Acute astrocytic reaction is associated with 3-month functional outcome after stroke treated with endovascular therapy.

INTRODUCTION: More than 50% of large vessel occlusion (LVO) acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT) remain severely disabled at 3 months. We hypothesized that acute astrocytic inflammatory response may play a pivotal role in post-AIS brain changes associated with poor functional outcome. We proposed to evaluate the level of YKL-40, a glycoprotein mainly released by reactive astrocytes. PATIENTS AND METHODS: A monocentric prospective cohort study was conducted on consecutive LVO AIS patients treated with EVT. Three blood samples (before, within 1 and 24-hour post-EVT) were collected to measure plasma YKL-40 concentrations. Functional outcome was assessed according to the modified Rankin Scale (mRS) score at 3 months. RESULTS: Between 2016 and 2020, 120 patients were included. The plasma concentration of YKL-40 before EVT was statistically and independently associated with 3-month worse functional outcome (adjusted cOR, 1.59; 95% CI [1.05-2.44], p = 0.027) but not the two following samples 1-hour and 24-hour post-EVT. Accordingly, we found that excellent functional outcome was associated with a lower level of YKL-40 before and within 1 h after EVT (p = 0.005 and p = 0.003, respectively) but not when measured 24 h after EVT (p = 0.2). DISCUSSION AND CONCLUSION: This study suggests that the astrocytic reaction to acute brain hypoxia, especially before recanalization, is associated with worse functional outcome. Such early biomarker of the astrocytic response in AIS may optimize individualized care in the future. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02900833.

Psychomotor retardation: What about the partial responders to magnetic transcranial stimulation in treatment resistant depression ?

OBJECTIVE: Psychomotor retardation is a core clinical component of Major Depressive Disorder responsible for disability and is known as a treatment response marker of biological treatments for depression. Our objective was to describe cognitive and motoric measures changes during a treatment by repetitive Transcranial Magnetic Stimulation (rTMS) within the THETAD-DEP trial for treatment-resistant depression (TRD), and compare those performances at the end of treatment and one month after between responders (>50% improvement on MADRS score), partial responders (25-50%) and non-reponders (no clinically relevant improvement). Our secondary aim was to investigate baseline psychomotor performances associated with non-response and response even partial. METHODS: Fifty-four patients with treatment-resistant unipolar depression and treated by either high frequency 10 Hz rTMS or iTBS for 4 weeks (20 sessions) underwent assessment including French Retardation Rating Scale for Depression (ERD), Verbal Fluency test, and Trail Making Test A. before, just after treatment and one month later. RESULTS: 20 patients were responders (R, 21 partial responders (PR) and 13 non-responders (NR). rTMS treatment improved psychomotor performances in the R and PR groups unlike NR patients whose psychomotor performance was not enhanced by treatment. At baseline, participants, later identified as partial responders, showed significantly higher performances than non-responders. CONCLUSION: Higher cognitivo-motor performances at baseline may be associated with clinical improvement after rTMS treatment. This work highlights the value of objective psychomotor testing for the identification of rTMS responders and partial responders, and thus may be useful for patient selection and protocol individualization such as treatment continuation for early partial responders.

The localization, origin, and impact of platelets in the tumor microenvironment are tumor type-dependent.

BACKGROUND: How platelets interact with and influence the tumor microenvironment (TME) remains poorly characterized. METHODS: We compared the presence and participation of platelets in the TME of two tumors characterized by highly different TME, PyMT AT-3 mammary tumors and B16F1 melanoma. RESULTS: We show that whereas firmly adherent platelets continuously line tumor vessels of both AT-3 and B16F1 tumors, abundant extravascular stromal clusters of platelets from thrombopoietin-independent origin were present only in AT-3 mammary tumors. We further show that platelets influence the angiogenic and inflammatory profiles of AT-3 and B16F1 tumors, though with very different outcomes according to tumor type. Whereas thrombocytopenia increased bleeding in both tumor types, it further caused severe endothelial degeneration associated with massive vascular leakage, tumor swelling, and increased infiltration of cytotoxic cells, only in AT-3 tumors. CONCLUSIONS: These results indicate that while platelets are integral components of solid tumors, their localization and origin in the TME, as well as their impact on its shaping, are tumor type-dependent.

Periodontitis in ischemic stroke: impact of Porphyromonas gingivalis on thrombus composition and ischemic stroke outcomes.

Background: Periodontitis is associated with an increased risk of ischemic stroke, but the mechanisms underlying this association remain unclear. Objectives: Our objective was to determine whether Porphyromonas gingivalis (Pg), a periodontal bacterium, could be detected within thrombus aspirates, modify thrombus composition, and endovascular therapy responses. Methods: The presence of Pg gingipain in 175 consecutive thrombi from patients with large vessel occlusion stroke enrolled in the multicenter research cohort compoCLOT was investigated by immunostaining. Thrombus blood cell composition according to gingipain status was analyzed in a subset of 63 patients. Results: Pg gingipain immunostaining was positive in 33.7% of thrombi (95% CI, 26.7%-40.8%). The percentage of near to complete reperfusion (modified Thrombolysis in Cerebral Infarction Score 2c/3) at the end of the procedure was lower in the Pgpos group than the Pgneg group (39.0% vs 57.8% respectively; adjusted odds ratio, 0.38; 95% CI, 0.19-0.77). At 3 months, 35.7% of patients in the Pgpos group had a favorable neurological outcome vs 49.5% in the Pgneg group (odds ratio, 0.65; 95% CI, 0.30-1.40). Quantitative analysis of a subset of 63 thrombi showed that neutrophil elastase content was significantly (P < .05) higher in Pgpos thrombi than in Pgneg thrombi. Conclusion: Our results indicate that intrathrombus Pg gingipain is associated with increased neutrophil content and resistance to endovascular therapy.

