Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

BACKGROUND: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Location-weighted versus Volume-weighted Mismatch at MRI for Response to Mechanical Thrombectomy in Acute Stroke.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7.

OBJECTIVE: Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. METHODS: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. RESULTS: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%). INTERPRETATION: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

Perfusion Imaging and Clinical Outcome in Acute Ischemic Stroke with Large Core.

OBJECTIVE: Mechanical thrombectomy (MT) is not recommended for acute stroke with large vessel occlusion (LVO) and a large volume of irreversibly injured tissue ("core"). Perfusion imaging may identify a subset of patients with large core who benefit from MT. METHODS: We compared two cohorts of LVO-related patients with large core (>50 ml on diffusion-weighted-imaging or CT-perfusion using RAPID), available perfusion imaging, and treated within 6 hours from onset by either MT + Best Medical Management (BMM) in one prospective study, or BMM alone in the pre-MT era from a prospective registry. Primary outcome was 90-day modified Rankin Scale ≤2. We searched for an interaction between treatment group and amount of penumbra as estimated by the mismatch ratio (MMRatio = critical hypoperfusion/core volume). RESULTS: Overall, 107 patients were included (56 MT + BMM and 51 BMM): Mean age was 68 ± 15 years, median core volume 99 ml (IQR: 72-131) and MMRatio 1.4 (IQR: 1.0-1.9). Baseline clinical and radiological variables were similar between the two groups, except for a higher intravenous thrombolysis rate in the BMM group. The MMRatio strongly modified the clinical outcome following MT (pinteraction < 0.001 for continuous MMRatio); MT was associated with a higher rate of good outcome in patients with, but not in those without, MMRatio>1.2 (adjusted OR [95% CI] = 6.8 [1.7-27.0] vs 0.7 [0.1-6.2], respectively). Similar findings were present for MMRatio ≥1.8 in the subgroup with core ≥70 ml. Parenchymal hemorrhage on follow-up imaging was more frequent in the MT + BMM group regardless of the MMRatio. INTERPRETATION: Perfusion imaging may help select which patients with large core should be considered for MT. Randomized studies are warranted. ANN NEUROL 2021;90:417-427.

Diagnostic utility of T2*-weighted GRE in migraine with aura attack. The cortical veins sign.

OBJECTIVE: To evaluate the frequency, distribution, and clinical associations of the dilated appearance of cerebral cortical veins, termed cortical veins sign on T2*-weighted gradient recalled-echo (T2*-GRE) in the acute setting of migraine with aura attack in adult patients. METHODS: We conducted a retrospective analysis of 60 consecutive patients admitted for acute neurological symptoms with a final diagnosis of migraine with aura (42%) or probable migraine with aura (58%) who underwent emergency brain magnetic resonance imaging and 60 non-migrainous control adults. The cortical veins sign was defined as a marked hypo-intensity and/or an apparent increased diameter of at least one cortical vein. We examined the prevalence, the spatial distribution, and the associations of cortical veins sign with clinical characteristics of migraine with aura. RESULTS: We detected the cortical veins sign in 25 patients (42%) with migraine with aura, compared to none in the control group (p < 0.0001). The spatial distribution of cortical veins sign was characterised by the predominantly bilateral and posterior location. Presence of cortical veins sign was associated with increased severity of aura (p = 0.05), and shorter delay to MRI (p = 0.02). CONCLUSION: In the setting of acute neurological symptoms, the presence of cortical veins sign is frequent in patients with migraine with aura and can be detected with good reliability. This imaging marker may help clinicians identify underlying migraine with aura.

Migraine and large artery atherosclerosis in young adults with ischemic stroke.

