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Antiretroviral therapy (ART) reduces human immunodeficiency virus type 1 (HIV-1) replication to undetectable levels but does not eliminate HIV-1 reservoirs, which persist in memory CD4+ T-cells of various antigenic specificities. Hepatitis C virus (HCV) coinfection is associated with an increase in HIV-DNA burden, but whether HCV-specific CD4+ T-cells are susceptible to HIV-1 infection and harbour replication-competent HIV reservoirs upon HCV resolution is unknown. In this cross-sectional study, we examined the impact of HCV infection on CD4+ T-cell susceptibility to HIV-1 infection in vitro and reservoir persistence during ART in subjects with chronic HCV infection and uninfected controls (n = 20/group) and longitudinally in one ART-treated HCV+HIV+ individual who spontaneously resolved multiple episodes of HCV infection. Memory CD4+ T-cells from subjects with chronic HCV exhibited superior permissiveness to productive HIV-1 infection in vitro (p = 0.03) compared to uninfected. This was proportional to plasma HCV-RNA levels (p = 0.046; r = 0.491). HCV-specific CD4+ T-cells distinguished from other antigenic specificities (e.g., Cytomegalovirus) by a CCR5+ (HIV-1 co-receptor), CXCR6+ (liver-homing marker) and CCR6+ (Th17 marker) phenotype and supported productive HIV-1 infection in vitro. In the HCV+ HIV+ subject, HCV-specific CD4+ T-cells carried replication-competent reservoir during acute HCV reinfection, with integrated HIV-DNA persisting in these cells upon HCV clearance. We provide evidence that HCV-specific CD4+ T-cells are targets of integrative HIV-1 infection and carry proviruses that persist during ART despite HCV resolution. Canadian Institutes of Health Research (CIHR) (PJT-173467, PJT-153052, PJT-178127, PJT-195736, HB2-164064, BR4-197730, MOP135260, FDN-143270, CTN222 and NHC142832), the National Institutes of Health (NIH) (U19AI159819), and Fonds de recherche du Québec-Santé (FRQS)-Réseau SIDA/maladies infectieuses.

Nano-rare diseases, affecting fewer than 30 individuals worldwide, are mostly genetic and severe, with no effective treatments available. Nucleic acid-based therapies, such as antisense oligonucleotides, allow for the targeted modulation of gene expression. Successes like nusinersen and ultrapersonalized treatments (for example, Milasen) highlight their potential. Other approaches, including viral gene therapy and CRISPR-Cas9, enable the addition or correction of genes. However, major challenges remain, including high costs, difficulties in conducting clinical trials, and inadequate regulatory frameworks, especially for "N-of-1" therapies. International initiatives are emerging to facilitate access to these innovative treatments in Europe and Switzerland. Les maladies nanorares, touchant moins de 30 personnes dans le monde, sont majoritairement génétiques, graves et sans traitement. Les thérapies basées sur les acides nucléiques, comme les oligonucléotides antisens, offrent des approches ciblées capables de moduler l’expression des gènes. Des succès comme le nusinersen et des traitements ultrapersonnalisés (par exemple, milasen) illustrent ce potentiel. D’autres technologies, telles que les vecteurs viraux et la CRISPR-Cas9, permettent d’ajouter ou de corriger des gènes. Cependant, ces innovations soulèvent des défis majeurs : coûts élevés, essais cliniques difficiles et cadres réglementaires inadaptés, notamment pour les approches « N-of-1 ». Des initiatives internationales visent à améliorer l’accès à ces thérapies en Europe et en Suisse.

