, randomized, assessor-blinded, parallel-group superiority trial. A total of 140 participants will be allocated to receive either virtual reality-based social cognitive training (VRSCT) + treatment as usual (TAU) or TAU alone. The experimental group will receive 12 weekly 1-hour sessions of VRSCT, aiming at improving psychosocial functioning and social cognition through exposure to virtual social environments. The intervention comprises 3 core modules, namely emotions, social understanding, and complex social interactions. The exact content and duration of TAU received by each participant will be mapped and documented upon trial completion. Assessments will be conducted at baseline, at cessation of the intervention (3 months post baseline), and at 6 months post baseline.RESULTS: Participant enrollment began in May 2024. As of February 2025 (initial manuscript submission), 34 participants had been enrolled, increasing to 97 participants as of December 2025. Completion of enrollment is expected in April 2026. Data analysis is expected to begin in October 2026 following the final 6-month follow-up assessment. Results are anticipated in December 2026 and will be disseminated through peer-reviewed publications.CONCLUSIONS: To our knowledge, STEPS is the hitherto largest randomized clinical trial globally investigating the effect of VRSCT for autistic adults. The results of this innovative intervention approach may significantly advance research in the field of autism. VRSCT holds potential to improve psychosocial functioning, quality of life, and co-occurring clinical symptoms, and to reduce social cognitive deficits in autistic adults. Establishing evidence-based interventions is crucial for addressing the debilitating psychosocial challenges faced by this population, especially considering the absence of established gold-standard treatments.</p
Facilitating the Implementation of Physician-Led Medication Reviews for Patients With Severe Mental Disorder and Diabetes:A Cost-Minimization Analysis
No full textBackground: By reporting the economic ramifications of implementing novel clinical interventions, researchers may facilitate direct implementation. We reported in a recently published randomized clinical trial that implementing physician-led medication reviews for 48 outpatients suffering from both severe mental disorders and diabetes reduced the median number of drugs and potentially inappropriate prescriptions (PIPs) by 1 compared to a median increase of 2 drugs and PIPs in the control group. Aim: The aim of the study was to investigate the economic impact of implementing physician-led medication reviews through interdisciplinary dialogue for psychiatric outpatients with diabetes. Methods: In a cost-minimization analysis, we estimated costs of redeemed prescriptions, contacts and services related to any hospital in Region Zealand or the Capital Region Denmark, medical utensils, medical examinations (e.g., imaging diagnostics) and costs of the intervention for those 48 patients who participated in the trial. Findings: We found no significant differences in costs between groups, although patients in the intervention group only had a median of 6.50 telephone calls with the healthcare system (IQR 3.00, 13.00) compared to 14 (IQR 9.00, 25.50) in the control group, which may be relatively time-saving. Conclusions: Within the limited scope assessed, the intervention was cost-neutral and led to a reduction in the number of prescribed drugs and PIPs.</p
Direct RNA sequencing identified solute carrier family 2 member 1 to improve neurological outcome prediction after cardiac arrest
No full textBACKGROUND: Cardiac arrest (CA) is a major cause of mortality and morbidity. Accurate prediction of neurological outcome and survival remains challenging. In this context, our study aimed to explore novel molecular biomarkers that could provide additional insights into the pathophysiology of brain injury after CA and potentially distinguish patients with no brain injury (CPC 1) from those with any degree of neurological damage from moderate injury up to death (CPC 2-5), and complement existing prognostic tools.METHODS: Whole blood samples collected 48 h after return of spontaneous circulation were analyzed by RNA sequencing in a subgroup of 50 CA patients from the monocenter North Pole cohort, and by quantitative PCR in 233 patients from the same cohort as well as in 511 patients from the multicenter TTM trial. The association of gene expression changes with 6-month neurological outcome (assessed by the Cerebral Performance Category (CPC) score) and survival was studied.RESULTS: In a discovery phase with a subset of 50 patients from the North Pole cohort (25 CPC 1 and 25 CPC 5), direct RNA sequencing identified the solute carrier family 2 member 1 (SLC2A1), a gene encoding a major glucose transporter at the blood-brain