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BackgroundMental disorders affect one in seven Australian children and although effective, evidenced based treatments exist, there is a critical shortage of mental health clinicians which has created a “treatment gap.” Artificial intelligence has the potential to address the high prevalence rates of mental disorders within overburdened mental health systems.MethodsThis was a non-randomized feasibility study to evaluate the novel application of voice technology to an evidence-based parenting intervention designed to support children’s mental health. We deployed an Amazon Alexa app to parents recruited from the community (N = 55) and to parents with children receiving psychological treatment (N = 4). Parents from the community used the app independently whereas parents from the clinical group used the app in conjunction with attending a six-week parenting program. The primary outcome measure, feasibility was assessed in terms of acceptability, via recruitment and retention rates, quantitative surveys and qualitative interviews.ResultsIn the community group, the recruitment rate was 23.8% and the retention rate 49.1%. In the clinical group, all 6 families approached for recruitment agreed to participate and 4 out of 6 completed the trial. Parents attending the parenting program spent on average, three times longer using the app than parents from the community. Overall, parents reported that the app contained easy-to-understand information on parenting, and that they could see the potential of voice technology to learn and practice parenting skills. Parents also faced several challenges, including difficulties with installation and interactions with the app and expressed privacy concerns related to voice technology. Further, parents reported that the voices used within the app sounded monotone and robotic.ConclusionWe offer specific recommendations that could foster a better voice assistant user experience for parents to support their children’s mental health. The app is highly scalable and has the potential to addresses many of the barriers faced by parents who attempt to access traditional parenting interventions.

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Abstract DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.

Background School refusal is a heterogenous problem which typically emerges in adolescence and co-occurs with internalising disorders. A substantial proportion of adolescents do not respond to existing treatment modalities; thus, novel, effective intervention options are needed. Partners in Parenting Plus (PiP+) is a coach-assisted, web-based intervention designed to empower parents to respond to adolescent internalising disorders. Aims To conduct a process evaluation of PiP+ and identify programme adaptations required to meet the needs of parents of adolescents who refuse school. Method Semi-structured interviews were conducted with 14 Australian mothers who had: (a) received the PiP+ programme (not tailored for school refusal) during a prior research trial; and (b) reported that their adolescent was refusing school during their participation in PiP+. Inductive thematic analysis was used to analyse interview transcripts. Results Participants were 41–53 years old (M = 47.8) and parenting adolescent children aged 14–17 years (M = 14.9). Three themes illustrated how PiP+ features met or could better meet the needs of parents of adolescents who were refusing school: (a) feeling heard, supported and respected; (b) relevance to me and my context; and (c) seeing positive changes. Participants had favourable views of PiP+, especially coached components. Participants requested programme enhancements to better meet the needs of parents of neurodiverse adolescents and discussed the impact of cumulative help-seeking ‘failures’ on self-efficacy and locus of control. Conclusions PiP+ was highly acceptable to the majority of parents navigating the issue of school refusal. This has implications for the enhancement of coach-assisted parenting interventions and the context-specific adaptation of PiP+ for school refusal.

Introduction/Objectives: With growing vaccination misinformation and mistrust, strategies to improve vaccination communication across community-based settings are needed. Methods: The Rural Adolescent Vaccine Enterprise (RAVE), a 5-year (2018-2022) stepped-wedge cluster randomized study, tested a clinic-based practice facilitation intervention designed to improve HPV vaccination. An exploratory aim sought to explore the use of partnerships between primary care clinics and a community partner of their choosing, to implement a social marketing campaign related to HPV immunization. We assessed perceptions about the value and success of the partnership, and barriers and facilitators to its implementation using a 29-item community partner survey, key informant interviews, and field notes from practice facilitators. Results: Of the initial 45 clinics participating in RAVE, 9 were unable to either start or complete the study, and 36 participants (80.0%) were actively engaged. Of these, 16/36 clinics (44.4%) reported establishing successful partnerships, 10 reported attempting to develop partnerships (27.8%), and another 10 reported not developing a partnership (27.8%), which were often caused by the COVID-19 pandemic. The most common partnership was with public health departments at 27.3%. Other partnerships involved libraries, school districts, and local businesses. More than half (63.7%) reported that creating messages regarding getting HPV vaccination was moderately to very challenging. Just under half reported (45.5%) that messaging was hard because of a lack of understanding about the seriousness of diseases caused by HPV, parents being against vaccines because of safety concerns, and religious values that result in a lack of openness to HPV vaccines. Community partners’ health priorities changed as a result of RAVE, with 80% prioritizing childhood immunizations as a result of the RAVE partnership. Conclusions: Community groups want to partner with primary care organizations to serve their patients and populations. More research is needed on how best to bring these groups together.

Summary: Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation.

