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Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia
No full textInternational audienceBackground Neurodevelopmental disorders (NDDs) may influence the course of Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, prior studies have focused on specific pairs of NDDs and variants of AD/FTD. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated the association between a neurodevelopmental vulnerability (DV) and the clinical presentation and age at onset of AD/FTD. Methods We prospectively and consecutively recruited 84 AD/FTD participants and 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and atypical (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. Participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k‐means clustering based on the questionnaire, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV− (without) cluster. This data‐driven approach enabled an unbiased classification of individuals with a DV, beyond traditional diagnostic labels. Results DV frequencies did not differ between the AD/FTD (18%) and control (15%) χ 2 = 0.205; p = 0.651); and between typical (21%) and atypical (11%) subgroups (Fisher's test, p = 0.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV− patients (95% CI [−14, −3.0]; p = 0.005), with a median onset age of 58 years (IQR: 15). Conclusions A DV could favor early‐onset AD/FTD, but may not affect susceptibility to typical and atypical variants of AD/FTD. The underlying neurophysiological processes involved require future investigation, with implications for precision medicine and individualized treatment strategies. Study Registration Numbers RnIPH 2023‐71 and Research Ethics Committee file No. 2023_765
Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis
No full textInternational audienceImportance: In women with multiple sclerosis (MS), disease-modifying therapy (DMT) management during pregnancy might impact relapse risk.Objective: To estimate the effect of DMT management during pregnancy on MS relapse rate and compare different therapeutic strategies.Design, setting, and participants: This was a multicenter retrospective cohort study using data from January 1990 to December 2023. Data were extracted in December 2023 from the French MS registry. Among 52 955 women in the registry, we included pregnancies identified through childbirths in patients with relapsing-onset MS who were monitored for at least 18 months before delivery and 9 months after. Pregnancies occurring less than 18 months apart or with missing month of birth were excluded.Exposures: Mediation analysis was used to estimate the total, direct, and indirect (mediated by DMT management) effects of pregnancy. Different therapeutic strategies were compared: DMT interruption, switching to or maintaining interferon β or glatiramer acetate, switching to or maintaining natalizumab until the third trimester, and switching to or maintaining intravenous anti-CD20 and interrupting it 3 months before conception.Main outcomes and measures: The primary outcome was the annualized relapse rate (ARR) during the preconception, gestation, and postpartum periods. Within a causal inference framework, counterfactual ARRs were estimated using longitudinal g-computation, combining a random forest algorithm for predicting DMTs, and a mixed-effects Poisson model for relapses.Results: We included 6341 pregnancies occurring in 4998 women (mean [SD] age at conception, 31.5 [4.5] years). DMT management during pregnancy significantly increased ARR during gestation (causal rate ratio [cRR], 1.13; 95% CI, 1.06-1.22) and postpartum (cRR, 1.08; 95% CI, 1.01-1.16) periods. This led to a deleterious total effect of pregnancy on ARR, particularly in women receiving natalizumab before pregnancy with prolonged interruption (ie, interruption before the second trimester or resumption more than 3 months after delivery; cRR, 2.18; 95% CI, 1.76-2.69), and in women receiving fingolimod (cRR, 2.15; 95% CI, 1.60-2.93). Compared to DMT interruption, anti-CD20 strategy was the most effective (cRR, 0.38; 95% CI, 0.25-0.52), followed by the natalizumab strategy with short interruption (cRR, 0.80; 95% CI, 0.71-0.90), whereas interferon β (cRR, 0.93; 95% CI, 0.86-0.99) and glatiramer acetate strategies (cRR, 0.91; 95% CI, 0.84-0.99) were less effective.Conclusion: In this study, DMT management during pregnancy significantly increased relapse risk, particularly in patients receiving natalizumab with prolonged interruption or fingolimod. The strategy based on the use of anti-CD20 before pregnancy was the most effective to mitigate this risk
A rare gain of function variant of hepatic lipase attenuates hypercholesterolemia and atherosclerosis in mice via an LDL receptor-independent mechanism
No full textInternational audienceAIMS: LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown. METHODS AND RESULTS: To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G versus wild-type HL (HL-WT) in hypercholesterolemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr-/-) mice. APOE*3.Leiden.CETP mice or Ldlr-/- mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3×1011 GC/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (-63% vs control; -58% vs HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (-98% vs control; -97% vs HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr-/- mice (-80% vs control; -77% vs HL-WT), and decreased atherosclerotic lesion size in the aortic root (-54% vs control; -41% vs HL-WT) and the aortic arch (-73% vs control; -70% vs HL-WT). CONCLUSIONS: HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolemia
Satisfactory and Similar Outcomes after Knee Arthroplasty Revisions in One or Two Stages for Infection, Following a Surgical Strategy Based on Robust Guidelines
No full textInternational audienceBackgroundThis study aimed to assess the outcomes of a one-stage or two-stage strategy after total knee arthroplasty revision (RTKA) for periprosthetic joint infection (PJI). MethodsThis single-center retrospective study included all TKA revisions for chronic infection operated on between 2010 and 2021, with at least two years of follow-up. The surgical strategy was based on the recommendations from the Philadelphia Consensus 2018.Patients were classified into five overlapping groups: mechanical failure, septic failure, controlled infection, cure of infection, and complete healing. Revision was defined as the need for further surgery with implant removal. There were 218 RTKAs included, with 182 two-stage revisions (83.5%) and 36 one-stage revisions (16.5%). The mean follow-up was 56.9 ± 30.8 months. At the last follow-up, 135 patients (61.9%) were classified as “complete healing,” 30 as “septic failure” (13.8%), 12 as “mechanical failure” (5.5%), 147 (67.4%) as “infection-cured,” and 41 (18.8%) as “controlled infection.” ResultsThere were 27 patients (14.8%) who had had septic failure, and 11 (6.1%) had mechanical failure in the two-stage group, versus three (8.3%) and one (2.8%), respectively, in the one stage group (P = 0.36). There were 128 “R2” or “complex revision cases” (58.7%) and 90 “R3” or “salvage cases” (41.3%) according to the Revision Knee Complexity Classification (RKCC). In multivariate analysis, the requirement of a flap (OR [odds ratio] = 0.28, [0.11 to 0.72]), RKCC grade of R3 (OR = 0.37, [0.21 to 0.68]), and an ASA (American Society of Anesthesiologists) score > 2 (OR = 0.51, [0.28 to 0.93]) were associated with lower rates of infection healing.ConclusionFollowing a surgical strategy based on robust guidelines, one- or two-stage TKA revision for PJI achieved satisfactory rates of complete healing and cure of infection despite 41% of very complex cases. Patients classified as R3, those requiring a flap, and those who had an ASA score greater than 2 were at higher risk of failure
Reduced quadriceps deficit following dry arthroscopy compared to standard fluid arthroscopy at the time of MPFL reconstruction
No full textInternational audienceAbstract Purpose Recurrent patellar dislocations (RPDs) are prevalent, particularly among adolescents. The ‘Menu à la carte’ technique facilitates personalized management of each patient through reconstruction of the medial patellofemoral ligament (MPFL) while simultaneously addressing other anatomical factors that may contribute to instability. Arthroscopy, frequently performed prior to stabilization surgery to identify and treat intra‐articular pathology, carries specific risks. Fluid arthroscopy can increase post‐operative effusion, while dry arthroscopy may expose cartilage to potential damage due to the absence of fluid, increasing friction and thermal effects. Concurrent knee arthroscopy to evaluate and address intra‐articular pathology at the time of MPFL may contribute to post‐operative quadriceps deficits that can significantly impact recovery. Therefore, this study aimed to evaluate and compare quadriceps recovery following either traditional fluid or dry arthroscopy at MPFL reconstruction. The hypothesis was that MPFL reconstruction with fluid arthroscopy would result in more significant quadriceps deficiency, more effusions, and decreased early post‐operative knee flexion compared to the dry arthroscopy group. Methods This retrospective study analyzed 66 patients who underwent MPFL reconstruction for RPD between February 2020 and February 2024. Exclusion criteria included trochleoplasty, tibial tubercle osteotomy, or missed isokinetic tests beyond 6 months post‐operatively. Patients underwent fluid arthroscopy until September 2021 and dry arthroscopy thereafter. Post‐operative follow‐up at 6 weeks recorded range of motion, patellar apprehension and clinical diagnosis of knee effusion, while isokinetic testing at 4–6 months compared peak torque and muscle strength between the fluid and air arthroscopy groups. Results Isokinetic tests revealed a significant deficit in quadriceps strength of the operated knees during MPFL reconstructions performed under fluid compared to those performed dry, both at concentric 60°/s (73.3 ± 33.8 vs. 95.5 ± 39.5 N m/kg; p = 0.02), and at concentric 240°/s (53.6 ± 27.0 vs. 66.5 ± 28.7 N m/kg; p = 0.04) between 4 and 6 months post‐operative. The limb symmetry index (LSI) showed a significant quadriceps strength deficit in the fluid arthroscopy group compared to the dry arthroscopy group, both at concentric 60°/s (63.8 ± 18.0 vs. 75.2 ± 17.2; p = 0.01) and 240°/s (69.6 ± 19.8 vs. 78.5 ± 13.6; p = 0.04). The fluid arthroscopy also demonstrated an increased incidence of post‐operative effusion (47% vs. 19%, p = 0.01) and decreased knee flexion (129.7 ± 13.9° vs 119.3 ± 16.3°, p = 0.01) when compared to the dry arthroscopy group at 6 weeks post‐operative. Conclusion This study has demonstrated a significant quadriceps strength deficit in isokinetic tests following fluid arthroscopy compared to dry arthroscopy as well as a higher incidence of effusion and flexion deficit post‐operative. These findings highlight the potential for dry arthroscopy to assess intra‐articular pathology during MPFL reconstruction. Level of Evidence Level III, retrospective, case–control study
New challenges for research and science: What is at stake?