barrier (GLUT1), as significantly upregulated in CPC 5 patients (dead with severe neurological impairment) compared to survivors without neurological sequelae (CPC 1). This upregulation was confirmed by quantitative PCR and extended to the entire North Pole cohort (p < 0.001). SLC2A1 was an independent predictor of neurological sequelae or death in this cohort. In the TTM trial, SLC2A1 was also upregulated in patients with neurological sequelae or death (p < 0.001) and was an independent predictor of neurological sequelae or death, providing an incremental predictive value to a baseline clinical model (odds ratio = 2.06, 95% confidence interval 1.31-3.4, p = 2.82E-03, and likelihood ratio test p < 0.001).CONCLUSION: Blood level of SLC2A1 is a tentative blood biomarker that may aid in neurological outcome prediction after CA and also provide new insights into post-CA injury mechanisms.</p
Cerebral near-infrared spectroscopy monitoring for prevention of death or neurodevelopmental disability in very preterm infants
No full textRATIONALE: Very preterm infants (i.e. born before 32 weeks of gestation) are at risk of cerebral injury and long-term neurodevelopmental impairment. Cerebral near-infrared spectroscopy (NIRS) enables continuous monitoring of cerebral oxygenation to guide clinical management. Interest in NIRS has grown in recent years, highlighting the need for better evidence to support its clinical efficacy in improving brain development and reducing neurological sequelae. This is an update of a Cochrane review first published in 2017.OBJECTIVES: To evaluate the beneficial and harmful effects of cerebral near-infrared spectroscopy (NIRS) monitoring versus no NIRS or blinded NIRS monitoring in very preterm infants.SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, three trial registries, and conference abstracts up to August 2025. We also checked reference lists of included studies and relevant systematic reviews.ELIGIBILITY CRITERIA: We included randomised clinical trials (RCTs) comparing cerebral NIRS monitoring versus no NIRS or blinded NIRS monitoring (where the treating healthcare professionals were unaware of the oxygenation levels) in very preterm infants.OUTCOMES: Our critical outcomes included all-cause mortality at longest follow-up, major neurodevelopmental disability in children aged 18 to 24 months (a composite outcome including cerebral palsy, severe neurodevelopmental impairment, blindness, and profound hearing impairment), and major brain injury prior to discharge. Our important outcomes included chronic lung disease at 36 weeks' gestational age, proven necrotising enterocolitis prior to discharge, retinopathy of prematurity (stage ≥ III) prior to discharge, and severe adverse reactions prior to discharge.RISK OF BIAS: We used Cochrane's original risk of bias tool (RoB 1).SYNTHESIS METHODS: We conducted meta-analyses using fixed-effect models to calculate risk ratios (RRs) and 95% confidence intervals (CIs) for all outcomes. We summarised the certainty of the evidence according to GRADE methods.INCLUDED STUDIES: We included five parallel-group RCTs published between 2016 and 2023 that enroled a total of 2415 infants, with sample sizes ranging from 23 to 1600 infants per trial. The mean gestational age ranged from 26.1 weeks to 33.1 weeks. Four trials were conducted in multiple hospitals in high-income countries across North America, Asia, and Europe. The remaining trial took place in a single hospital in Austria. The comparator was no NIRS in two trials and blinded NIRS in three trials. In all trials, infants in the NIRS group were treated according to brain oxygen saturation values with specific preset treatment regimens, while those in the control group received standard or usual care regardless of NIRS monitoring values. The trials involved infants with varying start times and durations of NIRS monitoring. Only one trial reported major neurodevelopmental disability, and two trials reported retinopathy of prematurity (stage ≥ III). All five trials provided data for the other main outcomes of this review. We identified five ongoing trials.SYNTHESIS OF RESULTS: NIRS monitoring compared with no NIRS or blinded NIRS monitoring likely results in little to no difference in all-cause mortality at longest follow-up (RR 0.99, 95% CI 0.82 to 1.18; I² = 46%; 5 studies, 2415 participants; moderate-certainty evidence) and major brain injury diagnosed by brain ultrasound prior to discharge (RR 0.99, 95% CI 0.84 to 1.17; I² = 13%; 5 studies, 2415 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of NIRS monitoring compared with blinded NIRS monitoring on major neurodevelopmental disability in children aged 18 to 24 months (RR 1.28, 95% CI 0.50 to 3.29; 1 study, 115 participants; very low-certainty evidence). NIRS monitoring compared with no NIRS or blinded NIRS monitoring likely results in