Abstract Background There has been limited focus on understanding the barriers and facilitators to meeting the broader psychosocial needs of young people with mental illness from the perspectives of young people. This is required to advance the local evidence base and inform service design and development. The aim of this qualitative study was to explore young people’s (10–25 years) and carers’ experiences of mental health services, focusing on barriers and facilitators to services supporting young people’s psychosocial functioning. Methods This study was conducted throughout 2022 in Tasmania, Australia. Young people with lived experience of mental illness were involved in all stages of this research. Semi-structured interviews were conducted with 32 young people aged 10–25 years with experience of mental illness, and 29 carers (n = 12 parent–child dyads). Qualitative analysis was guided by the Social-Ecological Framework to identify barriers and facilitators at the individual (young person/carer level), interpersonal, and service/systemic level. Results Young people and carers identified eight barriers and six facilitators across the various levels of the Social-Ecological Framework. Barriers included, at the individual level: (1) the complexity of young people’s psychosocial needs and (2) lack of awareness/knowledge of services available; at the interpersonal level: (3) negative experiences with adults and (4) fragmented communication between services and family; and at the systemic level: (5) lack of services; (6) long waiting periods; (7) limited service accessibility; and (8) the missing middle. Facilitators included, at the individual level: (1) education for carers; at the interpersonal level: (2) positive therapeutic relationships and (3) carer advocacy/support; and at the systemic level: (4) flexible or responsive services, (5) services that address the psychosocial factors; and (6) safe service environments. Conclusions This study identified key barriers and facilitators to accessing and utilising mental health services that may inform service design, development, policy and practice. To enhance their psychosocial functioning, young people and carers want lived-experience workers to provide practical wrap-around support, and mental health services that integrate health and social care, and are flexible, responsive and safe. These findings will inform the co-design of a community-based psychosocial service to support young people experiencing severe mental illness.

ABSTRACTPredicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice.

The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell–derived microglia, HSV-2–induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2–treated microglia exerted IKBKE-dependent type I IFN–mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.

BackgroundUnaddressed family adversity has potentially modifiable, negative biopsychosocial impacts across the life course. Little is known about how Australian health and social practitioners identify and respond to family adversity in community and primary health settings.ObjectiveTo describe, in two Australian community health services: (1) the number of adversities experienced by caregivers, (2) practitioner identification of caregivers experiencing adversity, (3) practitioner response to caregivers experiencing adversity, and (4) caregiver uptake of referrals.MethodsSurvey of caregivers of children aged 0–8 years attending community health services in Victoria and New South Wales (NSW). Analysis described frequencies of caregiver self-reported: (1) experiences of adversity, (2) practitioner identification of adversity, (3) practitioner response to adversity, and (4) referral uptake. Analyses were sub-grouped by three adversity domains and site.Results349 caregivers (Victoria: n = 234; NSW: n = 115) completed the survey of whom 88% reported experiencing one or more family adversities. The median number of adversities was 4 (2–6). Only 43% of participants were directly asked about or discussed an adversity with a practitioner in the previous 6 months (Victoria: 30%; NSW: 68%). Among caregivers experiencing adversity, 30% received direct support (Victoria: 23%; NSW: 43%), and 14% received a referral (Victoria: 10%; NSW: 22%) for at least one adversity. Overall, 74% of caregivers accepted referrals when extended.ConclusionThe needs of Australian families experiencing high rates of adversity are not systematically identified nor responded to in community health services. This leaves significant scope for reform and enhancement of service responses to families experiencing adversity.

Summary: Low circulating phosphate (Pi) leads to rickets, characterized by expansion of the hypertrophic chondrocytes (HCs) in the growth plate due to impaired HC apoptosis. Studies in HCs demonstrate that Pi activates the Raf/MEK/ERK1/2 and mitochondrial apoptotic pathways. To determine how Pi activates these pathways, a small-molecule screen was undertaken to identify inhibitors of Pi-induced ERK1/2 phosphorylation in HCs. Vascular endothelial growth factor receptor 2 (VEGFR2) was identified as a target. In vitro studies in HCs demonstrate that VEGFR2 inhibitors block Pi-induced pERK1/2 and caspase-9 cleavage. Like Pi, rhVEGF activates ERK1/2 and caspase-9 in HCs and induces phosphorylation of VEGFR2, confirming that Pi activates this signaling pathway in HCs. Chondrocyte-specific depletion of VEGFR2 leads to an increase in HCs, impaired vascular invasion, and a decrease in HC apoptosis. Thus, these studies define a role for VEGFR2 in transducing Pi signals and mediating its effects on growth plate maturation.