No full textInternational audienceNo abstract availabl
Liver Enzyme Elevation After Hepatitis C Virus Cure: Is There a Sex Effect? (ANRS CO13 HEPAVIH Cohort)
No full textInternational audienceWe read with great interest Zhang et al.'s work on liver enzyme elevation (LEE) after hepatitis C virus (HCV) cure [1]. While the authors found no evidence of an effect of HIV status on post-cure LEE, they showed that female sex, pretreatment alanine aminotransferase (ALT) and pretreatment cirrhosis were positively associated with this outcome. Their study limitations included its single-centre nature, the lack of data on alcohol use and the relatively small number of HIV-HCV co-infected individuals. We thus further explored the potential impact of HIV-related markers and alcohol use on post-HCV cure LEE in a larger sample of HIV-HCV co-infected adults enrolled in the French, prospective, multicentre cohort ANRS CO13 HEPAVIH [2]. Participants provided written informed consent. We selected participants cured from HCV thanks to direct-acting antiviral treatment (DAA), who had completed at least one clinical follow-up visit after HCV cure, and with available pretreatment data on age, sex, place of birth, body mass index, ALT and aspartate transaminase (AST) levels, CD4 cell count, HIV viral load, history or current cirrhosis or hepatocellular carcinoma and alcohol use (AUDIT-C [3]). We conducted a multivariable mixed-effects logistic regression model over the post-HCV cure follow-up period, with LEE as the outcome
Predicting the toxicity-efficacy ratio of venetoclax in real-world patients
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Olaparib, Temozolomide, and Concomitant Radiotherapy for Partially Resected or Biopsy-Only Glioblastoma First-Line Treatment: Results from the OLA-TMZ-RTE-01 Phase I Study
No full textInternational audienceAbstract Purpose: Radiochemotherapy remains the mainstay of glioblastoma (GBM) first-line treatment after extended surgery, but the prognosis is still poor. PARP inhibitors like olaparib may improve GBM outcomes. We implemented a phase I to IIa trial to assess the safety and efficacy of olaparib combined with standard radiochemotherapy as a first-line treatment in patients with unresected GBM. We herein present results of phase I. Patients and Methods: Based on the Stupp regimen, two sequential dose escalations of olaparib were performed to distinguish the radiotherapy period and the maintenance period for assessing the MTD of olaparib separately for each treatment period. Dose escalations were performed by a Time-to-Event Continual Reassessment Method. Results: A total of 30 patients were enrolled: 20 (66.7%) men, median age 59 years (range, 25–70), and 12 patients (42.9%) with Eastern Cooperative Oncology Group performance status of 0. Among them, 16 and 11 patients were assessable for determining MTD in each period. Hematologic dose-limiting toxicities were experienced by four and one patients in each sequential dose escalation, respectively. The MTD was olaparib 100 mg twice daily for 3 days a week in concomitant during both the radiochemotherapy and maintenance periods of the standard treatment. The median progression-free and overall survival were 6.2 and 19.8 months, respectively. The 2-year survival rate was 36.7% (22.9–58.7). Conclusions: Intermittent dosing of olaparib at radiosensitizing concentrations in concomitant with the Stupp protocol has an acceptable safety profile with promising outcomes in patients with unresectable GBM. Further efficacy determination is ongoing in the phase IIa step
