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Adult-onset diabetes increases one’s risk of neurodegenerative disease including Alzheimer’s disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aβ40, Aβ42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aβ40, Aβ42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Question Depression and anxiety are common among children and young people and can impact on the well-being of their parents/carers. Dominant intervention approaches include parent training; however, this approach does not directly address parents’ well-being. Our objective was to examine the effect of interventions, with at least a component to directly address the parents’ own well-being, on parents’ well-being outcomes, including stress, depression and anxiety.Study selection and analysis A systematic search was performed in the following: MEDLINE, EMBASE, CINAHL, AMED, PsycINFO, Scopus, CENTRAL, Web of Science Core Collection (six citation indexes) and WHO ICTRP from inception to 30 December 2023. Interventions that aimed to support parents/carers managing the impact of their child’s/young person’s mental health were eligible. EPHPP (Effective Public Health Practice Project) was used to quality appraise the included studies. A meta-analysis of relevant outcomes was conducted.Findings Fifteen studies were eligible comprising 812 parents/carers. Global methodological quality varied. Seven outcomes (anxiety, depression, stress, burden, self-efficacy, quality of life and knowledge of mood disorders) were synthesised at post-intervention. A small reduction in parental/carer anxiety favouring intervention was indicated in one of the analyses (g=−0.26, 95% CI −0.44 to –0.09, p=0.02), when excluding an influential case. Three outcomes were synthesised at follow-up, none of which were statistically significant.Conclusions Interventions directly addressing the well-being for parents of children with anxiety and/or depression appear not to be effective overall. Clearer conceptualisation of factors linked to parental distress is required to create more targeted interventions.PROSPERO registration number CRD42022344453.

Introduction Approximately 40% of children with diabetic ketoacidosis (DKA) develop acute kidney injury (AKI), which increases the risk of chronic kidney damage. At present, there is limited knowledge of racial or ethnic differences in diabetes-related kidney injury in children with diabetes. Understanding whether such differences exist will provide a foundation for addressing disparities in diabetes care that may continue into adulthood. Further, it is currently unclear which children are at risk to develop worsening or sustained DKA-related AKI. The primary aim is to determine whether race and ethnicity are associated with DKA-related AKI. The secondary aim is to determine factors associated with sustained AKI in children with DKA.Methods and analysis This retrospective, multicentre, cross-sectional study of children with type 1 or type 2 diabetes with DKA will be conducted through the Paediatric Emergency Medicine Collaborative Research Committee. Children aged 2–18 years who were treated in a participating emergency department between 1 January 2020 and 31 December 2023 will be included. Children with non-ketotic hyperglycaemic-hyperosmolar state or who were transferred from an outside facility will be excluded. The relevant predictor is race and ethnicity. The primary outcome is the presence of AKI, defined by Kidney Disease: Improving Global Outcomes criteria. The secondary outcome is ‘sustained’ AKI, defined as having AKI ≥48 hours, unresolved AKI at last creatinine measurement or need for renal replacement therapy. Statistical inference of the associations between predictors (ie, race and ethnicity) and outcomes (ie, AKI and sustained AKI) will use random effects regression models, accounting for hospital variation and clustering.Ethics and dissemination The Institutional Review Board of Children’s Minnesota approved this study. 12 additional sites have obtained institutional review board approval, and all sites will obtain local approval prior to participation. Results will be presented at local or national conferences and for publication in peer-reviewed journals.

Lanthanides are a series of elements essential to a wide range of applications, from clean energy production to healthcare. Despite their presence in multiple products and technologies, their toxicological characteristics have been only partly studied. Recently, our group has employed a genomic approach to extensively characterize the toxicity mechanisms of lanthanides. Even though we identified substantially different behaviors for mid and late lanthanides, the toxicological profiles of early lanthanides remained elusive. Here, we overcome this gap by describing a multidimensional genome-wide toxicogenomic study for two early lanthanides, namely, lanthanum and praseodymium. We used Saccharomyces cerevisiae as a model system since its genome shares many biological pathways with humans. By performing functional analysis and protein-protein interaction network analysis, we identified the main genes and proteins that participate in the yeast response to counter metal harmful effects. Moreover, our analysis also highlighted key enzymes that are dysregulated by early lanthanides, inducing cytotoxicity. Several of these genes and proteins have human orthologues, indicating that they may also participate in the human response against the metals. By highlighting the key genes and proteins in lanthanide-induced toxicity, this work may contribute to the development of new prophylactic and therapeutic strategies against lanthanide harmful exposures.

