Paediatric population screening for type 1 diabetes is emerging internationally. It is critically important to understand the acceptability of screening to inform these initiatives. In this systematic review, we aimed to assess the psychosocial impact, acceptability and ethics of screening for paediatric type 1 diabetes. We searched MEDLINE, EMBASE, APA PsycInfo, ASSIA, CINAHL, Web of Science, Scopus, and included quantitative, mixed methods and qualitative articles until 25 November 2025. We assessed the emotional, cognitive and behavioural implications, acceptability or ethics of type 1 diabetes early detection for parents and/or children. We used the mixed methods appraisal tool and critical appraisal skills checklists for quality assessment. We performed a mixed methods evidence synthesis, identifying key themes from qualitative data and merging with quantitative data to generate meta-inferences. Seventy articles (12 qualitative, 57 quantitative and one mixed methods) involving 62,244 parents and 6363 children aged <18 years were included. Seven articles (10.0

Introduction and Objective: There is no validated and reliable survey to assess the psychosocial impact of paediatric screening for T1D on families. We aimed to develop and validate a novel self-administered measure assessing the psychosocial impact on daily functioning, understanding of the results and broader lived experience. Methods: Individual interviews with parents and healthcare professionals were conducted and analysed for the key themes, using a standardised topic guide. An iterative survey development process included multiple versions of the survey, followed by statistical validation against a number of psychosocial measures assessing emotional state, wellbeing and quality of life. Final survey items were refined via cognitive debriefing interviews for acceptability, ease of completion and comprehension. Results: Thirty adults, aged ≥18 years took part in 1:1 interviews. Interview duration was 60-90 minutes (mean 70 minutes). Sixty-six adults completed the statistical validation survey, age range 21-67 years, 71% female, 57% white, 76% married/co-habiting and 90% college/university degree or higher degree educated. Child’s age, where reported (n=31) was 3-30 years. Participants were located across Europe, India, Pakistan, Saudi Arabia, Rwanda, the USA and UK. Exploratory Factor Analyses (EFA) evaluated the factor structure of the initial 19-item measure. Items were removed due to low item-to-total correlations, low commonalities and >50% endorsed strongly agree. The final 12-item measure demonstrated reliability (Cronbach’s α=0.84). The two subscales reflected Positive Impact of screening (6 items, α=0.86, M=24.0±4.9, range=11-30) and Negative Impact of screening (6 items, α=0.85, M=20.7±4.9, range=6-30). Conclusion: This novel questionnaire is a valid, robust and reliable assessment of psychosocial factors associated with screening for T1D. Disclosure K. Barnard-Kelly: Research Support; Current; Abbott Diabetes, Dexcom, Inc. J. Shapiro: Research Support; Current; American Diabetes Association, Leona M. and Harry B. Helmsley Charitable Trust, Eli Lilly and Company. C. Woombs: None. E. Barnard: None. O. Boiko: None. J. Vercauteren: None. C. Mathieu: Advisory Panel; Current; Abbott Diagnostics, Dexcom, Inc. Board Member; Current; European Association for the Study of Diabetes. Advisory Panel; Current; Novo Nordisk, Eli Lilly and Company, Sanofi, Vertex Pharmaceuticals Incorporated, Medtronic. A. Omar Alsaleh: None. C. Nicholls: Employee; Current; Sanofi. A. Mahieu: Employee; Current; Sanofi. S. Greenfield: None. L.M. Quinn: None. R. Dias: Other - Speaker fee; Ended; Sandoz International GmbH. Advisory Panel; Ended; Sanofi. Other - speaker fee; Ended; Sanofi. P. Narendran: Speaker's Bureau; Current; Lilly. Other - Speaker and advisory board; Current; Sanofi. Funding This work is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101132379 (EDENT1FI). The JU receives support from the European Union’s Horizon Europe research and innovation programme, The Leona M. and Harry B. Helmsley Charitable Trust, Breakthrough T1D, EFPIA, COCIR, Vaccines Europe, EuropaBio and MedTech. Additional funding is provided to associated UK partners through the UK Research and Innovation (UKRI) Guarantee Fund.