The coexistence of inflammatory bowel disease (IBD) and spondyloarthritis (SpA) poses significant diagnostic and therapeutic challenges. This study aimed to compare clinical characteristics and treatment profiles of patients with both SpA and IBD (SpA/IBD) to those with SpA or IBD alone. We performed a single-centre observational study including 62 consecutive patients with SpA/IBD followed between 2019 and 2022. Patients met Assessment of SpondyloArthritis International Society 2009 criteria for SpA and had confirmed IBD. Demographics, clinical features, imaging, and biologic disease-modifying antirheumatic drug (bDMARD) usage were collected. For comparison, we included 100 patients with a single diagnosis of SpA or IBD, representing the Maladies Inflammatoires SysT&#xe9;mIques Chroniques cohort enrolled over the same period. Among patients with SpA/IBD (51% male, 67% HLA-B27+), IBD was more often diagnosed first. Compared with SpA alone, patients with SpA/IBD had more psoriasis (27% vs 17%, P = .04), uveitis (27% vs 18%, P = .08), and smoking (66% vs 44.9%, P = .01), but lower HLA-B27 positivity (63% vs 80%, P = .002). They also received more bDMARDs (2.8 &#xb1; 1.7 vs 2.0 &#xb1; 1.15, P = .01). Compared with IBD alone, patients with SpA/IBD had higher rates of uveitis (27% vs 1%, P = .08), psoriasis (27% vs 20%, P = .04), smoking (66% vs 44.9%, P = .01), and greater disease activity (Harvey-Bradshaw Index at diagnosis 8.2 &#xb1; 5.7 vs 2.6 &#xb1; 3.1, P = .0006). Notably, 31.75% met criteria for difficult-to-manage disease, exceeding the 9% reported in SpA monodiagnosis. Combination bDMARD therapy was required in 9.7% of patients with SpA/IBD, significantly more than in single-diagnosis groups (P < .05). Patients with SpA/IBD exhibit more severe disease and therapeutic challenges, highlighting the need for tailored management and consideration of earlier combination biologic therapies.

The Republic of Guinea has faced an important challenge with human African trypanosomiasis (HAT), which was endemic over the last century. After initial control in the 1960s-1970s, HAT resurged in the 1990s along the Guinean coast, driven by economic and demographic pressures on the mangrove ecosystem. In response, the Guinean government established a national control program in 2002, focusing on medical mass screenings. In 2012, vector control using tiny targets was introduced in the East Boffa focus to reduce fly density and human-vector contact. However, the Ebola epidemic from 2013 to 2016 disrupted these efforts, leading to a reliance on passive screening. Resuming screenings in 2016-2017 revealed increased cases in all foci except the East Boffa area, where vector control had been effective. Vector control continued during the SARS-CoV2 pandemic and at the same time targeted door-to-door screenings were introduced to target high-risk individuals. Since 2018, around 30,000 at-risk individuals have been screened annually. These strategies reduced the total number of new cases below 1 per 10,000 inhabitants in endemic areas over the period 2019-2023, allowing to validate the elimination of HAT as a public health problem. The Guinean team and partners then focused on systematic spatial monitoring of patients and community engagement in vector control. The program also integrates control of other neglected tropical diseases and addresses new research questions, especially about anatomical and animal reservoirs for parasites. These efforts, combined with implementation of improved diagnostic tests and new oral treatments, through active involvement in multiple clinical trials and studies, now aim to interrupt HAT transmission by 2030.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV gene. Despite therapeutic advances with colchicine and interleukin-1 (IL-1) inhibitors, FMF shows marked interindividual variability, including among symptomatic heterozygotes, challenging genotype-phenotype correlations. To identify clinically meaningful subgroups of paediatric patients with FMF using a clustering approach and to characterise their clinical features and disease trajectories. We conducted a monocentric retrospective study including 185 paediatric patients diagnosed with FMF between 2004 and 2025 according to Eurofever criteria. Patients were stratified as genetically confirmed FMF (homozygous, compound heterozygous) or symptomatic heterozygotes. Demographic, clinical, laboratory and treatment data were collected longitudinally. Clustering analysis was used to identify clinically meaningful subgroups. The median age at onset was 2.5 years and the median diagnostic delay was 24 months. Ninety-three (50%) patients were symptomatic heterozygotes. Compared with genetically confirmed FMF, heterozygotes had milder disease, lower colchicine doses and less frequent IL-1 inhibitor use. Cluster analysis identified five distinct subgroups, ranging from asymptomatic or mild heterozygotes without treatment to early-onset homozygous patients with severe disease requiring higher-dose colchicine and IL-1 inhibitors. Not all heterozygous patients had a mild disease course. Sex, age at onset, genotype, attack frequency and inflammatory markers contributed to cluster differentiation. Severe phenotypes were enriched in female patients with early-onset M694V homozygosity. Cluster analysis identified heterogeneous patterns of disease expression, suggesting that the genotype alone does not fully explain clinical variability in FMF. These findings highlight the value of multidimensional approaches to better characterise disease heterogeneity.

