Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study

BackgroundMigraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.MethodsWe conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.ResultsNo significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.ConclusionThe evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated

DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P 5 .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P 5 6.6 3 1025) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription

Chirurgie robotisée en stimulation cérébrale profonde : étude de précision et expérience clinique

INTRODUCTION: Frameless robotic-assisted surgery using the ROSA® robot is an innovative technique for Deep Brain Stimulation (DBS) that has not been assessed in a large cohort of patients regarding the accuracy and the effectiveness of the technique yet. METHODS: An open label prospective single-center study was conducted on all patients undergoing DBS surgery between 2012 and 2016. Accuracy was evaluated by the radial error (RE) of the final lead position at the target level and was measured on intraoperative images (telemetric X-Rays for Group 1, O-Arm® CT scans for Group 2) and on postoperative images. Effectiveness of bilateral STN-DBS was evaluated for patients with advanced Parkinson’s Disease (PD) at 1-year follow-up regarding the UPDRS score and the dopaminergic treatment (LEDD). RESULTS: Regarding a total of 119 consecutive patients, the mean RE ranges from 0.72 to 0.88 mm, without significant difference between the different imaging modalities. Regarding a total of 102 consecutive patients at 1-year follow-up, bilateral STN-DBS had proved to be significantly effective (p<0.0001) with a mean improvement by 38% in UPDRS III, 17% in UPDRS I, 18% in UPDRS II, 51% in UPDRS IV, and a mean LEDD reduction of 49%. CONCLUSION: Frameless ROSA® robot-assisted surgery for bilateral STN-DBS in patients with advanced PD is more precise and safer then frame-based techniques but its long-term effectiveness needs to be more evaluated by studies involving a more homogenous population of patients.INTRODUCTION : La chirurgie robotisée en stimulation cérébrale profonde (SCP) utilisant le robot ROSA® est une technique chirurgicale permettant de s’affranchir du cadre stéréotaxique pour l’implantation des électrodes de SCP. Cette technique très innovante et prometteuse n’a pourtant pas encore été évaluée dans une large série de patients. MÉTHODES : Nous avons conduit une étude monocentrique prospective incluant tous les patients traités par SCP entre 2012 et 2016. Nous avons évalué la précision de notre technique chirurgicale en mesurant l’erreur radiale de l’électrode implantée au niveau de la cible sur les imageries intraopératoires (téléradiographies pour le groupe 1, scanners par O-Arm® pour le groupe 2) et postopératoires. Puis nous avons évalué chez les patients Parkinsoniens l’efficacité de la stimulation subthalamique bilatérale (STN-SCP) à un an par le score UPDRS et la dopathérapie. RÉSULTATS : Sur un ensemble de 119 patients consécutifs, l’erreur radiale moyenne était mesurée entre 0.72 et 0.88 mm, sans différence significative entre les différentes modalités d’imagerie. Sur un ensemble de 102 patients consécutifs, la STN-SCP entraînait de manière significative à un an (p<0.0001) une amélioration moyenne du score UPDRS III de 38%, du score UPDRS I de 17%, du score UPDRS II de 18%, du score UPDRS IV de 51% et une réduction moyenne de la dopathérapie de 49%. CONCLUSION : La chirurgie robotisée en SCP utilisant le robot ROSA® est une technique chirurgicale plus précise et plus sûre que les techniques utilisant le cadre stéréotaxique mais son efficacité à long terme nécessite d’être plus profondément évaluée dans une population homogène de patients

Frameless ROSA (R) robot-assisted lead implantation for deep brain stimulation: Technique and accuracy