little to no difference in chronic lung disease at 36 weeks of gestational age (RR 0.95, 95% CI 0.86 to 1.06; I² = 43%; 5 studies, 2415 participants; moderate-certainty evidence), proven necrosing enterocolitis prior to discharge (RR 1.08, 95% CI 0.85 to 1.37; I² = 0%; 5 studies, 2415 participants; moderate-certainty evidence), retinopathy of prematurity (stage ≥ 3) prior to discharge (RR 1.15, 95% CI 0.86 to 1.54; I² = 0%; 2 studies, 1745 participants; moderate-certainty evidence), and severe adverse reactions prior to discharge (RR 9.41, 95% CI 0.51 to 174.44; I² not applicable; 5 studies, 2415 participants; moderate-certainty evidence).AUTHORS' CONCLUSIONS: Overall, cerebral NIRS monitoring in very preterm infants likely results in little to no benefit for most measured outcomes. Compared with conventional monitoring, cerebral NIRS monitoring in very preterm infants likely results in little to no difference in all-cause mortality at longest follow-up and in major brain injury diagnosed by brain ultrasound prior to discharge, and we are unsure about its effect on major neurodevelopmental disability in children aged 18 to 24 months. Furthermore, NIRS monitoring likely results in little to no difference in the risk of chronic lung disease at 36 weeks' gestational age, proven necrotising enterocolitis prior to discharge, severe retinopathy of prematurity prior to discharge, and severe adverse reactions prior to discharge. Future randomised trials in very preterm infants should provide continuous NIRS monitoring from birth until cardiorespiratory stability to more accurately assess the potential benefits of the intervention. Further research is needed to understand and quantify performance differences among available NIRS devices and to evaluate their effects on long-term clinical outcomes. Few (if any) vital sign monitoring methods have demonstrated patient-relevant benefits in RCTs. For cerebral oximetry in preterm infants, trials using clinically meaningful endpoints (e.g. neurodevelopment at two years assessed with the Bayley Scales) may be infeasible due to the large sample sizes required. In this context, surrogate outcomes, such as electrophysiological markers of hypoxic brain injury, may offer a feasible alternative, provided they are rigorously validated against clinical endpoints.FUNDING: This Cochrane review had no dedicated funding.REGISTRATION: Protocol (2015): doi.org/10.1002/14651858.CD011506 Original review (2017): doi.org/10.1002/14651858.CD011506.pub2 Review update (2025): doi.org/10.1002/14651858.CD011506.pub3.</p
An Exploratory Study of the Impact of a CCL21-Derived C-Terminal Peptide on Dendritic Cell Lymph Node Homing
No full textThe effective trafficking of dendritic cells (DCs) to the lymph nodes (LNs), orchestrated by CC-chemokine receptor 7 (CCR7) and its ligand CCL21, is essential for the success of DC–based immunotherapies. This study explores the potential of C21TP, a naturally occurring basic peptide derived from the C-terminal of CCL21, to enhance DC homing to the draining LNs in a murine model of DC migration. C21TP, containing three clusters of basic residues, significantly boosts CCL21-mediated signaling and chemotaxis of DCs in vitro. In vivo, DCs formulated with C21TP prior to injection migrated more efficiently to the draining LNs than DCs alone or DCs formulated with a mutated version of C21TP, harboring substitutions in key basic residues. Further studies are needed to evaluate the impact of C21TP on T-cell priming efficacy in the context of DC–based immunotherapies. Nonetheless, C21TP’s ability to enhance lymph node homing of adoptively transferred cells without additional cellular modifications could offer a practical and scalable approach for advancing future DC–based vaccines.</p
Companionship counts:Investigating social housing conditions and welfare in privately owned rabbits
No full textRabbits are among the most popular companion animals. Despite being a social species, most companion rabbits are solitary housed due to challenges with pairing and cohabitation, which may compromise their welfare. This study therefore aimed to investigate the effects of social housing (solitary vs. social) and dyadic relationships (using a Friendship Index derived from rates of allogrooming and contact) on rabbit welfare. Moreover, dyad-related factors (sex combination, age difference, life stage combination, early socialisation, and neuter status) and resource-related factors (group size, spatial availability, enrichment, raised platforms, and visual barriers) previously linked to social dynamics in farmed and laboratory rabbits, were examined for their impact on dyadic relationships. This was assessed through behavioural observations based on home-pen videos collected by owners (in the morning, 5–10 a.m., and evening, 5–10 p.m.), using behavioural welfare indicators for rabbits. Linear and generalized linear mixed effects models were used to assess welfare outcomes and relationship indices, with ‘owner’ as a random effect. Video material of 122 rabbits from 74 owners were analysed, with approximately five hours per rabbit. Socially housed rabbits spent 21 % of scans in contact and 75 % in proximity to conspecifics. Agonistic interactions were rare. Solitary rabbits expressed significantly less behavioural diversity (P = 0.02) and more awake inactivity (P = 0.04) than socially housed rabbits, indicating improved welfare for the latter group. However, solitary rabbits spent significantly more time on environmental interaction (P = 0.03), plausibly due to their inability to socialise. A higher age difference was found to be significantly associated with a reduced Friendship Index (P = 0.002). Minimising the age difference may therefore be considered for future recommendations regarding pairing of companion rabbits. No significant effects of dyadic relationships on welfare were found; however the sample was biased towards positive relationships. The large housing space available to the rabbits may have contributed to the low level of agonistic behaviour and positive dyadic relationships. In summary, statistical inferences were hindered by data homogeneity and zero-inflation, likely due to convenience sampling, along with a lack of evidence-based welfare indicators for rabbits. Future studies should investigate optimal observation times and durations, as well as assess validity, reliability, and feasibility of existing behavioural welfare indicators for rabbits. Despite methodological limitations, this study provides insights into the social environment and welfare of companion rabbits, emphasizing the benefits of social housing and the potential advantages of minimizing age differences in rabbit dyads.</p
Understory vegetation development along 60-year chronosequences of oak, beech, and Norway spruce
No full textAfforestation in European countries often targets agricultural soil. New forests can provide habitats for specialist species, however, land-use legacies and fragmentation hinder biodiversity in post-agricultural habitats. The goal of this paper is to explore the effects of forest age, tree species, and the environment on the understory plant community in post-agricultural forest plantations. We used vegetation survey data from 60-year chronosequences of oak, beech, and Norway spruce sampled in 2001, 2013, and 2021, supplemented with data on soil chemistry, forest structure, management, and distance to the closest old forest. The development of understory communities was analysed with generalized mixed effect models and multivariate analyses. We assessed the abiotic and spatial factors shaping the community and the subsets of forest specialists, generalists, and open habitat species. Plant communities maintained low similarity to the old-forest reference, albeit increasing with time. Forest specialists prevalence increased over time while generalists remained abundant in all surveys. Environmental variables did not influence this trend. Open habitat species disappeared with canopy closure. Tree species influenced both the soil and light availability but correlated significantly only with the occurrence of open habitat species. Both abiotic and spatial factors partly explained the beta diversity of the whole community and of the specialists, generalists, and open habitat sub-communities. While the understory vegetation in post-agricultural forest plantations develops towards old-forest communities, major differences remain after nearly 60 years. Factors such as dispersal limitation and land use legacies may delay the establishment of specialized forest plant communities
Twelfth-Century Logic and Metaphysics:Alberic of Paris and His Contemporaries
No full textAlberic of Paris was one of the leading philosophers of the 12th century. He was the main rival to Peter Abelard and, according to John of Salisbury, “a most fierce opponent of the nominalist school.” But although he was an important figure in his time, Alberic is almost completely unknown today.This collection of essays is the first ever dedicated to exploring and contextualizing the views of Alberic and his followers, the Albricani. It discusses topics such as universals, time, mereology, divine foreknowledge, fallacies, and modal logic, and shows that Alberic was an original thinker in a vibrant intellectual milieu.Contributors are Andrew W. Arlig, Enrico Donato, Sten Ebbesen, Charles Girard, Heine Hansen, Peter King, John Marenbon, Sofia Orsino, Boaz Faraday Schuman, Caterina Tarlazzi, Paul Thom, and Wojciech Wciórka.Alberic of Paris was one of the leading philosophers of the 12th century. He was the main rival to Peter Abelard and, according to John of Salisbury, “a most fierce opponent of the nominalist school.” But although he was an important figure in his time, Alberic is almost completely unknown today.This collection of essays is the first ever dedicated to exploring and contextualizing the views of Alberic and his followers, the Albricani. It discusses topics such as universals, time, mereology, divine foreknowledge, fallacies, and modal logic, and shows that Alberic was an original thinker in a vibrant intellectual milieu.Contributors are Andrew W. Arlig, Enrico Donato, Sten Ebbesen, Charles Girard, Heine Hansen, Peter King, John Marenbon, Sofia Orsino, Boaz Faraday Schuman, Caterina Tarlazzi, Paul Thom, and Wojciech Wciórka