Abstract Advanced structural brain imaging techniques, such as diffusion tensor imaging (DTI), have been used to study the relationship between DTI-parameters and cognitive scores in multiple sclerosis (MS). In this study, we assessed cognitive function in 61 individuals with MS and a control group of 35 healthy individuals with the Symbol Digit Modalities Test, the California Verbal Learning Test-II, the Brief Visuospatial Memory Test-Revised, the Controlled Oral Word Association Test, and Stroop-test. We also acquired diffusion-weighted images (b = 1000; 32 directions), which were processed to obtain the following DTI scalars: fractional anisotropy, mean, axial, and radial diffusivity. The relation between DTI scalars and cognitive parameters was assessed through permutations. Although fractional anisotropy and axial diffusivity did not correlate with any of the cognitive tests, mean and radial diffusivity were negatively correlated with all of these tests. However, this effect was not specific to any specific white matter tract or cognitive test and demonstrated a general effect with only low to moderate individual voxel-based correlations of

Abstract Blooms of pigmented algae darken the surface of glaciers and ice sheets, thereby enhancing solar energy absorption and amplifying ice and snow melt. The impacts of algal pigment and community composition on surface darkening are still poorly understood. Here, we characterise glacier ice and snow algal pigment signatures on snow and bare ice surfaces and study their role in photophysiology and energy absorption on three glaciers in Southeast Greenland. Purpurogallin and astaxanthin esters dominated the glacier ice and snow algal pigment pools (mass ratios to chlorophyll a of 32 and 56, respectively). Algal biomass and pigments impacted chromophoric dissolved organic matter concentrations. Despite the effective absorption of astaxanthin esters at wavelengths where incoming irradiance peaks, the cellular energy absorption of snow algae was 95% lower than anticipated from their pigmentation, due to pigment packaging. The energy absorption of glacier ice algae was consequently ~ 5 × higher. On bare ice, snow algae may have locally contributed up to 13% to total biological radiative forcing, despite contributing 44% to total biomass. Our results give new insights into the impact of algal community composition on bare ice energy absorption and biomass accumulation during snow melt.

G protein-coupled receptors (GPCRs) enable cells to sense environmental cues and are indispensable for coordinating vital processes including quorum sensing, proliferation, and sexual reproduction. Here the authors, using heterologous GPCR expression and endogenous ligand production, enable synthetic mating in haploid yeast, and GPCR-mediated biosensing in diploid probiotic yeast.

Abstract Background The management of cognitive impairment is an important goal in the treatment of multiple sclerosis (MS). While cognitive rehabilitation has been proven to be effective in improving cognitive performance in MS, research in the elderly indicates a higher effectiveness of combined cognitive-motor rehabilitation. Here, we present the protocol of a randomised controlled clinical trial to assess whether a combined cognitive-motor telerehabilitation programme is more effective in improving working memory than only cognitive or motor training. Methods/design The CoMoTeMS-trial is a two-centre, randomised, controlled and blinded clinical trial. A total of 90 patients with MS will receive 12 weeks of either a combined cognitive-motor telerehabilitation programme or only cognitive or motor training. The primary outcome is a change in the digit span backwards. Secondary outcomes are other cognitive changes (Brief International Cognitive Assessment for Multiple Sclerosis and Backward Corsi), Expanded Disability Status Scale (EDSS), 6-Min Walk Test, 25-Foot Walk Test, 9-Hole Peg Test, anxiety and depression, fatigue, quality of life, cognitive and physical activity level, electroencephalography and magnetic resonance imaging of the brain. Discussion We hypothesise that the improvement in digit span backwards after 12 weeks of treatment will be significantly higher in the group treated with the combined cognitive-motor telerehabilitation programme, compared to the groups receiving only cognitive and only motor training. Trial registration ClinicalTrials.gov NCT05355389. Registered on 2 May 2022.

The accumulation and storage of nitrate by diatoms can contribute up to 1% of total pelagic nitrate and as much as 95% of total benthic nitrate, which indicates a potentially important contribution of diatoms to benthic nitrogen cycling, according to a global analysis

ObjectivesThe disease-modifying anti-rheumatic drug methotrexate (MTX) is recognized to reduce cardiovascular risk in patients with systemic inflammatory diseases. However, the molecular basis for these cardioprotective effects remains incompletely understood. This study evaluated the actions of low-dose MTX on the vascular endothelium.MethodsHuman endothelial cells (EC) were studied under in vitro conditions relevant to inflammatory arthritis. These included culture in a pro-inflammatory microenvironment and exposure to fluid shear stress (FSS) using a parallel plate model. Respectively treated cells were analyzed by RNA sequencing and quantitative real-time PCR for gene expression, by immunoblotting for protein expression, by phosphokinase activity arrays, by flow cytometry for cell cycle analyses and by mass spectrometry to assess folate metabolite levels.ResultsIn static conditions, MTX was efficiently taken up by EC and caused cell cycle arrest concurrent with modulation of cell signaling pathways. These responses were reversed by folinic acid (FA), suggesting that OCM is a predominant target of MTX. Under FSS, MTX did not affect cell proliferation or pro-inflammatory gene expression. Exposure to FSS downregulated endothelial one carbon metabolism (OCM) as evidenced by decreased expression of key OCM genes and metabolites.ConclusionWe found that FSS significantly downregulated OCM and thereby rendered EC less susceptible to the effects of MTX treatment. The impact of shear stress on OCM suggested that MTX does not directly modulate endothelial function. The cardioprotective actions of MTX likely reflect direct actions on inflammatory cells and indirect benefit on the vascular endothelium.