International audienceBACKGROUND: Frameless robotic-assisted surgery is an innovative technique for deep brain stimulation (DBS) that has not been assessed in a large cohort of patients.OBJECTIVE: To evaluate accuracy of DBS lead placement using the ROSA$^{(R)}$ robot (Zimmer Biomet) and a frameless registration.METHODS: All patients undergoing DBS surgery in our institution between 2012 and 2016 were prospectively included in an open label single-center study. Accuracy was evaluated by measuring the radial error (RE) of the first stylet implanted on each side and the RE of the final lead position at the target level. RE was measured on intraoperative telemetric X-rays (group 1), on intraoperative O-Arm$^{(R)}$ (Medtronic) computed tomography (CT) scans (group 2), and on postoperative CT scans or magnetic resonance imaging (MRI) in both groups.RESULTS: Of 144 consecutive patients, 119 were eligible for final analysis (123 DBS; 186 stylets; 192 leads). In group 1 (76 patients), the mean RE of the stylet was 0.57 $\pm$ 0.02 mm, 0.72 $\pm$ 0.03 mm for DBS lead measured intraoperatively, and 0.88 $\pm$ 0.04 mm for DBS lead measured postoperatively on CT scans. In group 2 (43 patients), the mean RE of the stylet was 0.68 $\pm$ 0.05 mm, 0.75 $\pm$ 0.04 mm for DBS lead measured intraoperatively; 0.86 $\pm$ 0.05 mm and 1.10 $\pm$ 0.08 mm for lead measured postoperatively on CT scans and on MRI, respectively No statistical difference regarding the RE of the final lead position was found between the different intraoperative imaging modalities and postoperative CT scans in both groups. CONCLUSION: Frameless ROSA (R) robot-assisted technique for DBS reached submillimeter accuracy. Intraoperative CT scans appeared to be reliable and sufficient to evaluatethe final lead position

Diagnostic, clinical management, and outcome of bone flap-related osteomyelitis after cranioplasty

Objectives: We aimed to describe diagnostic, management, and outcome of bone flap-related osteomyelitis after cranioplasty. Methods: Patients followed up in our tertiary care hospital for bone flap-related osteomyelitis after cranioplasty were included in a retrospective cohort (2008-2021). Determinants of treatment failure were assessed using logistic regression and Kaplan-Meier curves analysis. Results: The 144 included patients (81 [56.3%] males; median age 53.4 [interquartile range [IQR], 42.6-62.5] years) mostly presented wound abnormalities (n = 115, 79.9%). All infections were documented, the main pathogens being Staphylococcus aureus (n = 64, 44.4%), Cutibacterium acnes (n = 57, 39.6%), gram-negative bacilli (n = 40, 27.8%) and/or non-aureus staphylococci (n = 34, 23.6%). Surgery was performed in 140 (97.2%) cases, for bone flap removal (n = 102, 72.9%) or debridement with flap retention (n = 31, 22.1%), along with 12.7 (IQR, 8.0-14.0) weeks of antimicrobial therapy. After a follow-up of 117.1 (IQR, 62.5-235.5) weeks, 37 (26.1%) failures were observed: 16 (43.2%) infection persistence, three (8.1%) relapses, 22 (59.5%) superinfections and/or two (1.7%) infection-related deaths. Excluding superinfections, determinants of the 19 (13.4%) specific failures were an index craniectomy for brain tumor (odds ratio = 4.038, P = 0.033) and curettage of bone edges (odds ratio = 0.342, P = 0.048). Conclusion: Post-craniectomy bone flap osteomyelitis are difficult-to-treat infection, necessitating prolonged antimicrobial therapy with appropriate surgical debridement, and advocating for multidisciplinary management in dedicated reference centers

Table_e-1_Included_metabolites_in_pathways

Table e-1: Included metabolites in (sub-)pathway

Figure_e-7_Metabolite_correlation_between_measurements_and_over_time

Figure e-7: Metabolite correlations between measurements and over time for apoA1 and the S-HDL-FC ratio

Figure_e-5_Ratio_stratification_plots_migraine_depression

Figure e-5: ApoA1 and S-HDL-FC ratio stratification plots for migraine and depression in NESDA and LUMINA

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs