Hôpitaux Universitaires Henri-Mondor

A significant proportion of patients presenting a primary sclerosing cholangitis (PSC) will require liver transplantation (LT). The present study aimed to investigate graft loss and patient death in a large cohort of patients. We conducted a nationwide multicenter retrospective study including all adult patients transplanted for PSC in France From 1985 to 2019. Were included 571 patients; median follow-up after LT was 89.0 months (IQR, 43.0-151.0). Patient survival at 5, 10 and 20 years after LT was 88.2%, 81.2% and 62.6%. After exclusion of patients who died during the first month after LT, 37 patients (6.6%) died during the first 2 years and the main cause was malignancies (n = 15, 40.5%, including 12 cases of recurrent cholangiocellular carcinoma). After 2 years, 90 patients (17.2%) died; the two main causes were malignancies (n = 36, 40.0%, including 13 cases of colorectal cancer) and sepsis (n = 23, 25.6%, of which 7 were related to recurrent PSC). Graft survival at 5, 10 and 20 years was 89.5%,78.7% and 62.7%. Independent factors associated with late patient death (after 2 years) were an older age at LT, a bilio-digestive anastomosis and the use of preventive UDCA; independent factors associated with late graft loss were recurrent PSC, cellular rejection, a younger age at LT, and the use of tacrolimus (protective). Our results emphasise that the prognosis after LT for PSC could be improved by better detection of cholangiocellular carcinoma before LT, and colorectal cancer after LT.

Actinopathies are myopathies associated with pathogenic variants in ACTA1, a gene encoding the skeletal alpha-actin protein. Although patients most frequently have a severe congenital myopathy, an important clinical and myopathological variability has been described. Recently, a scapuloperoneal myopathy phenotype associated with ACTA1 has been reported. Here, we present a Russian woman with a late-onset, slowly progressive, scapuloperoneal actinopathy associated with an unpublished heterozygous pathogenic ACTA1 variant. We performed a thorough analysis of clinical, muscle imaging, muscle biopsy, genetic, protein and cardiac alpha-actin expression data from a 65-year-old woman with a scapuloperoneal myopathy phenotype. Disease onset was at around 30 years with proximal lower limbs muscle weakness, which slowly progressed towards an upper and lower limb distal involvement with prominent weakness of the fourth and fifth finger extensors. A muscle MRI showed a symmetric axial involvement, while lower limbs sections evidenced a severe symmetric involvement of quadriceps and biceps femoris long head, and a symmetric involvement of medial gastrocnemius associated with a right tibialis anterior involvement. Muscle biopsy showed cores and rods. The patient harboured the unpublished NM_001100.4:c.1001C > T, p.(Pro334Leu) ACTA1 variant. Immunofluorescence and western blot studies showed an increased expression of cardiac alpha-actin, an actin isoform which is normally predominant in the prenatal skeletal muscles and adult heart muscle, suggesting a possible role of this isoform in milder actinopathy phenotypes. We report a milder, late-onset, slowly progressive scapuloperoneal myopathy phenotype with cores and rods and cardiac alpha-actin overexpression, thus expanding the spectrum of actinopathies.

Functional neurological disorders (FNDs) are characterised by the presence of motor, sensory, or cognitive neurological symptoms not explained by a recognised neurological disorder. Chronic pain is not part of the diagnostic criteria for FND, but these two conditions frequently coexist. Our objective was to evaluate the frequency and mechanism-based characteristics of chronic pain symptoms in a single-center cohort of patients with FND. Data were collected prospectively using a standardised questionnaire and a face-to-face interview. In this study, 63 consecutive patients with FND were interviewed, 54 (86%) of whom reported chronic pain. The onset of pain was associated with a traumatic event in 41% of patients. Pain was described as permanent in 65% of patients, primarily localised to the lower limbs (83%), but actually affecting several other body regions in the vast majority of cases (89%). Pain intensity averaged 5 to 6 out of 10, and its impact on daily activities was rated at 5.5 out of 10 on the Brief Pain Inventory. The description of pain symptoms was more consistent with neuropathic pain or cognitive symptoms of central sensitization than with nociceptive pain or emotional symptoms of central sensitization. Chronic pain is the most frequently reported symptom by patients, even more than other clinical symptoms specific to FND. This pain has a significant impact on the daily lives of patients. Chronic pain is very common in patients with functional neurological disorders and is characterised by highly varied pathophysiological mechanisms. Given its frequency, heterogeneity, and potential impact on other aspects of the functional neurological disorder and on its prognosis, improved management of chronic pain is needed in these patients, particularly through the optimisation of symptomatic treatment strategies.