Obesity is increasingly encountered among patients requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory or cardiac failure. It alters respiratory and cardiovascular physiology and drug pharmacokinetics and introduces technical and logistical challenges that may complicate patient selection, ECMO initiation, cannulation, anticoagulation, and monitoring. This review summarizes current evidence regarding the epidemiology, physiological implications, outcomes, and management of obesity in patients supported with veno-venous (VV) or veno-arterial (VA) ECMO. Available evidence, largely retrospective and based on body mass index classifications, suggests that obesity should not be considered a contraindication to VV-ECMO, with outcomes comparable to or potentially better than those of patients without obesity. However, obesity-related respiratory mechanics may exaggerate the apparent severity of lung injury, emphasizing the need for optimized conventional ARDS management, including appropriate ventilatory strategies and prone positioning, before ECMO initiation. In contrast, outcomes during VA-ECMO are more heterogeneous, particularly in extracorporeal cardiopulmonary resuscitation (ECPR), and may be influenced by patient selection, comorbidities, and timing of support. Obesity also creates important technical challenges requiring individualized cannulation, anticoagulation, and perfusion strategies. Obesity alone should not preclude access to ECMO, particularly VV-ECMO. Successful management requires anticipation of obesity-related challenges, appropriate infrastructure, and structured multidisciplinary protocols. Further prospective studies are needed to clarify obesity-specific risks, optimize management strategies, and evaluate long-term outcomes.

The association of erythrocytosis, splenomegaly, and iron overload represents a complex diagnostic situation that may reveal hereditary stomatocytosis related to a PIEZO1 mutation. We report the case of a 76-year-old patient presenting with erythrocytosis, iron overload, and splenomegaly. The initial etiological workup was unremarkable. The identification of chronic hemolysis, associated with a decreased oxygen partial pressure at which 50% of haemoglobin is saturated with oxygen (venous P50) and abnormalities in erythrocyte deformability, guided further molecular investigations. Next-generation sequencing (NGS) identified a heterozygous pathogenic PIEZO1 mutation, confirming the diagnosis of stomatocytosis. This case highlights a misleading presentation of chronic hemolysis masked by polycythemia. Venous P50 appears to be a key discriminating marker. An integrated approach combining biological and molecular analyses is essential to avoid diagnostic delay.

Multidrug-resistant (MDR) Klebsiella pneumoniae is an increasingly important cause of recurrent urinary tract infections (UTIs). As bacteriophage therapy represents a promising alternative, we aimed to isolate and characterize bacteriophages targeting a clinical MDR K. pneumoniae strain causing recurrent UTI and evaluate their activity under urinary conditions. Three bacteriophages targeting an ESBL-producing K. pneumoniae clinical isolate were obtained and characterized by genome sequencing, electron microscopy, stability assays, one-step growth curves, and host-range analysis across 79 UTI isolates. Phage activity was quantified in LB medium and human urine. Three lytic phages (EDIRA083, EDIRA088, and EDIRA092) belonging to distinct genera were identified. Absence of lysogeny-associated, virulence, or antibiotic-resistance genes was confirmed. Capsule, LPS and maltoporin LamB were identified as receptors for EDIRA083 and EDIRA092. Host-range analysis revealed narrow activity for EDIRA083 and EDIRA088, whereas EDIRA092 infected 29% of the panel strains. In liquid phage infection assays, overall lytic activity was consistently higher and more sustained in human urine than in LB. These results identify three genetically distinct lytic phages targeting MDR K. pneumoniae. Their activity in urine supports further evaluation of these phages as candidates for therapeutic development against MDR Klebsiella UTI.