Background Glomerular filtration rate (GFR) is a key measure of kidney function but often inaccurately ascertained by serum creatinine and cystatin C in pediatrics. In this pilot trial, we evaluated the relationship between GFR calculated by using phase-contrast MRI (PC-MRI) biomarkers and GFR by .sup.125I-iothalamate clearance in youth undergoing bone marrow transplantation (BMT). Methods A total of twenty-one pediatric BMT candidates (8-21 years of age) were recruited for a research kidney PC-MRI. After completion of .sup.125I-iothalamate clearance, same-day PC-MRI measurements were completed of the kidney circulation without a gadolinium-based contrast agent. MRI included a non-contrast balanced-SSFP-triggered angiography to position ECG-gated breath-held 2D PC-MRI flow measurements (1.2 x 1.2 x 6 mm.sup.3). A multivariate model of MRI biomarkers estimating GFR (GFR-MRI) was selected using the elastic net approach. Results The GFR-MRI variables selected by elastic net included average heart rate during imaging (bpm), peak aorta flow below the kidney artery take-offs (ml/s), average kidney artery blood flow, average peak kidney vein blood flow, and average kidney vein blood flow (ml/s). The GFR-MRI model demonstrated strong agreement with GFR by .sup.125I-iothalamate (R.sup.2 = 0.65), which was stronger than what was observed with eGFR by the full age spectrum and Chronic Kidney Disease in Children under 25 (CKiD U25) approaches. Conclusion In this pilot study, noninvasive GFR-MRI showed strong agreement with gold standard GFR in youth scheduled for BMT. Further work is needed to evaluate whether non-contrast GFR-MRI holds promise to become a superior alternative to eGFR and GFR by clearance techniques. Graphical abstract, Author(s): Alex J. Barker [sup.1] [sup.2] , Alexander Berthusen [sup.1] , Tim Vigers [sup.3] [sup.4] , Michal Schafer [sup.5] , Lorna P. Browne [sup.1] , Petter Bjornstad [sup.3] [sup.6] Author [...]

Introduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. Methods: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. Results: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. Conclusions: Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury. Resumen: Antecedentes: La activación de la quinasa de adhesión focal (FAK) en podocitos juega un papel en la patogénesis de la enfermedad de cambios mínimos (ECM), pero su mecanismo de activación en dicha enfermedad es desconocido. En este estudio investigamos si la integrina β1 de los podocitos modula la activación de FAK y del daño podocitario en modelos experimentales de la ECM. Métodos: Utilizamos lipopolisacárido (LPS) y suero de pacientes con ECM para inducir daño podocitario in vivo e in vitro, respectivamente. Realizamos estudios funcionales usando inhibidores específicos de la integrina β1 in vivo e in vitro, así como estudios histológicos, western blots y técnicas de inmunofluorescencia para evaluar cambios morfológicos y moleculares en podocitos. Usando ELISA medimos los niveles séricos de LPS en 35 niños con ECM o sospecha de ECM (síndrome nefrótico idiopático [SNI]) y en 18 individuos sanos. Resultados: Los ratones inyectados con LPS desarrollaron cambios morfológicos (fusión de pedicelos, con apariencia normal de los glomérulos) y moleculares (pérdida de la expresión de sinaptopodina, cambio en la localización de la nefrina fosforilada y fosforilzación de FAK), que son característicos de la ECM en humanos. La administración de un inhibidor de la integrina β1 en ratones disminuyó la fosforilación de FAK, proteinuria y daño podocitario que ocurre tras la inyección de LPS. En niños con ECM/SNI, los niveles séricos de LPS fueron más elevados que en controles. En cultivos de podocitos humanos, la adicción de un inhibidor de la integrina β1 al suero de niños con ECM en recaída evitó cambios en el citoesqueleto. Conclusiones: La integrina β1 de los podocitos actúa como mediador de la activación de la FAK y del daño podocitario en modelos experimentales de la ECM.

