INTRODUCTION:Genome sequencing (GS) is reshaping newborn screening (NBS) by enabling the early detection of a broader range of rare, treatable and/or actionable disorders. In the context of rapid therapeutic advances, international pilot programs - many coordinated within the International Consortium on Newborn Sequencing (ICoNS) - are evaluating genome-based NBS (gNBS) as a preventive public health strategy. MATERIALS AND METHODS:We reviewed published international gNBS pilot studies, with particular attention to discussions related to endocrine disorders. We integrated insights from the French PERIGENOMED-CLINICS 1 (PGC1) project, including its curated gene list and collaboration mainly with the FIRENDO French network dedicated to rare endocrine diseases. RESULTS:No publications were identified specifically addressing gNBS in rare pediatric endocrine diseases as a unified domain. In comparative analyses of gNBS pilot programs, endocrine disorders represented approximately 10% of included conditions, with marked heterogeneity across initiatives and no primary endocrine disorder uniformly retained. Analysis of the PGC1 dataset identified 125 endocrine and endocrine-adjacent gene-disease dyads (14% of all project dyads), divided into list 1 ("treatable", n=62) and list 2 ("actionable", n=63). List 1 predominantly included early-onset, hormonally driven disorders, whereas list 2 extended toward obesity-related and multisystem syndromic conditions. Stratification by clinical actionability revealed four categories ranging from time-critical neonatal conditions to surveillance-driven and long-term risk phenotypes, underscoring substantial variability in timing of intervention, penetrance, and level of evidence supporting early benefit. CONCLUSION:Genomic NBS is transforming rare disease management, including endocrine diseases, by enabling earlier diagnosis, precision care, and coordinated professional and family-based interventions, marking a paradigm shift in population health.

BACKGROUND AND OBJECTIVES:Cerebral small vessel disease (cSVD), characterized by pathologic changes in the structure and function of small brain vessels, is detectable on brain MRI in the absence of clinical symptoms. However, imaging cerebral small vessels themselves in vivo remains costly and challenging. There is growing interest in investigating whether retinal microvascular imaging features could be proxies for changes in the brain microvasculature. Using a multipronged approach, we explored the relation of retinal microvascular characteristics with MRI markers of cSVD (MRI-cSVD). METHODS:First, we explored this relationship in older community persons from the population-based 3C-Dijon cohort. MRI-cSVD was assessed on a 1.5-Tesla MRI at baseline, comprising white matter hyperintensity volume (WMHV), lacunes, and a composite extreme cSVD phenotype (WMHV extreme distributions and presence/absence of lacunes). At 10-year follow-up, participants underwent measurements of retinal microvascular features on fundus using the Singapore "I" Vessel Assessment software. To support 3C-Dijon findings, we conducted a comprehensive literature review up to July 2024 from PubMed/EMBASE and used 2-sample Mendelian randomization (MR) leveraging large-scale genome-wide association studies, to assess causality and directionality. RESULTS:In 670 3C-Dijon participants (median age 70.7, 65.7% women), multivariable analyses (adjusted for age, sex, axial length, and cardiovascular risk factors) showed a significant association of lower arteriolar fractal dimension (FDa) with extreme cSVD (odds ratio [OR] 1.68, 95% CI 1.20-2.34) after multiple testing correction (p < 0.0042), and at p < 0.05, associations of lower FDa and smaller arteriolar caliber with larger WMHV (β = 0.0534 [95% CI 0.0075-0.0569] and 0.0519 [95% CI 0.0045-0.0993]), and of greater venular tortuosity (TORTv) with lacunes (OR 1.45, 95% CI 1.05-2.00). Lower FDa was also associated with poorer executive function. The systematic review of the literature identified 12 studies (N = 7,796) that showed mostly consistent direction of effects for FDa (5/6 studies), TORTv (4/6), and arteriolar caliber (10/11), although statistical significance was observed in 5 individual studies only. Two-sample MR based on large genome-wide association studies (N = 5,292-52,798) showed evidence for a potentially causal association of greater TORTv with extreme cSVD and larger WMHV (p = 0.0017 and 0.049), with no evidence for reverse causation. DISCUSSION:We provide multimodal evidence that geometric characteristics of the retinal microvasculature are associated with increased burden of MRI-cSVD and possibly worse executive function.