INTRODUCTION: Migraine is a risk factor for ischemic stroke, but the mechanisms of stroke associated with migraine are debated. The aim of this study was to investigate the association between migraine and large artery atherosclerosis (LAA) in young adults with ischemic stroke. METHODS: Patients aged between 18 and 54 years consecutively treated for first acute ischemic stroke in a university hospital stroke unit between January 2017 and December 2019 were included in this cross-sectional study. Migraine status was systematically assessed by the same headache specialist. Stenotic and nonstenotic LAA of extracranial and intracranial cerebral arteries were evaluated and graded using the ASCOD (atherosclerosis, small-vessel disease, cardiac pathology, other causes, dissection) criteria. We adjusted the association between migraine and LAA for traditional risk factors. RESULTS: A total of 415 patients were included (mean age [standard deviation], 43.9 [8.7] years; 258/415 [62.2%] men). Migraine with aura (MWA) was diagnosed in 76 patients, and migraine without aura (MWoA) in 68 patients. Patients with migraine had fewer traditional cardiovascular risk factors. Stenotic LAA (10/144 [6.9%] vs. 42/271 [15.5%]; p < 0.001) and LAA of any grade (35/144 [24.3%] vs. 138/271 [50.9%]; p < 0.001) were significantly less frequent in patients with migraine than in patients without migraine, respectively. Multivariable analysis adjusting for age, sex, overweight, tobacco use, hypertension, diabetes, and hyperlipidemia showed a negative association between migraine and LAA of any grade (odds ratio [OR] = 0.44, 95% confidence interval [CI: 0.254-0.78], p = 0.005). This negative association was found for both MWoA (OR = 0.42, 95% CI [0.204-0.88], p = 0.020) and MWA (OR = 0.47, 95% CI [0.228-0.96], p = 0.037) compared to no migraine. CONCLUSION: In this study of young adults with ischemic stroke, migraine had a negative association with LAA. This negative association was independent of traditional vascular risk factors and was found for both MWA and MWoA.

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

BACKGROUND: The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. OBJECTIVE: To determine whether rifaximin prevents overt HE after TIPS compared with placebo. DESIGN: Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). PARTICIPANTS: 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. INTERVENTION: Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. MEASUREMENTS: The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. RESULTS: An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. LIMITATIONS: The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. CONCLUSION: In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. PRIMARY FUNDING SOURCE: French Public Health Ministry.

ASCOD Phenotyping of Stroke With Anterior Large Vessel Occlusion Treated by Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Determining the mechanism of large vessel occlusion related acute ischemic stroke is of major importance to initiate a tailored secondary prevention strategy. We investigated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection (ASCOD) classification the distribution of the causes of large vessel occlusion related acute ischemic stroke treated by mechanical thrombectomy. METHODS: This was a predefined substudy of the FRAME (French Acute Multimodal Imaging to Select Patient for Mechanical Thrombectomy). Each patient underwent a systematic etiological workup including brain and vascular imaging, electrocardiogram monitoring lasting at least 24 hours and routine blood tests. Stroke mechanisms were systematically evaluated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection grading system at 3 months. We defined single potential cause by one cause graded 1 in a single domain, possible cause as a cause graded 1 or 2 regardless of overlap, and no identified cause without grade 1 nor 2 causes. RESULTS: A total of 215 patients (mean age 70±14; 50% male) were included. A single potential cause was identified in 148 (69%). Cardio-embolism (53%) was the most frequent, followed by atherosclerosis (9%), dissection (5%) and other causes (1%). Atrial fibrillation accounted for 88% of C1. Overlap between grade 1 causes was uncommon (3%). Possible causes were identified in 168 patients (83%) and 16 (7%) had no cause identified after the initial evaluation. CONCLUSIONS: Cardio-embolism, especially atrial fibrillation, was the major cause of large vessel occlusion related acute ischemic stroke. This finding emphasizes the yield of paroxysmal atrial fibrillation detection in those patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03045146.