Abstract Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4–69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6–54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30–3.36] and 2.06 [95% CI 1.43–2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions.

Summary Directed evolution is a powerful method to optimize proteins and metabolic reactions towards user‐defined goals. It usually involves subjecting genes or pathways to iterative rounds of mutagenesis, selection and amplification. While powerful, systematic searches through large sequence‐spaces is a labour‐intensive task, and can be further limited by a priori knowledge about the optimal initial search space, and/or limits in terms of screening throughput. Here, we demonstrate an integrated directed evolution workflow for metabolic pathway enzymes that continuously generate enzyme variants using the recently developed orthogonal replication system, OrthoRep and screens for optimal performance in high‐throughput using a transcription factor‐based biosensor. We demonstrate the strengths of this workflow by evolving a rate‐limiting enzymatic reaction of the biosynthetic pathway for cis,cis‐muconic acid (CCM), a precursor used for bioplastic and coatings, in Saccharomyces cerevisiae. After two weeks of simply iterating between passaging of cells to generate variant enzymes via OrthoRep and high‐throughput sorting of best‐performing variants using a transcription factor‐based biosensor for CCM, we ultimately identified variant enzymes improving CCM titers > 13‐fold compared with reference enzymes. Taken together, the combination of synthetic biology tools as adopted in this study is an efficient approach to debottleneck repetitive workflows associated with directed evolution of metabolic enzymes.

Background: As a result of globalisation and the growing importance of environmental and social issues, construction companies are expected to reduce the environmental impact of their day-to-day activities and make the industry more environmentally friendly. Many research works published have ignored the critical parameters and dimensions of green supply-chain management (GSCM) and logistics performance as environmental protective practices in the construction industry. Therefore, there is a need to investigate how the construction sector should implement GSCM programmes and logistics performance as environmentally friendly practices in their business activities, which would be beneficial to all stakeholders. Objectives: The present study intends to fill this gap by analysing the impact of environmentally friendly practices, such as GSCM and logistics performance in the construction industry in southern Gauteng. This study considered regulatory pressure, green information systems, green packaging, reverse logistics and logistics performance as environmental protective practices. Method: This study adopted a quantitative approach to survey a sample of 440 suppliers and purchasers’ managers from construction companies in the southern Gauteng province. A judgemental or purposive sampling technique was applied to collect data from respondents. Data were analysed with the aid of Statistical Package for Social Science (SPSS 27.0) and Analysis of Moment Structures (AMOS 27.0). In addition, confirmatory factor analysis and structural equation modelling were used to analyse the relationship between constructs and test the hypotheses. Results: This study revealed that regulatory pressure, green information systems, green packaging and reverse logistics significantly influence logistics performance of construction companies. Conclusion: Study demonstrated that through GSCM and logistics performance, construction companies can correlate their business activities and the environment effectively.

Abstract Background Cognitive behavioural therapy (CBT) is the most widely recognised and efficacious psychological therapy for the treatment of anxiety disorders in children and adults. However, suboptimal remission rates indicate room for improvement in treatments, particularly when both children and their parents have anxiety disorders. Bidirectional transmission and maintenance of anxiety within parent–child dyads could be better targeted by CBT, to improve treatment outcomes for children and parents with anxiety disorders. This study aimed to develop and evaluate the feasibility and acceptability of a concurrent parent–child enhanced CBT intervention that targets the individual’s anxiety disorder(s), as well as the bidirectional factors that influence and maintain anxiety in the dyad. Methods Feasibility and acceptability of the proposed CBT protocol will be evaluated in an open-label pilot trial of the intervention utilising qualitative and quantitative data collection. Ten parent–child dyad participants (n = 20) with anxiety disorders will be recruited for the proposed intervention. The intervention is based on an empirically supported 10-week CBT programme for anxiety disorders in adults, adapted to be delivered to parent–child dyads concurrently, and to target anxious modelling and overprotective behaviours through joint observational exposures. Intervention feasibility will be explored by pre-post symptom change on a range of clinician- and self-report measures to determine preliminary indications of participants’ intervention response and effect size calculations to estimate sample size for a future definitive randomised controlled trial (RCT). Additional feasibility measures will include recruitment rates, completion rates, and adherence to programme requirements. To explore participant acceptability of the intervention, qualitative interviews will be conducted with five parent–child dyads who complete the intervention (n = 10), along with five parent–child dyads with anxiety symptoms who express interest in the intervention (n = 10). Acceptability measures will include prospective and retrospective quantitative self-report and qualitative interview data. Discussion This pilot trial will utilise a mixed-methods design to determine the feasibility and acceptability of delivering an enhanced CBT intervention for the concurrent treatment of parent–child dyads with anxiety disorders. The results of this trial will inform the development and implementation of a future definitive randomised clinical trial to evaluate intervention efficacy. Trial registration Australian and New Zealand Clinical Trials Registry, ANZCTR1261900033410 . Prospectively registered: pre-results. Registered 04 March 2019.

Abstract Graph-theoretical analysis is a novel tool to understand the organisation of the brain. We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.