Background Newborn screening (NBS) has progressively expanded through technological innovations, from tandem mass spectrometry enabling expanded NBS (eNBS) to the prospect of genomic NBS (gNBS). While these developments promise earlier diagnosis and richer information, they also raise concerns regarding actionability, uncertainty, equity and psychosocial impact. As technological feasibility alone does not ensure public confidence, parental perspectives are central to evaluating future expansions. Using acceptability concept as an anticipatory lens, this study assessed parental views on NBS expansion in France, examining its determinants, distinguishing test modalities, and exploring whether genomics raises specific concerns. Methods A nationwide cross-sectional survey (September 2022–February 2023) included 1,640 parents recruited postpartum in maternity wards and through an online quota panel. Acceptability of eNBS and gNBS, intermediate evaluative components, and sociodemographic characteristics were assessed. Analyses combined descriptive statistics, multivariable regression, and thematic analysis of free-text comments. Results Support was very high for eNBS (93%) and remained high for gNBS (89%), with genetics mainly shifting responses from complete to partial acceptability. Affective attitude and perceived effectiveness were the strongest predictors of both outcomes, while ethical concerns distinguished assured from conditional support. Most parents prioritised minimising uncertain results, whereas a smaller subgroup accepted greater ambiguity. Foreign-born and single parents reported lower levels of complete acceptability, while health-sector workers and parents with rare-disease experience were more supportive. No independent association with the age of the youngest child was observed. Conclusion Parental acceptability of eNBS and gNBS is high but nuanced, shaped primarily by anticipated health benefits, emotional orientation and tolerance for uncertainty, with trust and social distance modulating support. As genomic expansion progresses, implementation will require proportionate, culturally adapted information and clear governance, and should be informed by real-world evidence from pilots such as PERIGENOMED. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ClinicalTrials.gov, [NCT06111456][1]. Last verified: October 2023. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol, data collection tools, and information sheets for families were approved by the Ethics Committee for Research of the University of Burgundy-Franche-Comté on September 8, 2022 (S7 File). Participation was voluntary. All participants received written information describing the study objectives, procedures, data collected, and their rights. In accordance with French regulations for non-interventional research, participation was based on informed non-opposition, documented by completion of the questionnaire after receipt of the information notice. For Population 1, information was provided on-site by trained research staff during the maternity stay, using a written information and non-opposition notice. For Population 2, the same information was provided on the first page of the online questionnaire. Data were collected anonymously and analysed in accordance with applicable data protection regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data underlying the results of this study contain sensitive personal information collected from parents in a postpartum context and cannot be shared publicly due to ethical and legal restrictions, in accordance with the approval granted by the Ethics Committee for Research of the University of Burgundy–Franche-Comté. An anonymised dataset is available from the corresponding author for researchers who meet the criteria for access to confidential data, subject to approval by the relevant ethics committee and the signing of a data use agreement. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06111456&atom=%2Fmedrxiv%2Fearly%2F2026%2F02%2F24%2F2026.02.22.26346822.atom

BACKGROUND:Newborn screening (NBS) has progressively expanded through technological innovations, from tandem mass spectrometry enabling expanded NBS (eNBS) to the prospect of genomic NBS (gNBS). While these developments promise earlier diagnosis and richer information, they also raise concerns regarding actionability, uncertainty, equity and psychosocial impact. As technological feasibility alone does not ensure public confidence, parental perspectives are central to evaluating future expansions. This study assessed parental views on NBS expansion in France, examining its determinants and whether genomics raises specific concerns. METHODS:A nationwide cross-sectional survey (September 2022-February 2023) included 1,640 parents recruited postpartum in maternity wards and through an online quota panel. Acceptability of eNBS and gNBS was assessed alongside intermediate components from the Theoretical Framework of Acceptability (affective attitude, perceived effectiveness, ethicality), a technical trade-off scenario, and individual characteristics. Analyses combined descriptive statistics, multivariable regression, and thematic analysis of free-text comments. RESULTS:Support was very high for eNBS (93%) and remained high for gNBS (89%), with genetics mainly shifting responses from complete to partial acceptability. Affective attitude and perceived effectiveness were the strongest predictors of both outcomes, while ethical concerns distinguished assured from conditional support. Most parents prioritised minimising uncertain results, whereas a smaller subgroup accepted greater ambiguity. Foreign-born and single parents reported lower levels of complete acceptability, while health-sector workers and parents with rare-disease experience were more supportive. No independent association with the age of the youngest child was observed. CONCLUSION:Parental acceptability of eNBS and gNBS is high but nuanced, shaped primarily by anticipated health benefits, emotional orientation and tolerance for uncertainty, with trust and social distance modulating support. As genomic expansion progresses, implementation will require proportionate, culturally adapted information and clear governance, and should be informed by real-world evidence from pilots such as PERIGENOMED.