Mismatch Profile Influences Outcome After Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is the recommended treatment for acute ischemic stroke caused by anterior circulation large vessel occlusion. However, despite a high rate of reperfusion, the clinical response to successful MT remains highly variable in the early time window where optimal imaging selection criteria have not been established. We hypothesize that the baseline perfusion imaging profile may help forecast the clinical response to MT in this setting. METHODS: We conducted a prospective multicenter cohort study of patients with large vessel occlusion-related acute ischemic stroke treated by MT within 6 hours. Treatment decisions and the modified Rankin Scale evaluation at 3 months were performed blinded to the results of baseline perfusion imaging. Study groups were defined a posteriori based on predefined imaging profiles: target mismatch (TMM; core volume <70 mL/mismatch ratio >1.2 and mismatch volume >10 mL) versus no TMM or mismatch (MM; mismatch ratio >1.2 and volume >10 mL) versus no MM. Functional recovery (modified Rankin Scale, 0-2) at 3 months was compared based on imaging profile at baseline and whether reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved. RESULTS: Two hundred eighteen patients (mean age, 71±15 years; median National Institutes of Health Stroke Scale score, 17 [interquartile range, 12-21]) were enrolled. Perfusion imaging profiles were 71% TMM and 82% MM. The rate of functional recovery was 54% overall. Both TMM and MM profiles were independently associated with a higher rate on functional recovery at 3 months Adjusted odds ratios were 3.3 (95% CI, 1.4-7.9) for TMM and 5.9 (95% CI, 1.8-19.6) for MM. Reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved in 86% and was more frequent in TMM and MM patients. Reperfusion was associated with a higher rate of functional recovery in MM and TMM patients but not among those with no MM. CONCLUSIONS: In this cohort study, about 80% of the patients with a large vessel occlusion-related acute ischemic stroke had evidence of penumbra, regardless of infarction volume. Perfusion imaging profiles predict the clinical response to MT.

Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial.

BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society.

Can tramadol really induce hyponatraemia? A pharmacovigilance study.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Evolution of medication consumption in a working environment in France: Results of the four waves of the "Drugs and Work" study (1986-2016).

OBJECTIVES: Previous studies in the working environment have underlined the high prevalence of drug consumption. The aim of this study was to present the main characteristics of this consumption in French workers and to identify changes from the 1986, 1996, 2006 and 2016 surveys. METHODS: The design was a repeated cross-sectional study in 1986, 1996, 2006 and 2016. At each wave, demographic and socio-professional characteristics, self-reported consumption of medications during the week before the occupational medical visit, and perceived difficult working conditions and extraprofessional problems were collected among a sample of workers. Factors associated with consumption of any drug and of main therapeutic classes were investigated through multivariate logistic regression models, using 2016 as the reference for investigating temporal trends. RESULTS: Prevalence of use of any drug was significantly higher in 2016, with marked changes observed in comparison with 1986: absolute decrease of psychotropic (-5.1%, p < 0.0001), antibiotics (-2.7%, p < 0.0001) and cardiovascular drug use (-3.8%, p < 0.0001), increase of analgesic use (+8.3%, p < 0.0001). Difficult working conditions, age and female gender were independently associated with analgesic drug use, and extraprofessional problems and female gender associated with psychotropic drug use. CONCLUSIONS: This analysis of self-reported drug use in the working environment illustrates the global patterns of medication use in a French active population over 3 decades. The favorable development in the level of consumption of psychotropic drugs should not underestimate the attention to be paid to the determinants of chronic consumption, or possible transfers to less stigmatized medications.

Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study.