Intact mineralization of the auditory ossicles - the smallest bones in the body - is essential for sound transmission in the middle ear, while ossicular hypomineralization is associated with conductive hearing loss. Here, we performed a high-resolution analysis of the ossicles in vitamin D receptor deficient mice (Vdr-/-), which are characterized by hypocalcemia and skeletal mineralization defects, and investigated whether local hypomineralization can be prevented by feeding a calcium-rich rescue diet (Vdr-/- res). In Vdr-/- mice fed a regular diet (Vdr-/- reg), quantitative backscattered electron imaging (qBEI) revealed an increased void volume (porosity, p0.05 vs. WT) and partial rescue of porosity and CaWidth (p=0.02 and p=0.04 vs. WT) were observed. Compared with Hyp mice, a model of X-linked hypophosphatemic rickets, Vdr-/- reg mice showed a lower osteoid volume in the ossicles (p=0.0002), but similar values in the lumbar spine. These results are consistent with later postnatal impairment of mineral homeostasis in Vdr-/- mice than in Hyp mice, underscoring the importance of intact mineral homeostasis for ossicle mineralization during development. In conclusion, we revealed a distinct phenotype of hypomineralization in the auditory ossicles of Vdr-/- mice that can be partially prevented by a rescue diet. Since a positive effect of a calcium-rich diet on ossicular mineralization was demonstrated, our results open new treatment strategies for conductive hearing loss. Future studies should investigate the impact of improved ossicular mineralization on hearing function.

The HYPSO-1 satellite, a 6U CubeSat carrying a hyperspectral imager, was launched on 13 January 2022, with the Goal of imaging ocean color in support of marine research. This article describes the development and current status of the mission and payload operations, including examples of agile planning, captures with low revisit time and time series acquired during a campaign. The in-orbit performance of the hyperspectral instrument is also characterized. The usable spectral range of the instrument is in the range of 430 nm to 800 nm over 120 bands after binning during nominal captures. The spatial resolvability is found empirically to be below 2.2 pixels in terms of Full-Width at Half-Maximum (FWHM) at 565 nm. This measure corresponds to an inherent ground resolvable resolution of 142 m across-track for close to nadir capture. In the across-track direction, there are 1216 pixels available, which gives a swath width of 70 km. However, the 684 center pixels are used for nominal captures. With the nominal pixels used in the across-track direction, the nadir swath-width is 40 km. The spectral resolution in terms of FWHM is estimated to be close to 5 nm at the center wavelength of 600 nm, and the Signal-to-Noise Ratio (SNR) is evaluated to be greater than 300 at 450 nm to 500 nm for Top-of-Atmosphere (ToA) signals. Examples of images from the first months of operations are also shown.

Abstract Background Mental Health First Aid (MHFA) training teaches community members how to provide initial support to someone with a mental health problem. Key gaps in the evidence base supporting the training are the longevity of effects beyond 6 months, effects on mental health first aid behavior, and the impact of support on the recipient of aid. This study aimed to evaluate the effect of the Youth MHFA course 3 years after training. Methods 384 Australian parents of an adolescent aged 12–15 were randomized to receive either the 14-h Youth MHFA course or the 15-h Australian Red Cross Provide First Aid course. This paper reports outcomes at baseline and 3 years later. Primary outcomes were cases of adolescent mental health problems, and parental support towards their adolescent if they developed a mental health problem, rated by the parent and adolescent. Secondary outcomes included parent knowledge about youth mental health problems, intentions and confidence in supporting a young person, stigmatizing attitudes, and help-seeking for mental health problems. Data were analyzed with mixed-effects models with group by measurement occasion interactions. Results 3-year follow-up data was obtained from 149 parents and 118 adolescents, who were aged 16.5 years on average. Between baseline and 3-year follow-up, there was a non-significant reduction in adolescent cases of mental health problems relative to the control group (odds ratios (OR) 0.16–0.17), a non-significant improvement in parental support reported by adolescents with a mental health problem (OR 2.80–4.31), and a non-significant improvement in the quality of support that parents reported providing to their adolescents with a mental health problem (d = 0.38). Secondary outcomes that showed significant improvements relative to the control group were parental knowledge about youth mental health problems (d = 0.31) and adolescent perceptions of general social support from their parents (d = 0.35). Conclusions This paper reports on the longest follow-up of Mental Health First Aid training in a controlled trial. Three years after training, participants had maintained their improved knowledge about mental health problems. There were some indications of other positive effects, but the study was underpowered to clearly show benefits to mental health first aid skills and recipients of aid. Trial registration ACTRN 12612000390886 , registered retrospectively 5/4/2012, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347502

The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50 lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K, 53% for 1750 K). At the lowest intensity (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K, 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.