Spontaneous subarachnoid hemorrhage (sSAH) is a critical neurological condition with high mortality and significant long-term sequelae. Delayed cerebral ischemia (DCI) is a significant contributor to poor clinical outcomes. Despite advances in management, early predictors of clinical outcomes and DCI remain unclear. This study investigates whether serum ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a neuronal injury biomarker, can predict functional outcomes, mortality, and DCI in patients with sSAH. A prospective observational study was conducted from January 2022 to June 2024, enrolling adults (≥18 years) with sSAH confirmed by neuroimaging on admission. Blood samples were collected at 24 hours (T0), 72 hours (T1), and 7 days (T2) after sSAH onset. UCH-L1 levels were measured using an automated analyzer. Outcomes were functional status, assessed by the modified Rankin Scale at 14 days and 3 months, mortality, the occurrence of DCI, and determination of UCH-L1 cutoff values predictive of poor prognosis. A total of 102 patients with sSAH were included. UCH-L1 levels measured 24 hours after admission were independent predictors of poor outcomes ( P < .001) and DCI ( P = .026). The optimal UCH-L1 cutoff for predicting poor outcomes at 14 days and 3 months was 174.6 pg/mL (odds ratio 10.55, 95% CI 4.23-26.36 and odds ratio 7.79, 95% CI 3.11-19.52, respectively). Early serum UCH-L1 levels are significant predictors of clinical outcomes, mortality, and DCI in patients with sSAH, suggesting that UCH-L1 could be a promising biomarker for guiding early prophylactic and therapeutic interventions in the management of sSAH.

ABSTRACTAcute chest syndrome (ACS) is a severe complication of sickle cell disease (SCD) occurring in ~50% of patients, some presenting frequent episodes. We lack tools to identify patients at high risk of ACS occurrence or frequent episodes. Epidemiological studies have found an association between asthma and ACS, but whether this link is causal is unclear. We used polygenic scores (PGS) to analyze whether the genetic propensity for asthma was associated with ACS and could be used to stratify the risk of ACS. We identified that PGS for asthma (PGSasthma) was associated with ACS rate (number of episodes per year), but not ACS occurrence, in both the CSSCD (n = 1278) and the GEN‐MOD (n = 406) prospective SCD cohorts, independently of fetal hemoglobin (HbF) (β = 0.17, standard error = 0.06, p = 0.006). This effect was most pronounced in patients with low HbF levels. Combining PGSasthma and HbF identified a population at high risk of frequent ACS after a first episode: individuals within the highest PGSasthma quintile and the lowest HbF quintile. Finally, we found that the genetic correlation between these two conditions only partially overlapped. This suggests that genetically determined asthma is not the unique contributor to the genetic propensity for ACS and that other genetic determinants may also play a role. In sum, our results suggest that patients with a high genetic propensity for asthma are prone to frequent ACS if not protected by high HbF levels. Combining PGSasthma and HbF may allow identifying patients at high risk of frequent ACS after a first episode for personalized management.

Calpainopathies, including limb-girdle muscular dystrophy recessive type 1 (LGMD R1) and the rare dominant type 4 (LGMD D4), are genetic neuromuscular disorders caused by pathogenic variants in the CAPN3 gene, which encodes calpain-3, a muscle-specific cysteine protease. This protein plays a crucial role in muscle remodelling, calcium homeostasis, and myogenesis regulation. LGMD R1, the most common form of LGMD, is characterized by progressive, symmetrical muscle weakness primarily affecting the shoulder and pelvic girdles, with an onset ranging from childhood to adulthood. It affects about 1 in 100,000 individuals. The clinical spectrum is wide, with three main phenotypes: pelvifemoral myopathy, scapulohumeral myopathy, and isolated hyperCKemia. LGMD D4 is characterized generally by a milder phenotype with variable but frequent axial muscle involvement. Diagnostic algorithm include serum CK levels dosage, muscle imaging, and sometimes a muscle biopsy, with definitive diagnosis confirmed by CAPN3 gene testing. Calpainopathies have no cure and care is focused on physiotherapy, management of muscle contractures, moderate physical activity, and orthosis. The newly established French National Diagnosis and Care Protocol (NDCP) aim to standardize the diagnosis and care of calpainopathies. The protocol emphasizes early diagnosis, personalized patient care, genetic assessment and prevention of disease progression. This initiative aims to reduce diagnostic delays and improve patient outcomes through a harmonized multidisciplinary approach, informed by the latest clinical and research expertise.