Acute community-acquired pneumonia (CAP) is a leading cause of infection-related mortality worldwide. Endotoxemia, characterized by elevated plasma lipopolysaccharide (LPS), is a key driver of inflammation and thrombosis in Gram-negative sepsis and has been suggested to occur in severe pneumonia, irrespective of etiology. However, current immunoassays for LPS quantification lack sensitivity and specificity. We aimed to quantify plasma LPS in severe CAP patients, including COVID-19, using a validated mass spectrometry method, and to explore associations with immune activation, coagulation, gut translocation, and clinical outcomes. In this prospective ancillary study of the LYMPHONIE cohort, we included 34 non-COVID-19 severe CAP (sCAP), 34 severe COVID-19 (sCOVID-19) and 34 matched healthy volunteers. Plasma LPS was measured by LC–MS/MS detecting 3-hydroxy fatty acids of lipid A. Clinical data, immune biomarkers, coagulation biomarkers, and gut injury markers were measured. Unexpectedly, median plasma LPS concentrations were significantly lower in sCAP patients (724 pmol/ml in sCAP; 750 pmol/ml in sCOVID-19) compared to healthy volunteers (1009 pmol/ml, p < 0.001). LPS levels did not correlate with severity scores or mortality. Low positive correlations were observed between LPS and markers of endothelial activation (sVCAM-1) and coagulation (D-dimer). However, patients with high LPS showed no increased risk of thrombotic or cardiovascular events. Using a highly specific LC–MS/MS method, we found no evidence of increased circulating LPS in severe pneumonia patients, challenging the hypothesis of gut-derived endotoxemia as a major contributor to systemic inflammation in severe CAP, including COVID-19. Take-home message Using a highly specific mass-spectrometry assay, we found no evidence of elevated circulating lipopolysaccharide in severe community-acquired pneumonia, including COVID-19. These findings challenge the concept that gut-derived endotoxemia is a major driver of systemic inflammation in severe pneumonia. Tweet Mass spectrometry reveals no rise in plasma LPS in severe pneumonia or COVID-19, questioning gut endotoxemia’s role in inflammation.

But de l’étude Analyser les résultats obtenus après pancréatectomie distale (PD) chez les patients atteints de néoplasie endocrinienne multiple de type 1 (NEM1) pour néoplasme neuroendocrine pancréatique (NNE-P), en s’intéressant aux complications postopératoires et à la survie à long terme. Patients et méthodes Les patients atteints de NEM1 issus de la cohorte française MEN1 opérés d’une PD pour des NNE-P entre 1990 et 2022 ont été inclus dans l’étude. Les complications postopératoires précoces et tardives, le contrôle sécrétoire, la survie sans maladie pancréatique et la survie globale ont été évalués. Résultats Sur les 62 patients inclus, 41 (66 %) ont été opérés pour des NNE-P non fonctionnels, 14 (23 %) pour des insulinomes, 4 (6 %) pour VIPome et 3 (5 %) pour glucagonome. La durée médiane de suivi était de 84 mois (intervalle : 12–335). Aucun décès n’a été observé dans les 90jours suivant l’opération. Des complications postopératoires de grade III–V selon la classification de Clavien-Dindo sont survenues chez 16 % des patients (n=11). Quatorze patients (23 %) ont développé des fistules pancréatiques. Vingt-quatre patients (39 %) ont développé un diabète sucré et 8 patients (13 %) ont présenté une insuffisance exocrine pancréatique. Le taux de contrôle sécrétoire était de 90 %. L’âge moyen au moment du décès était de 56±10,9 ans. La survie globale à 5 ans et à 10 ans était de 93,0 % (IC [85–100]) et de 86,7 % (IC [76,2–98,5]). La survie sans métastases hépatiques à dix ans était significativement plus courte lorsque la pancréatectomie distale était pratiquée pour des NNE-P non fonctionnelles par rapport aux insulinomes : 60,4 % (IC [47–79]) contre 83,3 % (IC [68–87]) (p=0,007). Conclusion La pancréatectomie distale chez les patients atteints de NEM1 est une intervention chirurgicale sûre, présentant une morbidité acceptable et une mortalité postopératoire très faible. Des études supplémentaires sont nécessaires pour standardiser l’étendue du curage ganglionnaire lors de la pancréatectomie distale chez les patients atteints de NEM1.