Since the COVID-19 outbreak in Wuhan City in December of 2019, numerous model predictions on the COVID-19 epidemics in Wuhan and other parts of China have been reported. These model predictions have shown a wide range of variations. In our study, we demonstrate that nonidentifiability in model calibrations using the confirmed-case data is the main reason for such wide variations. Using the Akaike Information Criterion (AIC) for model selection, we show that an SIR model performs much better than an SEIR model in representing the information contained in the confirmed-case data. This indicates that predictions using more complex models may not be more reliable compared to using a simpler model. We present our model predictions for the COVID-19 epidemic in Wuhan after the lockdown and quarantine of the city on January 23, 2020. We also report our results of modeling the impacts of the strict quarantine measures undertaken in the city after February 7 on the time course of the epidemic, and modeling the potential of a second outbreak after the return-to-work in the city.

Objective Youth mental health problems have been identified as a major public health concern. However, there are a number of parent populations that remain under‐engaged with face‐to‐face parenting programs, which include fathers, and parents of lower socioeconomic position and rural location. This review aimed to evaluate the evidence for technology‐assisted parenting programs for youth mental health and parenting outcomes; as well as the extent to which they engage underserved parent populations and how they can be better tailored for these groups in an Australian context. Methods Employing the PRISMA method, we conducted a systematic review of randomised controlled trials of technology‐assisted parenting programs for youth mental health problems. Results We identified 43 articles that met inclusion criteria, consisting of 25 randomised controlled trials along with 8 and 10 articles describing intervention development and follow‐up, respectively. Some evidence was found to support the use of technology‐assisted parenting programs, particularly to improve externalising problems and parenting skills. Additionally, program development and recruitment strategies to engage underserved parents were under‐utilised among studies reviewed. Conclusions Findings from this review indicate that technology‐assisted parenting programs may present an effective alternative to traditional face‐to‐face programs. However, more comprehensive and evidence‐based strategies are required for program development and recruitment to capitalise on the advantages of technology‐assisted programs to enhance engagement with underserved parent populations. Further research should investigate program attributes and engagement strategies for diverse parent populations.

Background: Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi. Methods: Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes. Findings: We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels. Interpretation: These data hold promise for beneficial use of STING-targeting therapy in lupus. Funding: The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.

Marginalization, widely associated with poverty, inequality, and underdevelopment restricts access to resources, limits freedom of choice, inhibits the development of individual capabilities, and makes it challenging to escape from marginalized circumstances. We examine marginality in mathematics teaching and its complexities in the tightly centralized educational system in the Philippines by identifying the different situations that contribute to how mathematics teachers can be excluded from certain educational practices that would normally fall within their mandate as professional teachers. Adopting Gatzweiler and Baumüller's (Marginality: Addressing the nexus of poverty, exclusion and ecology, Springer:27-40, 2014) framework, we interviewed 15 mathematics teachers from different geographical locations around the country. We identified and organized the drivers of marginality into biophysical and societal causal clusters that enable or constrain teachers to act as professionals. Biophysical causal clusters include mathematics curriculum and mathematics assessments among others while societal causal clusters include various directives, interpretations, and realities surrounding the biophysical causal clusters. Discussions about the complexities brought about by these clusters and how teachers act or respond as they navigate around them are highlighted. Recommendations for concrete de-marginalization actions are offered.

Abstract Background There is well-established evidence that Mental Health First Aid (MHFA) training improves knowledge about how to support someone developing a mental health problem, but less evidence that this support improves the mental health of the recipient of aid. This randomised controlled trial aimed to assess the long-term effects of MHFA training of parents on the mental health of their adolescent children. Methods 384 Australian parents of an adolescent aged 12–15 were randomised to receive either the 14-h Youth MHFA course or the 15-h Australian Red Cross Provide First Aid course. Outcomes were assessed at baseline, 1-year, and 2-year follow-up in both parents and adolescents. Primary outcomes were cases of adolescent mental health problems, and parental support towards their adolescent if they developed a mental health problem, rated by the parent and adolescent. Secondary outcomes included parent knowledge about mental health problems, intentions and confidence in supporting a young person, stigmatizing attitudes, and help-seeking for mental health problems. Results Parent and adolescent reports showed no significant difference between training groups in the proportion of cases of adolescents with a mental health problem over time (ps > .05). There was also no significant difference between training groups in the quality of parental support provided to their adolescent at 1- or 2-year follow-up (ps > .05). In contrast, some secondary outcomes showed benefits from the Youth MHFA training relative to the control, with increased parental knowledge about mental health problems at 1-year (d = 0.43) and 2-year follow-up (d = 0.26), and increased confidence to help a young person (d = 0.26) and intentions to provide effective support (d = 0.22) at 1-year follow-up. Conclusions The study showed some improvements in mental health literacy in training recipients, but could not detect changes in the mental health of adolescents and the support provided to them by their parents if they had a mental health problem. However, there was a lack of power to detect primary outcome effects and therefore the question of whether MHFA training leads to better outcomes in the recipients of aid remains to be further explored. Trial registration ACTRN12612000390886, registered retrospectively 5/4/2012.

Background Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR. Methods Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation. Results Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (pConclusion Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors. Trial registration ClinicalTrials.gov Identifier:NCT01395719.