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Autoreactive CD4 T cells, recognizing liver-self-antigens such as SepSecS, are potentially main drivers of the chronic inflammatory response during autoimmune hepatitis (AIH). Previous studies have uncovered SepSecS epitopes often associated with HLA-DRB1*03 or HLA-DRB1*04 restriction, two alleles enriched in AIH population. However, HLA restriction of numerous SepSecS epitopes remains incomplete and it is still unclear if they could be presented by non-HLA-DR molecules. Here, we investigated epitope recognition and HLA restriction of SepSecS-specific CD4 T cells from AIH patients. Seventeen TCR&#x3b1;&#x3b2; from top expanded SepSecS-specific CD4 T cells of five AIH patients from our previous studies were cloned into murine hybridoma T cell line. Epitope reactivity of each TCR cell line was identified thanks to its IL-2 secretion following culture with 20-mer overlapping peptides of SepSecS protein and immortalized B cell lines. HLA restriction was defined using HLA blocking antibodies. 484 SepSecS-specific TCRs from nine AIH patients were analyzed using GLIPH2 algorithm. CD154 activation-induced marker assay was used to evaluate SepSecS epitope reactivity in AIH patients (n=11). Six SepSecS amino acid regions were recognized in vitro by autoreactive TCRs with four distinct class II HLA restrictions, including non-HLA-DR restrictions. GLIPH2 algorithm clustered SepSecS-specific TCRs into six groups. 6% of total SepSecS-specific TCR clonotypes shared common CDR3&#x3b2; motifs linked to the recognition of HLA-DPA1*02:01/HLA-DPB1*01:01-restricted SepSecS152-179 epitope. Ex vivo peptide stimulation assay revealed that SepSecS152-179 epitope represents between 15% and 67% of total SepSecS CD4 T cell reactivity in HLA-DPA1*02:01&#x223c;HLA-DPB1*01:01 AIH patients (n=5). We highlighted that SepSecS epitopes could be presented by HLA-DR and non-HLA-DR molecules to autoreactive CD4 TCRs with potentially conserved CDR3 motifs for common epitope recognition. In AIH, SepSecS is a key autoantigen targeted by the adaptive immune system, but only few T cell epitopes are defined and associated with a precise HLA restriction. By reconstructing TCRs from top expanded SepSecS-specific CD4 T cells of AIH patients, we identified new T-cell epitopes and their specific class II HLA restriction, including peptides presented by non-HLA-DR molecules. From a clinical perspective, these findings could be used to develop tools to track the frequency of autoreactive T cells in patients. This work could also pave the way for self-antigen-specific immunotherapies, such as peptide-based desensitization or the development of HLA-multimer technologies to selectively deplete or reprogram pathogenic T cells without inducing systemic immunosuppression.

Albinism is characterized by generalized hypopigmentation and ocular features resulting from impaired melanin biosynthesis. Most known pathogenic variants are rare (MAF&#xa0;<&#xa0;0.001) and found in coding regions. The role of non-coding variants, especially those with higher allele frequencies, is generally not investigated. Our next generation sequencing panel that includes the entire sequence of five major albinism genes (TYR, OCA2, SLC45A2, GPR143 and HPS1) identified compound OCA2 heterozygosity in a patient with a rare (MAF:0,0003) coding variant, NM_000275.3:c.1025&#xa0;A&#xa0;>&#xa0;G;p.(Tyr342Cys) and a more common intronic variant, NM_000275.3:c.574-19&#xa0;A&#xa0;>&#xa0;G (MAF:0,0087, with 80 homozygotes in the control population GnomADv4.1.0). In silico prediction tools indicated that this intronic variant could alter splicing. RT-PCR analysis on RNA extracted from the patient's blood revealed the skipping of exons 6 and 7, which resulted in the in-frame deletion of 78 amino acids. Protein modelling suggested that this deletion disrupts the GOLD-like domain and leads to the loss of conserved N-glycosylation sites, likely impairing protein folding and intracellular trafficking. These findings provided strong evidence for a deleterious effect on OCA2 function. Therefore, the variant was classified as likely pathogenic, allowing to establish the diagnosis in the patient. The relatively high allele frequency of this variant suggests that it behaves as a hypomorphic allele leading to disease in a compound heterozygous state. This underscores that intronic variants outside the canonical splice sites must be taken in consideration and functionally tested, and that common variants should not be systematically discarded in the diagnosis of albinism, and, similarly, of other rare diseases.