OBJECTIVES: We aimed to investigate whether abatacept used in patients for RA was associated with an increased risk of reporting overall cancer and specific cancers, including breast, lung, lymphoma, melanoma and non-melanoma skin cancer when compared with other biologic DMARDs (bDMARDs). METHODS: We performed an observational study within VigiBase, the World Health Organization's global database of individual case safety reports, from 2007 to 2017 to compare the cases of cancer reported in RA patients exposed to abatacept with those reported in RA patients exposed to other bDMARDs. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CIs of the exposure odds among spontaneous reporting of cancers to the exposure odds among other reported adverse effects. RESULTS: We identified 15 846 adverse effects reported in RA patients who received abatacept and 290 568 adverse effects reported in RA patients treated with other bDMARDs. Compared with other bDMARDs, the use of abatacept was not associated with an increased risk of reporting cancer overall [ROR 0.98 (95% CI 0.91, 1.05)]. Analyses by specific cancer sites showed a significantly increased ROR for melanoma [1.58 (95% CI 1.17, 2.08)], but not for other specific cancer sites. CONCLUSION: Compared with other bDMARDs, exposure to abatacept in RA patients was only significantly associated with an increased risk of reporting melanoma. This increased risk is consistent with the properties of abatacept (CTLA-4 agonist) since it has an opposite action than ipilimumab, an antibody that blocks CTLA-4 and is approved for the treatment of malignant melanoma. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT03980639.

Parkinsonism associated with gabapentinoid drugs: A pharmacoepidemiologic study.

BACKGROUND: Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin. METHODS: A disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism. RESULTS: Among 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine. CONCLUSIONS: This study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.

Role of serotonin and norepinephrine transporters in antidepressant-induced arterial hypertension: a pharmacoepidemiological-pharmacodynamic study.

PURPOSE: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH. METHODS: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. RESULTS: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x - 2.55, R2 = 0.68, Pearson coefficient correlation = 0.82). CONCLUSION: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Drug-induced tics: An observational postmarketing study.

OBJECTIVES: While drug-induced tics have been described, in particular with neuroleptics, psychostimulants, or anti-epileptics, the strength and the direction of these associations are still debated. The aim of this study was to investigate the association between tics and drug exposure through a two-step analysis in two pharmacovigilance databases. METHODS: We first performed a descriptive clinical analysis of cases registered in the French pharmacovigilance database (FPVD) from January 1985 to December 2018. We then performed a disproportionality analysis in VigiBase®, the WHO pharmacovigilance database, from January 1967 to June 2019, through the calculation of reporting odds ratio (ROR). RESULTS: The drugs most frequently associated with tics in the FPVD were methylphenidate, lamotrigine, montelukast, tramadol, mirtazapine, venlafaxine, aripiprazole, and risperidone. In VigiBase®, we found a significant ROR with methylphenidate (ROR 37.54, 95% confidence interval [CI] 34.81-40.48), montelukast (ROR 12.18, 95% CI 10.29-14.41), aripiprazole (ROR 7.40, 95% CI 6.35-8.62), risperidone (ROR 4.40, 95% CI 3.72-5.21), and venlafaxine (ROR 1.52, 95% CI 1.14-2.03). CONCLUSION: This postmarketing study confirmed a potential harmful association with methylphenidate (the highest association, as expected), aripiprazole, risperidone, lamotrigine, and venlafaxine and, interestingly, found a strong signal with montelukast, which, to our knowledge, had never been published before.

IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors.

The oncofetal IGF2 mRNA binding proteins (IGF2BPs) are upregulated in most cancers but their paralogue-specific roles in tumor cells remain poorly understood. In a panel of five cancer-derived cell lines, IGF2BP1 shows highly conserved oncogenic potential. Consistently, the deletion of IGF2BP1 impairs the growth and metastasis of ovarian cancer-derived cells in nude mice. Gene expression analyses in ovarian cancer-derived cells reveal that the knockdown of IGF2BPs is associated with the downregulation of mRNAs that are prone to miRNA regulation. All three IGF2BPs preferentially associate upstream of miRNA binding sites (MBSs) in the 3'UTR of mRNAs. The downregulation of mRNAs co-regulated by miRNAs and IGF2BP1 is abrogated at low miRNA abundance or when miRNAs are depleted. IGF2BP1 associates with these target mRNAs in RISC-free complexes and its deletion enhances their association with AGO2. The knockdown of most miRNA-regulated target mRNAs of IGF2BP1 impairs tumor cell properties. In four primary cancers, elevated synthesis of these target mRNAs is largely associated with upregulated IGF2BP1 mRNA levels. In ovarian cancer, the enhanced expression of IGF2BP1 and most of its miRNA-controlled target mRNAs is associated with poor prognosis. In conclusion, these findings indicate that IGF2BP1 enhances an aggressive tumor cell phenotype by antagonizing miRNA-impaired gene expression.