The Contributions of Microbial Interactions to Abrupt Ecosystem Changes during the Late Quaternary*
No full textAbrupt ecosystem shifts during the Late Quaternary coincided with major climatic changes and intensified human activities, but the precise causes of these shifts remain debated. Here, building on previous hypotheses and work, we propose a new hypothesis that both plant beneficial and antagonistic soil microorganisms were the proximate drivers of Late Quaternary change. We synthesized evidence from paleoecological studies and contemporary ecosystems to understand how microbes and their interactions with plants shift ecosystem function. Because relevant paleoecological data are nonexistent, we reanalyzed a contemporary survey from grasslands and woodlands across Europe to test the general role of microbial diversity versus climate in controlling ecosystem function. Our models found that the richness of different microbial groups, including Proteobacteria, mycorrhizas, and plant fungal pathogens, were more strongly associated with the magnitude of direct effects on net primary productivity than temperature and precipitation. The richness of most of these groups was also influenced by climate, supporting our hypothesis that climate change may have indirectly caused past ecosystem shifts by changing microbial composition and function. We end by highlighting the potential of environmental DNA to reconstruct the biota and conditions of past ecosystems. Ultimately, improving our understanding of how microbes drove past ecosystem shifts may improve our ability to respond to future environmental changes.</p
Improving Outcome Reporting in Paediatric Airway Management in Clinical Trials (IMPACT):A Study Protocol for Core Outcomes and Clinical Endpoints
No full textBACKGROUND: Although clinical trials are fundamental to advancing evidence-based practice, significant heterogeneity in outcome reporting poses a considerable challenge to the validity of systematic reviews. This inconsistency impedes the ability to compare, synthesise and interpret research findings effectively. In the field of paediatric airway management, this issue is particularly relevant because of the low incidence of critical events and the related high morbidity and mortality. The issue of inadequate and variable outcome reporting in clinical trials has been widely acknowledged, necessitating initiatives to enhance the quality of future research.OBJECTIVE: This protocol delineates the methodology used for the development of standardised, consensus-based outcome definitions and reporting items specifically tailored to paediatric airway management trials. The goal is to create guidance that will serve as an extension to the established SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) frameworks, leading to enhanced trial reproducibility and transparency and ultimately improve pediatric airway research, systematic reviews and advance patient care and safety.METHODS: This project will adhere to the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network's framework for guideline development. The methodology will be structured into four distinct phases: (1) a scoping review to comprehensively identify outcomes and variables currently reported in paediatric airway management trials; (2) a three-round Delphi process involving a multidisciplinary panel of experts to prioritise and refine outcomes and variables; (3) a consensus meeting to achieve agreement on the final set of reporting items, which will then be prepared for publication and (4) dissemination.CONCLUSIONS: The finalised outcome reporting guidelines, in the form of SPIRIT and CONSORT extensions for paediatric airway management, will be disseminated through various channels to maximise their reach and impact. These include publication in peer-reviewed journals, presentation at major international conferences and submission to relevant international reporting registries, such as the EQUATOR, SPIRIT and CONSORT registries. Active engagement with key stakeholders, including journal editors, research funders, regulatory bodies and clinician networks and national and international societies, will be a crucial component of the dissemination strategy.</p