The occurrence of foreign body (FB) infections in patients with Staphylococcus aureus bacteraemia (SAB) can lead to serious complications. We therefore sought to evaluate the host risk factors and bacterial determinants associated with FB infection following SAB. We retrospectively included patients hospitalized with a SAB and carrying FB, over a four-year period. Factors associated with FB infection were assessed with multivariable logistic regression analysis. Bacterial determinants (lineage and virulence factors) were determined using whole genome sequencing. We included 104 patients of whom 40 patients (38.5%) with FB infection. Factors associated with FB infection were community-acquired SAB (OR&#xa0;=&#xa0;3.8; 95% confidence interval, CI [1.36-10.59]; p&#xa0;=&#xa0;0.011), Charlson's score >3 (OR&#xa0;=&#xa0;0.39; 95% CI [0.16.-0.99]; p&#xa0;=&#xa0;0.048 and unknown source of infection (OR&#xa0;=&#xa0;3.54; 95% CI [1.34-9.33]; p&#xa0;=&#xa0;0.011). No clonal complex or virulence gene was associated with a risk of FB infection in patients with SAB. FB infection is frequent in patients with SAB, particularly when the bacteremia is community-acquired. Our results suggest that bacterial characteristics (clonal complex or virulence factors) are not involved in the occurrence of FB infection in patients with SAB.

Hyaloid vessel regression is essential for vitreous transparency and normal vision, yet how this transient vascular network is dismantled remains unclear. Here we show that postnatal hyaloid regression in mice is not driven by a measurable increase in apoptosis, but instead by coordinated endothelial and mural cell delamination, extravascular redistribution and a transient plasticity program marked by Snail1 and Slug induction. Notch1 signalling peaks during the regression window, and vascular endothelial-specific Notch1 deletion causes persistent hyaloid vessels, with excessive proliferation and failure of endothelial and mural cell disengagement. Mechanistically, loss of Notch1 preserves endothelial identity, suppresses an endothelial-mesenchymal transition-like transcriptional program and reduces expression of the Wnt co-recepteors Lrp5 and Lrp6. Wnt pathway mutant phenocopies the delamination defect, supporting functional convergence between Notch1 and Wnt signalling during vessel involution. Together, these findings identify Notch1 as a key driver of developmental vascular pruning. They also redefine hyaloid regression as an apoptosis-non-exclusive remodelling process, with broader implications for physiological and pathological vascular remodelling, and may guide therapeutic strategies to modulate vascular regression in ocular disorders.

Primary hyperoxalurias (PH) are rare recessive autosomal genetic diseases inducing increased hepatic oxalate production. Apart from genetic background, their prognosis depends mainly on diagnosis delay. We recently reported shorter diagnosis delay in children compared with adults (1.2 (0.1-3.0) versus 30 (17-36) years) in a French PH cohort of 52 patients diagnosed between 2015 and 2019. In 2020, the first RNA interfering therapy was approved, leading to increased awareness and communication from reference centres, scientific societies and pharmaceutical companies. Our aim was to evaluate whether diagnosis delay was improved in this global setting. We performed a retrospective study including all consecutive patients that received a positive genetic test for PH in our expert genetic laboratory in Lyon between January 2020 and December 2024. We compared outcomes with the historical cohort. Diagnosis delay was defined by the time between the first symptoms and the result of genetic test. In total, 62 patients (37 children) were included. Forty-two (78%) patients had PH type 1, 5 (8%) had PH2 and 11 (18%) had PH3. The diagnosis delay remained significantly shorter in children as compared to adults (0.75 (1.10) versus 15 (16.21) years, p&#x2009;<&#x2009;0.05), but decreased in both sub-groups when compared to the previous study. The delay in PH diagnosis in France has been halved over the past five years. This improvement may be associated with recent therapeutic developments and increased awareness of the disease. Earlier diagnosis may enable earlier management, which might ultimately contribute to improved overall prognosis.

Current guidelines for the management of meticillin-susceptible Staphyloccocus aureus bloodstream infection/bacteraemia (SAB) recommend intravenous (flu)cloxacillin as the first-line treatment. This is based on decades of clinical practice. The high acute kidney injury rates seen with (flu)cloxacillin in the recently published SNAP trial, which is the largest randomized clinical trial ever in S. aureus bacteraemia (SAB), shows us the need to regularly test and question our usual clinical practice. Acute kidney injury is common in SAB when high doses of (flu)cloxacillin are used. The contribution of (flu)cloxacillin to developing or exacerbating acute kidney injury is likely to have been under recognized until now. Caution needs to be taken with (flu)cloxacillin. Cefazolin provides a safer and equally efficacious treatment for SAB. We discuss how this new evidence might be combined with our existing knowledge and the results of the CloCeBa trial to guide us how to appropriately manage our patients.

FIREFISH was a multicentre, open-label, two-part, phase 2 trial that assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of risdiplam in children with type 1 spinal muscular atrophy and two SMN2 copies, aged 1-7 months at enrolment. Part 1 assessed safety and determined the dose for part 2. In part 2, treatment with risdiplam for 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The aim of the 3-year open-label extension reported here was to assess long-term safety and efficacy of risdiplam. The 3-year extension of the FIREFISH trial was a multicentre, open-label study in 17 centres across 12 countries (in Asia, Europe, Brazil, and the USA). Children with a confirmed genetic diagnosis of spinal muscular atrophy and two copies of the SMN2 gene who had completed 2 years of risdiplam treatment were eligible to continue in the open-label extension study, during which risdiplam was administered once daily by oral syringe or feeding tube at the pivotal dose of 0&#xb7;20 mg/kg for infants younger than 2 years, at 0&#xb7;25 mg/kg for children aged 2 years and older with bodyweight below 20 kg, and at 5 mg for children aged 2 years and older with bodyweight of 20 kg or more. Adverse events were assessed as part of physical assessments every 13 weeks. More comprehensive assessments every 26 weeks included level of respiratory support and efficacy assessments of motor function in addition to safety and physical assessments. Outcomes assessed during the open-label extension study included adverse events, survival and event-free survival (defined as being alive with no permanent ventilation), growth measures, swallowing, feeding, and motor function. Motor function was assessed with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the gross motor subscale of the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), and the Hammersmith Infant Neurological Examination, Module 2 (HINE-2). For all children, safety data including adverse events, serious and non-serious adverse events of special interest; ophthalmology assessments; laboratory assessments; vital signs; ECGs; and other protocol-specified tests deemed critical to the safety evaluation of the study, were collected up to 30 days after the last dose. Survival and event-free survival are reported at year 5 for all enrolled children. Adverse events are reported at year 5 for all children who received at least one dose of risdiplam (safety population). All other efficacy endpoints are reported at year 5 for the population who received the pivotal dose. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Between Dec 23, 2016, and Nov 19, 2018, 62 children aged 1-7 months were enrolled in FIREFISH parts 1 and 2. After 2 years in the study (parts 1 and 2), 55 children continued risdiplam treatment into the open-label extension for a further 3 years. The study was completed on Dec 22, 2023, at which time 52 children (84%) had completed 5 years of risdiplam treatment. After 5 years of risdiplam treatment, 56 children (90%) were alive, and 50 (80%) were alive without the need for permanent ventilation. In the pivotal-dose population (n=58), 17 children (29%) did not require invasive or non-invasive respiratory support at year 5 and 13 (22%) did not require hospitalisations during the study. Upward trajectories for motor function responses were observed between years 1 and 5. The number of children who could sit without support for at least 5 s and 30 s was maintained during the 3-year extension, with 36 children (62%) and 34 children (59%), respectively, doing so by year 5. Similarly, for HINE-2, eight children (14%) reached the stable sit milestone and 26 (45%) met pivots at year 5. By year 5, four children (7%) could stand without support as assessed by both the BSID-III and HINE-2. No children could walk independently, but six (10%) met the HINE-2 cruising milestone. The mean HINE-2 total score increased from baseline (0&#xb7;93 [90% CI 0&#xb7;72-1&#xb7;14]) to year 4 (14&#xb7;22 [12&#xb7;66-15&#xb7;79]), remaining stable thereafter. Mean CHOP-INTEND scores increased from 22&#xb7;47 at baseline (90% CI 20&#xb7;97-23&#xb7;96) and stabilised at around 50 at year 5, with scores of &#x2265;40 for 38 children (66%), &#x2265;50 for 29 children (50%), and &#x2265;60 for 11 children (19%) at year 5. Most children maintained oral feeding (n=42; 72%) and swallowing (n=46; 79%) abilities, and growth was consistent with typical patterns seen in type 1 spinal muscular atrophy. Safety findings over 5 years were consistent with the results from the primary analysis. Most adverse events were mild or moderate. The most frequently reported adverse events were pyrexia (65% [n=40]), upper respiratory tract infection (63% [n=39]), and pneumonia (50% [n=31]). Pneumonia was the most frequently reported serious adverse event in 28 children (45%). No new safety findings were reported and no treatment-related events led to withdrawal from study treatment. Unlike the natural history of children with type 1 spinal muscular atrophy, after 5 years of risdiplam treatment, most children in FIREFISH were alive without needing permanent ventilation, were able to swallow and feed orally, and had reached motor milestones not typically observed in untreated patients. These results show long-term continuous efficacy and safety of risdiplam in children with type 1 spinal muscular atrophy. F Hoffmann-La Roche.