The ‘coronavirus disease of 2019’ crisis has recently forced an expedited adoption of teleconsultation (TC) in most medical domains. Short-term digital interventions have generally been associated with feasibility, clinical benefits, user satisfaction, and cost-effectiveness in patients with multiple sclerosis (MS) but outcomes after repeated utilization over extended periods need to be further evaluated. In this feasibility study, 60 subjects with MS were 1:1 randomized to receive standard care augmented by four TCs using an audiovisual Internet platform (intervention) versus standard care alone (controls), over a period of 12 months. Effects on functional status, medical costs, and satisfaction were explored as secondary outcomes. Eighty-nine out of 108 scheduled TCs (82.4%) were completed, and 26 patients could complete at least one TC (86.7%), meeting our prespecified feasibility target of 80%. The intervention did not lead to significant differences in functional status (with the potential exception of fatigue) nor medical costs. Most interventional patients declared themselves to be (very) satisfied about the quality of care and technical aspects associated with the TCs. Our results demonstrate that longitudinal clinical monitoring using real-time audiovisual TC over the Internet is feasible and well-received by patients with MS. Such an approach can be a promising new care strategy.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disorder of the central nervous system. Accelerated brain volume loss (BVL) has emerged as a promising magnetic resonance imaging marker (MRI) of neurodegeneration, correlating with present and future clinical disability. We have systematically selected MS patients fulfilling ‘no evidence of disease activity-3′ (NEDA-3) criteria under high-efficacy disease-modifying treatment (DMT) from the database of two Belgian MS centers. BVL between both MRI scans demarcating the NEDA-3 period was assessed and compared with a group of prospectively recruited healthy volunteers who were matched for age and gender. Annualized whole brain volume percentage change was similar between 29 MS patients achieving NEDA-3 and 24 healthy controls (−0.25 ± 0.49 versus −0.24 ± 0.20, p = 0.9992; median follow-up 21 versus 33 months; respectively). In contrast, we found a mean BVL increase of 72%, as compared with the former, in a second control group of MS patients (n = 21) whom had been excluded from the NEDA-3 group due to disease activity (p = 0.1371). Our results suggest that neurodegeneration in MS can slow down to the rate of normal aging once inflammatory disease activity has been extinguished and advocate for an early introduction of high-efficacy DMT to reduce the risk of future clinical disability.

Understanding how regulators of inflammation affect nucleic acid sensing is important for targeting research against inflammatory diseases and conditions. Here, the authors identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells.

Background: Cognitive dysfunction is a frequent manifestation of multiple sclerosis (MS) but its effect on locomotor rehabilitation is unknown. Objective: To study the impact of cognitive impairment on locomotor rehabilitation outcome in people with MS. Methods: We performed a retrospective analysis involving ambulatory patients with MS who were admitted for intensive, inpatient, multidisciplinary rehabilitation at the National Multiple Sclerosis Center of Melsbroek between the years 2012 and 2017. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used to determine the cognitive status of subjects as either impaired (COG–) or preserved (COG+). Locomotor outcome was compared between groups with the difference in 6-minute walk test (6MWT) measured at admission and discharge (Δ6MWT). In addition, individual test scores of the BRB-N for attention (Paced Auditory Serial Addition Test 2” and 3”), visuospatial learning/memory (7/24 Spatial Recall Test), verbal learning/memory (Selective Reminding Test) and verbal fluency (Controlled Oral Word Association Test) were correlated to the Δ6MWT. Results: A total of 318 complete and unique records were identified. Both groups showed a significant within-group Δ6MWT during hospitalization (COG+: 47.51 m; COG–: 40.97 m; P

Abstract Background Preventive efforts targeting childhood anxiety and depression symptoms have the potential to alter the developmental trajectory of depression and anxiety disorders across the lifespan. Substantial previous research suggests that modifiable parenting factors such as parental aversiveness and over-involvement are associated with childhood anxiety, depressive and internalising symptoms, indicating that parents can play a critical role in prevention. The Parenting Resilient Kids study is a new evidence-based online parenting program designed to prevent anxiety and depression problems in primary school-aged children by reducing family-based risk factors and enhancing protective factors through increased positive interactions between parent and child. Methods/design The current study is a parallel group superiority randomised controlled trial with parent-child dyads randomised to the intervention or active-control group in a 1:1 ratio. The intervention group will receive the Parenting Resilient Kids program consisting of a feedback report on parenting behaviours and up to 12 interactive online modules personalised based on responses to the parent survey. The active-control group will receive a standardised package of online educational materials about child development and wellbeing. The trial website is programmed to run a stratified random allocation sequence (based on parent gender) to determine group membership. We aim to recruit 340 parent-child dyads (170 dyads per group). We hypothesise that the intervention group will show greater improvement in parenting risk and protective factors from baseline to 3-month follow-up (primary outcome), which will in turn mediate changes in child depressive and anxiety symptoms from baseline to 12 and 24 months (co-primary outcomes). We also hypothesise that the intervention group will show greater benefits from baseline to 3-, 12- and 24-month follow-up, with regard to: child depressive and anxiety symptoms (co-primary outcomes); and child and parent health-related quality of life, and overall family functioning (secondary outcomes). Discussion This randomised controlled trial will examine the efficacy of the Parenting Resilient Kids program as a preventive intervention for anxiety and depression symptoms in primary school-aged children, as well as changes in child and parent health-related quality of life. Findings from this study will examine design features that render web-based prevention programs effective and the extent to which parents can be engaged and motivated to change through a minimally guided parenting program. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): Trial ID ACTRN12616000621415 Registered on 13 May 2016. Updated on 3 March 2017.