BackgroundCoronavirus disease 2019 (COVID-19) can affect multiple organs, especially the lungs, which may lead to intensive care unit (ICU) admission in the case of acute respiratory distress syndrome (ARDS). Other unfavorable outcomes can occur such as need for orotracheal intubation (OTI) and/or extracorporeal membrane oxygenation (ECMO) and even death. We took advantage of national surveillance data from ICU admissions managed by Santé publique France to investigate the factors associated with mortality, severe ARDS, ICU-free days as well as need for invasive ventilatory support in mainland France between February 2020 and June 2021.MethodsThis nationwide cohort study analyzed critically ill COVID-19 patients admitted to ICU. We used Fine and Gray’s model and linear and logistic regressions to assess the factors associated with different outcomes. The main variable of interest was the first three periods of the pandemic: period 1 (February to July 2020), period 2 (August to December 2020) and period 3 (January to June 2021). We stratified all analyses according to predefined age groups: <45, 45–64 and ≥65 years.ResultsThe 15,423 included patients were mainly men (70%). Mean age was 64.1 ± 13.0 years. Mortality remained high throughout all three pandemic periods. The third pandemic period was associated with a higher risk of severe ARDS in patients aged ≥65 years as well as more ICU-free days and less use of invasive respiratory support regardless of age. Obesity was associated with a lower risk of death in patients aged ≥45 and a higher risk of severe ARDS and requiring invasive respiratory support in patients aged ≥65. Male sex was associated with a higher risk of death regardless of age, a higher risk of severe ARDS in patients aged ≥45 as well as fewer ICU-free days and a higher risk of using invasive respiratory support in patients aged ≥65.ConclusionPrognosis did not significantly improve over time for COVID-19 patients admitted to ICU, however our findings highlight obesity and male sex as key factors in most severe COVID-19 cases, particularly in the elderly. This study also showed a reduction in the use of invasive respiratory support, irrespective of patient severity.

BACKGROUND:Hip osteoarthritis (OA) can cause pain, restricted locomotor activity and functional impairments but it remains difficult to predict functional decline over time. OBJECTIVES:The aims of this study were to identify functional decline trajectories in people with hip OA using the Hip disability and Osteoarthritis Outcome Score (HOOS) domains and to determine radiological and gait predictors of typical trajectories. METHODS:Consecutive people with hip OA with no indication for total hip replacement at baseline were included. Radiological, clinical (HOOS) and gait analyses were collected at baseline, and clinical follow-up was carried out every 6 months for 3 years. HOOS trajectories were estimated by group-based trajectory modeling. Predictive factors were identified by multivariate logistic regression, and their discriminatory power was assessed using the area under the ROC (receiver operating characteristic) curve. RESULTS:Two distinct trajectories were highlighted for all HOOS domains: Traj1 (progressor) and Traj2 (non-progressor). Using a multivariate analysis, gait speed was found to be predictive of Traj1 for HOOS symptoms/stiffness (odds ratio [OR] 0.61, 95 % CI 0.45 to 0.83, AUC (area under the curve) = 75 %) and for HOOS pain (OR = 0.72, 95 % CI 0.53 to 0.97, AUC = 72 %). Moreover, maximum hip extension was found to be predictive of Traj1 for HOOS sports and leisure (OR = 0.78, 95 % CI 0.69 to 0.89, AUC = 81 %) and HOOS quality of life (OR = 0.84, 95 % CI 0.73 to 0.95, AUC = 66 %). CONCLUSION:This study identified 2 typical trajectories of functional decline (progressor/non-progressor) for the 5 HOOS domains. It also demonstrated the predictive validity of 2 gait parameters (gait speed and maximum hip extension) for functional decline. DATABASE REGISTRATION:NCT02042586.

This systematic literature review aimed at gathering available datareporting Quality of Life (QoL) in patients with Multiple Endocrine Neoplasia type 1 (MEN1) in order to identify the determinants of QoL for people living with this condition. To this end, a systematic review following PRISMA guidelines was conducted. We included eleven studies, methodologically valid, published between 2003 and 2022. Ten of the eleven publications reported quantitative analyses. Only one study presented a qualitative study. The analysis of the available data showed that patients' QoL is highly variable: while some patients maintained a near-normal lifestyle, many experienced a decline in their QoL. This decline affected general health, social functioning and psychological well-being. Physical symptoms, intensive medical follow-up and fear of disease recurrence strongly influenced their perception. QoL appeared to be influenced by several determinants, such as age at MEN1 diagnosis, number of previous surgical procedures and their consequences for the daily life, and the at least annual recurrence of medical appointments. Anxiety and fear of recurrence were very common, affecting more than half of all patients in the available studies. The family's role as moral support seemed to mitigate the negative effects of MEN1 on QoL. Job retention and the financial cost of the disease were also important determinants. This systematic review enabled us to highlight various biopsychosocial determinants of patients' quality of life. Social determinants, and in particular the family support, which was only marginally investigated in the selected studies, would be important to investigate further.