There is no consensus on functional imaging modalities for lesion assessment in medullary thyroid carcinoma. The aim of this single-center retrospective study was to analyze the performance of [18F]F-DOPA-PET/CT, [18F]F-FDG-PET/CT and morphologic imaging in a cohort of patients with medullary thyroid carcinoma and extrathyroidal lesions. Forty-three patients (10 women and 33 men; median age, 62.8 years), including 28 with RET mutation (germline: n=13, somatic: n=15), all with extrathyroidal morphological lesions, underwent conventional imaging, plus [18F]F-DOPA-PET/CT with early and late acquisitions (n=40), [18F]F-FDG-PET/CT (n=29) or both (n=26), for initial staging or follow-up. PET/CT scans were analyzed visually and semi-quantitatively (SUVmax of the hottest lesion). The gold-standard was based on histology and imaging follow-up. According to the gold-standard, a median 2 extrathyroidal regions were involved per patient. Per-patient sensitivity was 95.0% (38/40) for [18F]F-DOPA-PET/CT, 93.1% (27/29) for [18F]F-FDG-PET/CT, and 76.9% (30/39) for morphologic imaging. [18F]F-DOPA-PET/CT identified more hepatic and osteomedullary involvement than did [18F]F-FDG-PET/CT. The combination of both PET modalities detected at least 1 additional metastatic site in 10/26 patients (38.5%). [18F]F-DOPA SUVmax was significantly higher on early than late acquisitions (p = 0.0001) and correlated positively with blood calcitonin (p = 0.0069). [18F]F-FDG SUVmax correlated with shorter calcitonin doubling time (p = 0.0203). SUVmax and RET status did not correlate. Our results provide insight into the complementary role of [18F]F-DOPA and [18F]F-FDG PET/CT in a high-risk population with morphologically proven metastatic disease.

Relapsing polychondritis (RP) is a rare, multisystem inflammatory disease characterized by heterogeneous clinical manifestations and a substantial impact on patients' daily functioning and well-being. Health-related quality of life (HR-QoL) in RP remains insufficiently characterized, and no disease-specific measurement tool is available so far. This study aimed to develop and validate the RP-QoL, a multilingual, patient-reported outcome instrument specifically designed to assess HR-QoL in individuals with RP. The RP-QoL was developed within the European Reference Network ReCONNET using a structured four-step approach: (1) identification of relevant HR-QoL domains through systematic literature review, an international patient survey, and expert consensus; (2) item generation; (3) pilot testing including cognitive debriefing; and (4) comprehensive psychometric validation. Validation analyses included assessment of internal consistency, structural validity, construct validity, convergent validity with the SF-36, and criterion-related validity. Domain identification incorporated input from 274 patients across 22 countries, leading to a 31-item pilot questionnaire with a 28-day recall period and 5-point response scale. Cognitive debriefing confirmed clarity, relevance, and feasibility. Validation in 239 patients from 19 countries (median age 55&#x2009;years; 80% female) demonstrated excellent internal consistency (Cronbach's &#x3b1;&#x2009;=&#x2009;0.96). Exploratory factor analysis supported near-unidimensionality, with the first factor explaining 46.6% of variance. RP-QoL scores correlated strongly with disease impact (&#x3c1;&#x2009;=&#x2009;-0.62, p< 0.0001) and SF-36 physical (&#x3c1;&#x2009;=&#x2009;0.65) and mental (&#x3c1;&#x2009;=&#x2009;0.55, p< 0.0001) components (both p< 0.0001, p< 0.0001). Discriminative ability was high (AUC&#x2009;=&#x2009;0.87). The RP-QoL is the first validated, disease-specific HR-QoL instrument for RP, with robust psychometric performance and applicability in both clinical practice and research.

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