Background: Medication error is a global threat to patient safety, particularly in pediatrics. Yet, this issue remains understudied in this population, in both hospital and community settings. Objectives: To characterize medication errors involving pediatrics reported to the French Medication Error Guichet, and compare them with medication errors in adults, in each of the hospital and community settings. Methods: This was a retrospective secondary data analysis of medication errors reported throughout 2013-2017. Descriptive and multivariate analyses were performed to compare actual and potential medication error reports between pediatrics (aged 18 and

Background: Multiple sclerosis (MS) is characterized by a great inter-individual variability in disease course and severity. Some patients experience a rather mild course, controversially called ‘benign MS’ (BMS). The usefulness of this entity in clinical practice remains unclear. Methods: We performed a literature search in PubMed, Web of Science and Cochrane Library databases from November 1980 to December 2015, using the following key words: benign multiple sclerosis, diagnosis, imaging, prognosis, predictive, natural history and predefined inclusion criteria. Results: Our search yielded 26 publications. Most definitions were based on the Expanded Disease Status Scale (EDSS), which is heavily weighted towards physical disability. Between 30 and 80% of relapsing-remitting MS patients have EDSS

BACKGROUND:Ischaemia-reperfusion injury in kidney transplantation leads to delayed graft function (DGF), which is associated with reduced long term graft function. Remote ischaemic conditioning (RIC) improved early kidney graft function in a porcine model of donation after brain death and was associated with improved long-term cardiac outcome after myocardial ischaemia. This randomised, double-blinded trial evaluated the effect of RIC on kidney graft outcome in the first year, and examined the predictive value of a new measure of initial kidney graft function, i.e. the estimated time to a 50% reduction in plasma creatinine post-transplantation (tCr50). METHODS:A total of 225 patients undergoing deceased donor kidney transplantation were randomised to RIC or a sham procedure performed prior to kidney reperfusion. Up to four repetitive cycles of five minutes of leg ischaemia and five minutes of reperfusion were given. GFR, plasma creatinine, cystatin C and neutrophil gelatinase associated lipocalin (NGAL) were measured at three and twelve months and estimated GFR was calculated using four different equations. Other secondary outcomes were identified from patient files. RESULTS:RIC did not affect GFR or other outcomes when compared to the sham procedure at three or twelve months. tCr50 correlated with one year graft function (p

BackgroundEarly markers to predict delayed kidney graft function (DGF) may support clinical management. We studied the ability of four biomarkers (neutrophil gelatinase associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), cystatin C, and YKL-40) to predict DGF after deceased donor transplantation, and their association with early graft function and GFR at three and twelve months.Methods225 deceased donor kidney transplant recipients were included. Biomarkers were measured using automated assays or ELISA. We calculated their ability to predict the need for dialysis post-transplant and correlated with the estimated time to a 50% reduction in plasma creatinine (tCr50), measured glomerular filtration rate (mGFR) and estimated GFR (eGFR).ResultsAll biomarkers measured at Day 1, except urinary L-FABP, significantly correlated with tCr50 and mGFR at Day 5. Plasma NGAL at Day 1 and a timed urine output predicted DGF (AUC = 0.91 and AUC 0.98). Nil or only weak correlations were identified between early biomarker levels and mGFR or eGFR at three or twelve months.ConclusionHigh plasma NGAL at Day 1 predicts DGF and is associated with initial graft function, but may not prove better than P-creatinine or a timed urine output. Early biomarker levels do not correlate with one-year graft function.Trial registrationClinicalTrials.gov NCT01395719.

DLL1 and DLL4 are Notch ligands with high structural similarity but context-dependent functional differences. Here, we analyze their functional divergence using cellular co-culture assays, biochemical studies, and in vivo experiments. DLL1 and DLL4 activate NOTCH1 and NOTCH2 differently in cell-based assays and this discriminating potential lies in the region between the N-terminus and EGF repeat three. Mice expressing chimeric ligands indicate that the ectodomains dictate ligand function during somitogenesis, and that during myogenesis even regions C-terminal to EGF3 are interchangeable. Substitution of NOTCH1-interface residues in the MNNL and DSL domains of DLL1 with the corresponding amino acids of DLL4, however, does not disrupt DLL1 function in vivo. Collectively, our data show that DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2, establishing that the ectodomains dictate selective ligand function in vivo, and that features outside the known binding interface contribute to their differences.