Continuous glucose monitoring (CGM) has transformed diabetes management by providing continuous, real-time insights into glucose dynamics, while enhancing the lived experience of individuals with type 1 diabetes. In established type 1 diabetes, CGM-derived measures of glucose management, such as time in range, time above range, time below range and glycaemic variability, have become integral tools to optimise therapy, reduce episodes of hypoglycaemia and guide clinical decision-making. More recently, CGM has emerged as a promising tool to detect early hyperglycaemia and other glucose abnormalities in individuals with early-stage type 1 diabetes, for whom current screening and staging methods, including fasting glucose, HbA1c and the OGTT, remain limited by episodic sampling, participant burden and variable reproducibility. This review examines the rationale, evidence and practical considerations for integrating CGM into early-stage type 1 diabetes research and clinical frameworks. We discuss its potential to complement existing metabolic and immunological markers, as well as the technical, analytical and regulatory challenges that must be addressed for CGM to serve as a reliable tool for screening, staging and monitoring and as a clinical endpoint in early-stage type 1 diabetes.

HTLV-1 is an enigmatic retrovirus triggering a debilitating neuroinflammatory disease, HTLV-1-associated myelopathy (HAM), with unknown pathogenesis. Both HTLV-1 infection and HAM predominantly affect women and non-white neglected populations. HAM is lacking disease-modifying treatment, as current treatment is mostly symptomatic and inspired by either HIV-1 or multiple sclerosis therapeutic strategies. We used systems biology analyses of novel and publicly available data comprising (epi)genomics, transcriptomics, metabolomics and proteomics of multi-ancestry cohorts from a total of > 2500 People Living with HTLV-1 from 5 countries (Brazil, Peru, Japan, UK, US). Leveraging an unique admixed Brazilian cohort, genome-wide association study (GWAS) revealed African-specific variants in inflammasome sensor AIM2 with genome-wide significance (p < 5x10-8). Suggestive loci (p > 5x10-8) corresponding to metabolic, immune and neuronal genes were validated using published Japanese GWAS. Polygenic risk score and proviral load were independent disease predictors across ancestries. Systems biology analysis revealed neuronal/synaptic signaling, monocyte count, glucose/lipid metabolism, and neurocognition/depression as genetically linked to HAM. In silico drug screening identified estrogen blocker Fulvestrant as the top hit, while also confirming existing (pre)clinical data for HDAC inhibitors and immunosuppressants. Validated GWAS genes were overexpressed in HAM patients' whole blood and CD4 T-cells, as well as in spinal cord astrocytes, oligodendrocytes, and microglia by single-cell RNAseq. We experimentally confirmed decreased ApoA1/lipid/cholesterol levels, higher monocyte levels and lower neurocognitive scores in multi-ancestry cohorts. We found striking biological similarities between retroviral Hbz/Tax overexpression, Hbz interactome and HAM multi-omics findings: enrichment for lipid/cholesterol metabolism, estrogen signaling, neurodegenerative diseases, and viral pathways including EBV, recently identified as the major driver of multiple sclerosis. In conclusion, our data-driven approach uncovers novel disease mechanisms and therapeutic targets, and a validated polygenic risk score allowing targeted surveillance for high-risk individuals. A strong molecular overlap to other neurodegenerative/neuroinflammatory diseases reveals shared neuropathogenic pathways between unrelated viruses.

Introduction The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the EDENT1FI Master Protocol, the project aims to harmonise and standardise screening for early-stage type 1 diabetes and care.Methods and analysis Public health islet autoantibody screening is conducted in the Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Sweden and the UK. Between November 2023 (start date) and October 2028 (planned end date), an estimated number of 200 000 children and adolescents aged 1–17 years are expected to be screened. Screening is performed in capillary blood, examining different islet autoantibodies (autoantibodies against insulin, glutamic acid decarboxylase-65, insulinoma-associated antigen-2 and/or zinc transporter-8). Positive screening results undergo confirmation through a second antibody method. A second (venous) blood sample is requested if at least two autoantibodies are detected, to confirm the autoantibody status. Children and adolescents with confirmed two or more autoantibodies are invited to metabolic staging (oral glucose tolerance test, haemoglobin A1c (HbA1c), random glucose, optionally continuous glucose monitoring); an educational programme and recommendations for monitoring are provided. The feasibility and acceptability of screening are evaluated by feedback questionnaires. Pseudonymised data is collated in the EDENT1FI Registry. Study outcomes include country-specific screening rates, prevalences of stage 1 and stage 2 type 1 diabetes, number in EDENT1FI Registry, proportion with DKA and symptoms at clinical diagnosis and median HbA1c.Ethics and dissemination Following the EDENT1FI Master Protocol, site-specific protocols are developed and approved by local ethics committees (Technical University of Munich, Medical Faculty, Nr. 70/14; Medizinische Hochschule Hannover, Nr. 9588_BO_S_2021; Technische Universität Dresden, Nr. BO-EK-356082020; Center for Sundhed Region Hovedstaden, Nr. H-22053116; Swedish Ethical Review Authority, Nr. 2023-00312-01; National Health Service Health Research Authority and Health Care Research Wales, IRAS (Integrated Research Application System) project ID 309252; Italian National Institute of Health, National ethics committee for clinical trials of public research bodies (EPR) and other national public institutions, Prot. PRE BIO CE Nr. 0059835; Charles University in Prague, Ethics Committee for Multi-Centric Clinical Trials of the University Hopital Motol and 2nd Faculty of Medicine, Nr. 1271/23; Bioethics Committee at the Medical University of Warsaw, Nr. 21/2024 and KB/6/R/2024; Associação Protectora dos Diabéticos de Portugal, Nr. 211/2024). Results are disseminated through peer-reviewed journals and conference presentations and will be shared openly.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997–2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