Abstract Background Depression is a public health problem and common amongst adolescents. Cognitive behavioural therapy (CBT) is widely used to treat adolescent depression but existing research does not provide clear conclusions regarding the relative effectiveness of different delivery modalities. Objectives The primary aim is to estimate the relative efficacy of different modes of CBT delivery compared with each other and control conditions for reducing depressive symptoms in adolescents. The secondary aim is to compare the different modes of delivery with regard to intervention completion/attrition (a proxy for intervention acceptability). Search Methods The Cochrane Depression, Anxiety and Neurosis Clinical Trials Register was searched in April 2020. MEDLINE, PsycInfo, EMBASE, four other electronic databases, the CENTRAL trial registry, Google Scholar and Google were searched in November 2020, together with reference checking, citation searching and hand‐searching of two databases. Selection Criteria Randomised controlled trials (RCTs) of CBT interventions (irrespective of delivery mode) to reduce symptoms of depression in young people aged 10–19 years with clinically relevant symptoms or diagnosis of depression were included. Data Collection and Analysis Screening and data extraction were completed by two authors independently, with discrepancies addressed by a third author. CBT interventions were categorised as follows: group CBT, individual CBT, remote CBT, guided self‐help, and unguided self‐help. Effect on depressive symptom score was estimated across validated self‐report measures using Hedges' g standardised mean difference. Acceptability was estimated based on loss to follow‐up as an odds ratio. Treatment rankings were developed using the surface under the cumulative ranking curve (SUCRA). Pairwise meta‐analyses were conducted using random effects models where there were two or more head‐to‐head trials. Network analyses were conducted using random effects models. Main Results Sixty‐eight studies were included in the review. The mean age of participants ranged from 10 to 19.5 years, and on average 60% of participants were female. The majority of studies were conducted in schools (28) or universities (6); other settings included primary care, clinical settings and the home. The number of CBT sessions ranged from 1 to 16, the frequency of delivery from once every 2 weeks to twice a week and the duration of each session from 20 min to 2 h. The risk of bias was low across all domains for 23 studies, 24 studies had some concerns and the remaining 21 were assessed to be at high risk of bias. Sixty‐two RCTs (representing 6435 participants) were included in the pairwise and network meta‐analyses for post‐intervention depressive symptom score at post‐intervention. All pre‐specified treatment and control categories were represented by at least one RCT. Although most CBT approaches, except remote CBT, demonstrated superiority over no intervention, no approaches performed clearly better than or equivalent to another. The highest and lowest ranking interventions were guided self‐help (SUCRA 83%) and unguided self‐help (SUCRA 51%), respectively (very low certainty in treatment ranking). Nineteen RCTs (3260 participants) were included in the pairwise and network meta‐analyses for 6 to 12 month follow‐up depressive symptom score. Neither guided self‐help nor remote CBT were evaluated in the RCTs for this time point. Effects were generally attenuated for 6‐ to 12‐month outcomes compared to posttest. No interventions demonstrated superiority to no intervention, although unguided self‐help and group CBT both demonstrated superiority compared to TAU. No CBT approach demonstrated clear superiority over another. The highest and lowest ranking approaches were unguided self‐help and individual CBT, respectively. Sixty‐two RCTs (7347 participants) were included in the pairwise and network meta‐analyses for intervention acceptability. All pre‐specified treatment and control categories were represented by at least one RCT. Although point estimates tended to favour no intervention, no active treatments were clearly inferior. No CBT approach demonstrated clear superiority over another. The highest and lowest ranking active interventions were individual CBT and group CBT respectively. Pairwise meta‐analytic findings were similar to those of the network meta‐analysis for all analyses. There may be age‐based subgroup effects on post‐intervention depressive symptoms. Using the no intervention control group as the reference, the magnitudes of effects appear to be larger for the oldest age categories compared to the other subgroups for each given comparison. However, they were generally less precise and formal testing only indicated a significant difference for group CBT. Findings were robust to pre‐specified sensitivity analyses separating out the type of placebo and excluding cluster‐RCTs, as well as an additional analysis excluding studies where we had imputed standard deviations. Authors' Conclusions At posttreatment, all active treatments (group CBT, individual CBT, guided self‐help, and unguided self‐help) except for remote CBT were more effective than no treatment. Guided self‐help was the most highly ranked intervention but only evaluated in trials with the oldest adolescents (16–19 years). Moreover, the studies of guided self‐help vary in the type and amount of therapist support provided and longer‐term results are needed to determine whether effects persist. The magnitude of effects was generally attenuated for 6‐ to 12‐month outcomes. Although unguided self‐help was the lowest‐ranked active intervention at post‐intervention, it was the highest ranked at follow‐up. This suggests the need for further research into whether interventions with self‐directed elements enable young people to maintain effects by continuing or revisiting the intervention independently, and whether therapist support would improve long‐term outcomes. There was no clear evidence that any active treatments were more acceptable to participants than any others. The relative effectiveness of intervention delivery modes must be taken into account in the context of the needs and preferences of individual young people, particularly as the differences between effect sizes were relatively small. Further research into the type and amount of therapist support that is most acceptable to young people and most cost‐effective would be particularly useful.