Risk of Intracerebral Hemorrhage and Mortality After Convexity Subarachnoid Hemorrhage in Cerebral Amyloid Angiopathy.

Background and Purpose- Convexity subarachnoid hemorrhage (cSAH) is an increasingly recognized presentation of cerebral amyloid angiopathy (CAA), usually revealed by transient symptoms, but data on its outcome are limited. We compared the risk of future intracerebral hemorrhage (ICH), cSAH, and death in patients with CAA after cSAH and after lobar ICH. Methods- Consecutive patients with probable CAA, based on the Boston criteria, presenting with cSAH (CAA-cSAH) or lobar ICH (CAA-ICH) were included. We obtained baseline clinical and magnetic resonance imaging data and follow-up information. Univariable and multivariable analyses were used to compare incidence rate for symptomatic ICH, symptomatic cSAH, and late-death (beyond 30 days) between patients with CAA-cSAH and CAA-ICH. Results- Among 105 patients (mean age, 76.7±7.5 years) enrolled, 44 participants presented with CAA-cSAH and 61 with CAA-ICH. The median follow-up was 22.2 months (interquartile range, 12.6-34.4). The symptomatic ICH rate (per person-year) was 10.5% (95% CI, 5.6-19.4) in patients with CAA-cSAH compared with 8.5% (95% CI, 4.4-16.4) in those with CAA-ICH (adjusted hazard ratio, 1.05; 95% CI, 0.32-3.43). The annual incidence rates of symptomatic cSAH (9.9% versus 3.8%; adjusted hazard ratio, 1.77; 95% CI, 0.43-7.28) and death (9.5% versus 17.8%; adjusted hazard ratio, 0.56; 95% CI, 0.22-1.43) were not significantly different between patients with CAA-cSAH and those with CAA-ICH. Conclusions- Patients with CAA-related cSAH have a poor outcome, with similar high risk of future ICH and long-term mortality than CAA patients after lobar ICH. Our findings may have important prognostic implication and guide management of patients with cSAH in CAA.

Predictive Value of Susceptibility Vessel Sign for Arterial Recanalization and Clinical Improvement in Ischemic Stroke.

Background and Purpose- Our goal was to evaluate whether the presence of a low signal intensity known as susceptibility vessel sign (SVS) on T2*-gradient echo imaging sequence was predictive of arterial recanalization and the early clinical improvement after mechanical thrombectomy. Methods- This observational study was based on a prospective database of acute ischemic strokes treated by mechanical thrombectomy. Inclusion criteria were patients with acute anterior ischemic stroke, diagnosed by magnetic resonance imaging, including a T2*-gradient echo imaging sequence, and treated by mechanical thrombectomy. Two independent readers assessed the presence of an SVS. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction score of 2b-3 after mechanical thrombectomy. Early clinical improvement was estimated by the difference between the baseline National Institutes of Health Stroke Scale and the National Institutes of Health Stroke Scale on day 1 after treatment Results- The SVS was detected in 137 (76%) out of 180 patients. The kappa interrater agreement was 0.71 with a 95% CI of 0.59 to 0.82. Successful recanalization was associated with an SVS+ with odds ratio, 2.48; 95% CI, 1.05-5.74; P=0.03. The early clinical improvement was better in patients with an SVS+ (median, -6; interquartile range, -11 to 0) compared with SVS- patients (median, -1; interquartile range, -10 to 3) with P=0.01. Conclusions- The visualization of SVS is a reliable and easily accessible predictive factor of recanalization success and early clinical improvement.