Abstract To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ( $$\pm$$ ± standard deviation) was 44.0 ( $$\pm$$ ± 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9–10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34–96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Background HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. Patients and methods We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1 NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. Results We found that systemic IL-6 was positively correlated with both age ( r = 0.50, p < 0.001) and GlycA ( r = 0.45, p = 0.00049) in asymptomatics, revealing an ‘inflammaging” signature which was absent in HAM/TSP. GlycA levels were higher in women ( p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ ( p = 0.007) and IL-17A ( p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers ( CASP5/CXCL10/FCGR1A/STAT1 ), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. Conclusions An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.

PURPOSE:Familial Mediterranean Fever (FMF) and Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) are clinically distinct autoinflammatory disorders caused by mutations in the pyrin-encoding gene MEFV. We investigated the transcriptional, phenotypical, and functional characteristics of patient neutrophils to explore their potential role in FMF and PAAND pathophysiology.METHODS:RNA sequencing was performed to discover transcriptional aberrancies. The phenotypical features, degranulation properties, and phagocytic capacity of neutrophils were assessed by flow cytometry. Production of reactive oxygen species (ROS), myeloperoxidase (MPO) release, and chemotactic responses were investigated via chemiluminescence, ELISA, and Boyden chamber assays, respectively.RESULTS:Neutrophils from PAAND and FMF patients showed a partially overlapping, activated gene expression profile with increased expression of S100A8, S100A9, S100A12, IL-4R, CD48, F5, MMP9, and NFKB. Increased MMP9 and S100A8/A9 expression levels were accompanied by high plasma concentrations of the encoded proteins. Phenotypical analysis revealed that neutrophils from FMF patients exhibited an immature character with downregulation of chemoattractant receptors CXCR2, C5aR, and BLTR1 and increased expression of Toll-like receptor 4 (TLR4) and TLR9. PAAND neutrophils displayed an increased random, but reduced CXCL8-induced migration. A tendency for enhanced random migration was observed for FMF neutrophils. PAAND neutrophils showed a moderately but significantly enhanced phagocytic activity as opposed to neutrophils from FMF patients. Neutrophils from both patient groups showed increased MPO release and ROS production.CONCLUSIONS:Neutrophils from patients with FMF and PAAND, carrying different mutations in the MEFV gene, share a pro-inflammatory phenotype yet demonstrate diverse features, underscoring the distinction between both diseases.

Background The COVID-19 pandemic has prompted a lockdown in many countries to control the exponential spread of the SARS-CoV-2 virus, hereby reducing the time-varying basic reproduction number ( R t ) to below one. Governments are looking for evidence to balance the demand of their citizens to ease some of the restriction, against the fear of a new peak in infections. In this study, we wanted to quantify the relative contribution of mobility restrictions, and that of behavioral changes that occurred already before the lockdowns, on the reduction of transmission during lockdowns in Western countries in early 2020. Methods Incidence data of cases and deaths from the first wave of infections for 35 Western countries (32 European, plus Israel, USA and Canada) were analyzed using epidemiological compartment models in a Bayesian framework. Mobility data was used to estimate the timing of changes associated with a lockdown, and was correlated with estimated reductions of R t . Results Across all countries, the initial median estimate for R t was 3.6 (95% IQR 2.4–5.2), and it was reduced to 0.78 (95% IQR 0.58–1.01) during lockdown. 48% (18–65%) of the reduction occurred already in the week before lockdown, with lockdown itself causing the remaining drop in transmission. A lower R t during lockdown was independently associated with an increased time spent at home (0.21 per 10% more time, p < 0.007), and decreased mobility related to retail and recreation (0.07 per 10% less mobility, p < 0.008). Conclusions In a Western population unaware of the risk, SARS-CoV-2 can be highly contagious with a reproduction number R 0 > 5. Our results are consistent with evidence that recreational activities (including restaurant and bar visits) enable super-spreading events. Exiting from lockdown therefore requires continued physical distancing and tight control on this kind of activities.