Abstract Introduction Parent-carers of children and young people (CYP) with mental health problems are at greater risk of poor outcomes, such as poor physical and mental health. Peer interventions for parent-carers of CYP with disabilities may improve parent-carer outcomes. This qualitative study investigates parent-carer experiences of using Parental Minds (PM), a multi-component peer support service for parent-carers of CYP with disabilities. Methods Twelve current service-users and four staff/volunteers at PM participated in one-to-one semi-structured interviews. All participants were white females, except for one service-user who was male. All interviews were recorded and transcribed verbatim. Thematic analysis of results was used to explore perceived benefits and disadvantages of PM and possible behaviour change mechanisms. Results Three themes and eight subthemes were identified. Participants identified that internal and external factors influence their self-concept. The identification of themselves as a priority, and empowerment by reassurance and affirmation lead to improved parent-carer self-efficacy and agency to better care for their CYP. Participants described the difficulty of speaking honestly with friends and family about what they experience because it is perceived as different to what “normal” parents experience. From participant accounts, PM enables the construction of a support network and links external services to help manage family circumstances rather than offer curative treatment/intervention. Proactive and immediate advice which is constantly and consistently available was valued by participants. Participants expressed the need for a flexible range of service components which provide holistic support that encompasses both health and social care. Conclusions PM was perceived to be beneficial as a multi-component peer support service which increases parenting self-efficacy and empowerment, reduces isolation, improves access to services, and is tailored to individual needs. Parent-carers reported benefits in parenting and wellbeing practices. The development of a refined logic model will inform a future study of the effectiveness of PM on parent-carer outcomes.

Abstract Background Parent carers of disabled children are at increased risk of physical and mental health problems. The Healthy Parent Carers (HPC) programme is a manualised peer‐led group‐based programme that aims to promote parent carer health and wellbeing. Previously, the programme had been delivered in person, with recruitment and delivery managed in a research context. This study explored implementation by two delivery partner organisations in the United Kingdom. Facilitator Training and Delivery Manuals were modified for online delivery using Zoom due to COVID‐19. Methods The study methodology utilised the Replicating Effective Programs framework. A series of stakeholder workshops informed the development of the Implementation Logic Model and an Implementation Package. After delivering the programme, delivery partner organisations and facilitators participated in a workshop to discuss experiences of implementing the programme. A wider group of stakeholders, including commissioners, Parent Carer Forums and charity organisations representatives and researchers subsequently met to consider the sustainability and potential barriers to delivering the programme outside the research context. Results This study explored implementation by two delivery partner organisations in the United Kingdom that were able to recruit facilitators, who we trained, and they recruited participants and delivered the programme to parent carers in different localities using Zoom. The co‐created Implementation Logic Model and Implementation Package were subsequently refined to enable the further roll‐out of the programme with other delivery partner organisations. Conclusions This study provides insight and understanding of how the HPC programme can be implemented sustainably outside of the research context. Further research will evaluate the effectiveness of the programme and refine the implementation processes. Patient and Public Contribution Parent carers, delivery partner organisation staff and service commissioners were consulted on the design, delivery and reporting of the research.

There is a limited published literature reporting dose-dependent data for in vivo tumorigenesis prevalence in different organs of various rodent models after exposure to low, single doses of charged particle beams. The goal of this study is to reduce uncertainties in estimating particle-radiation-induced risk of lung tumorigenesis for manned travel into deep space by improving our understanding of the high-LET-dependent dose-response from exposure to individual ion beams after low particle doses (0.03-0.80 Gy). Female CB6F1 mice were irradiated with low single doses of either oxygen, silicon, titanium, or iron ions at various energies to cover a range of dose-averaged LET values from 0.2-193 keV/µm, using 137Cs γ-rays as the reference radiation. Sham-treated controls were included in each individual experiment totally 398 animals across the 5 studies reported. Based on power calculations, between 40-156 mice were included in each of the treatment groups. Tumor prevalence at 16 months after radiation exposure was determined and compared to the age-matched, sham-treated animals. Results indicate that lung tumor prevalence is non-linear as a function of dose with suggestions of threshold doses depending on the LET of the beams. Histopathological evaluations of the tumors showed that the majority of tumors were benign bronchioloalveolar adenomas with occasional carcinomas or lymphosarcomas which may have resulted from metastases from other sites.

Europium is a lanthanide metal that is highly valued in optoelectronics. Even though europium is used in many commercial products, its toxicological profile has only been partially characterized, with most studies focusing on identifying lethal doses in different systems or bioaccumulation in vivo. This paper describes a genome-wide toxicogenomic study of europium in Saccharomyces cerevisiae, which shares many biological functions with humans. By using a multidimensional approach and functional and network analyses, we have identified a group of genes and proteins associated with the yeast responses to ameliorate metal toxicity, which include metal discharge paths through vesicle-mediated transport, paths to regulate biologically relevant cations, and processes to reduce metal-induced stress. Furthermore, the analyses indicated that europium promotes yeast toxicity by disrupting the function of chaperones and cochaperones, which have metal-binding sites. Several of the genes and proteins highlighted in our study have human orthologues, suggesting they may participate in europium-induced toxicity in humans. By identifying the endogenous targets of europium as well as the already existing paths that can decrease its toxicity, we can determine specific genes and proteins that may help to develop future therapeutic strategies.