BACKGROUND:5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in PDGFRB. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes. MATERIAL AND METHODS:The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place. RESULTS:As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use. CONCLUSION:The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.

BACKGROUND:Shprintzen-Goldberg syndrome (SGS) shares skeletal features with Marfan syndrome (MFS), but differs in its craniofacial and neurodevelopmental features. Cardiovascular features have been specifically investigated in few of the 57 known patients with SGS described in the literature, making it difficult to determine their prevalence and characteristics. METHODS:We reviewed the medical records of an international cohort of 29 patients, with a particular focus on cardiovascular features. Data were compared with those of MFS. RESULTS:The sex ratio was 1.9 and median age was 23 years (range: 4-54). 13 patients (44.8%) had mitral regurgitation (MR), 11 (37.9%) had a thoracic aortic aneurysm (TAA) and 9 (31.1%) had aortic regurgitation (AR). No cases of aortic dissection were reported. None had beta-blockers as a primary prevention of aortic events. The Kaplan-Meier method revealed a 30 years risk of 47%, 33% and 22% for occurrence of MR, TAA and AR, respectively. A statistically significant association was found between variants in the Dachshund Homology Domain and the risk of aortic aneurysm (11/20 vs 0/9, p=0.036). CONCLUSION:Patients with SGS also significantly have cardiovascular manifestations, encouraging the implementation of a follow-up and preventive cardiovascular treatment identical to that of MFS.

OBJECTIVE:Following the first French multicenter pilot study (AnDDI-Prenatome) focused on the implementation of prenatal exome sequencing (pES), this ancillary study aims to explore the ethical and clinical issues raised by pES within multidisciplinary prenatal diagnosis centers. METHODS:33 healthcare professionals involved in the management of couples undergoing prenatal diagnosis (PND) took part in focus groups (2 with clinical geneticists, 3 with professionals from multidisciplinary prenatal diagnosis centers (MPDC), 1 with biologists). Each focus group was analyzed using the thematic analysis method. RESULTS:Professionals emphasized the importance of having a clear understanding of pES and the criteria for its prescription. Geneticists highlighted the need for a framework to clarify the implications of consent for patients and stressed the importance of offering structured support to assist couples in their decision-making process. Biologists and geneticists expressed a desire for effective multidisciplinary coordination of the care pathway, particularly in situations where the results were uncertain. CONCLUSION:These results will help to establish French recommendations for the prescription of pES.

INTRODUCTION:International pilot projects focusing on next-generation sequencing in newborn screening (NBS), that is, genomic NBS (gNBS), have been established thanks to continuous therapeutic progress and the massive development of new genetic technologies with rapidly decreasing costs. Given the highly encouraging results of the French SeDeN project regarding anticipated acceptability among professionals and parents, it is now appropriate to launch a similar pilot project in France, in collaboration with other international initiatives under the International Consortium on Newborn Sequencing framework. METHODS AND ANALYSIS:PERIGENOMED is a large-scale project designed to provide the first concrete evidence on the relevance of gNBS in France. It includes two clinical trials. We present here the design chosen for the first clinical trial (PERIGENOMED-CLINICS 1). PERIGENOMED-CLINICS 1 aims to assess the feasibility, real-world acceptability, psychosocial impact and organisational pathways of panel-based genomic newborn screening in France, involving 2500 participants. Solo-GS targeting two lists of gene-disease dyads responsible for treatable (list 1; 400 genes, 171 diseases/group of diseases) or actionable (list 2 optional; 407 genes, 218 diseases/group of diseases) rare and severe early-onset diseases will be proposed in five health institutions. Ancillary social and impact studies will also be included. ETHICS AND DISSEMINATION:All study procedures have been reviewed and approved by relevant French ethics committees and regulatory authorities (CPP Est II-2024-A02224-43, 1 January 2025). Results of the project will be disseminated through peer-reviewed publications, national and international conferences, and public engagement initiatives, in coordination with stakeholders. TRIAL REGISTRATION NUMBER:NCT06875089.