Transdisciplinary research aims to investigate complex problems by integrating knowledge from multiple disciplines through knowledge co-creation. Initiating and planning transdisciplinary research requires a thorough review of the literature within many disciplines, demanding that researchers conciliate meanings of concepts from different disciplines, define the boundaries of each discipline within the topic and identify synergies between disciplines. Thus, conducting a transdisciplinary literature review can pose a challenge to researchers, and little guidance is available on how to approach this challenge in a systematic way. To address this, we develop a protocol for transdisciplinary literature reviews, extending the heuristics proposed by Leavy (2011). We describe how researchers can determine the relevant bodies of knowledge for the issue investigated, how they can locate and summarise relevant literature from all relevant disciplines, how they can determine the scope of each discipline within the project and how they can visualise the interaction between disciplines in regards to the topic researched. We also suggest methods for researchers to create new interactions between disciplines and propose new conceptual frameworks on the basis of the literature synthesis performed in the transdisciplinary literature review. To demonstrate how our framework can be employed to review literature on complex issues while integrating knowledge from multiple disciplines, we use the issue of accessibility of mHealth technologies as a case study and apply our guidelines to conduct a transdisciplinary literature review on the topic. We integrate findings from the social sciences, ethics, economics, law, psychology, medicine and engineering, among other disciplines to examine the accessibility of mHealth and propose promising areas for future transdisciplinary projects. The findings from this case study suggest the proposed transdisciplinary review guidelines can be used as a sole research methodology for initial transdisciplinary research projects, as well as an auxiliary tool for larger transdisciplinary projects.

The COVID-19 pandemic has prompted a lockdown in many countries to control the exponential spread of the SARS-CoV-2 virus. This resulted in curbing the epidemic by reducing the time-varying basic reproduction number (Rt) to below one. Governments are looking for evidence to balance the demand of their citizens to ease some of the restriction, against the fear of a second peak in infections. More details on the specific circumstances that promote exponential spread (i.e. Rt>1) and the measures that contributed most to a reduction in Rt are needed. Here we show that in 33 of 35 Western countries (32 European, plus Israel, USA and Canada), Rt fell to around or below one during lockdown (March - May 2020). One third of the effect happened already on average 6 days before the lockdown, with lockdown itself causing another major drop in transmission. Country-wide compulsory usage of masks was implemented only in Slovakia 10 days into lockdown, and on its own reduced transmission by half. During lockdown, decreased mobility in retail and recreation was an independent predictor of lower Rt during lockdown, while changes in other types of mobility were not. These results are consistent with anecdotal evidence that large recreational gatherings are super-spreading events, and may even suggest that infections during day-to-day contact at work are not sufficient to spark exponential growth. Our data suggest measures that will contribute to avoiding a second peak include a tight control on circumstances that facilitate massive spread such as large gatherings especially indoors, physical distancing, and mask use.

Adherence is one of the most crucial determinants of treatment response to antiretroviral therapy (ART). An analytical cross-sectional study was conducted in 24 Care and Treatment Centres (CTC) in Dar es Salaam and Iringa regions in Tanzania. Data was collected using questionnaire and appointments records. A total of 943 patients attending at the care and treatment sites in Dar es Salaam and Iringa were recruited. Adherence based on keeping appointments and on four days recall was 65% and 70%, respectively. Adherence based on taking ART more than 95% of the time in one month was 83%. Satisfaction with health services, having treatment support, having knowledge on the use of ART, early presentation to CTC, and being on ART for more than one year, were associated with good adherence. Being in the urban region, using traditional medicine, medicine side effects and alcohol consumption problems negatively associated with adherence to ART. Keywords: Adherence barriers, antiretroviral therapy, HIV, Tanzania, rural, urban