Exacerbation of thromboinflammation by JAK2V617F mutation worsens the prognosis of cerebral venous sinus thrombosis.

ABSTRACT: Cerebral venous sinus thrombosis (CVST) is an uncommon venous thromboembolic event accounting for <1% of strokes resulting in brain parenchymal injuries. JAK2V617F mutation, the most frequent driving mutation of myeloproliferative neoplasms, has been reported to be associated with worse clinical outcomes in patients with CVST. We investigated whether hematopoietic JAK2V617F expression predisposes to specific pathophysiological processes and/or worse prognosis after CVST. Using an in vivo mouse model of CVST, we analyzed clinical, biological, and imaging outcomes in mice with hematopoietic-restricted Jak2V617F expression, compared with wild-type Jak2 mice. In parallel, we studied a human cohort of JAK2V617F-positive or -negative CVST. Early after CVST, mice with hematopoietic Jak2V617F expression had increased adhesion of platelets and neutrophils in cerebral veins located in the vicinity of CVST. On day 1, Jak2V617F mice had a worse outcome characterized by significantly more frequent and severe intracranial hemorrhages (ICHs) and higher mortality rates. Peripheral neutrophil activation was enhanced, as indicated by higher circulating platelet-neutrophil aggregates, upregulated CD11b expression, and higher myeloperoxydase plasma level. Concurrently, immunohistological and brain homogenate analysis showed higher neutrophil infiltration and increased blood-brain barrier disruption. Similarly, patients with JAK2V617F-positive CVST tended to present higher thrombotic burden and had significantly higher systemic immune-inflammation index, a systemic thromboinflammatory marker, than patients who were JAK2V617F-negative. In mice with CVST, our study corroborates that Jak2V617F mutation leads to a specific pattern including increased thrombotic burden, ICH, and mortality. The exacerbated thromboinflammatory response, observed both in mice and patients positive for JAK2V617F, could contribute to hemorrhagic complications.

Neutrophil activation in patients treated with endovascular therapy is associated with unfavorable outcomes and mitigated by intravenous thrombolysis.

BACKGROUND: Accumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT. METHODS: A single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3-6 at 3 months. RESULTS: Between 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR -2.1-150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline -0.8 ng/mL (IQR -7.6-6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes. CONCLUSIONS: A peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation.

Effective neutrophil migration to sites of inflammation is crucial for host immunity. A coordinated cascade of steps allows intravascular leukocytes to counteract the shear stress, transmigrate through the endothelial layer, and move toward the extravascular, static environment. Those events are tightly orchestrated by integrins, but, while the molecular mechanisms leading to their activation have been characterized, the regulatory pathways promoting their detachment remain elusive. In light of this, it has long been known that platelet-endothelial cell adhesion molecule (Pecam1, also known as CD31) deficiency blocks leukocyte transmigration at the level of the outer vessel wall, yet the associated cellular defects are controversial. In this study, we combined an unbiased proteomic study with in vitro and in vivo single-cell tracking in mice to study the dynamics and role of CD31 during neutrophil migration. We found that CD31 localizes to the uropod of migrating neutrophils along with closed ß2-integrin and is required for essential neutrophil actin/integrin polarization. Accordingly, the uropod of Pecam1-/- neutrophils is unable to detach from the extracellular matrix, while antagonizing integrin binding to extracellular matrix components rescues this in vivo migratory defect. Conversely, we showed that sustaining CD31 co-signaling actively favors uropod detachment and effective migration of extravasated neutrophils to sites of inflammation in vivo. Altogether, our results suggest that CD31 acts as a molecular rheostat controlling integrin-mediated adhesion at the uropod of egressed neutrophils, thereby triggering their detachment from the outer vessel wall to reach the inflammatory sites.

Dynamics of Depressive and Psychomotor Symptoms During Electroconvulsive Therapy in Older Depressive Patients: A Case Series.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for patients experiencing a major depressive episode, especially older ones. Identification of specific responses within early ECT sessions remains an issue of debate, however. Hence, this pilot study prospectively examined the outcome in terms of depressive signs, symptom by symptom, throughout a course of ECT, concentrating particularly on psychomotor retardation symptoms. METHODS: Nine patients were clinically evaluated several times during the ECT course, before the first session and then weekly (over 3-6 weeks, according to their evolution), by completing the Montgomery-Åsberg Depression Rating Scale (MADRS), the Mini-Mental State Examination test, and the French Retardation Rating Scale for Depression for assessing the severity of psychomotor retardation. RESULTS: Nonparametric Friedman tests showed significant positive changes in mood disorders during ECT in older depressive patients (mean, -27.3% of initial MADRS total score). Fast improvement in French Retardation Rating Scale for Depression score was observed at t1 (ie, after 3-4 ECT sessions), whereas a slightly delayed improvement in the MADRS scores was found at t2 (ie, after 5-6 ECT sessions). Moreover, the scores for items linked to the motor component of psychomotor retardation (eg, gait, postural control, fatigability) were the first to significantly decrease during the first 2 weeks of the ECT course compared with the cognitive component. CONCLUSIONS: Interestingly, participants' concentration on daily functional activities, their interest and fatigability, and their reported state of sadness were the first to progress, representing possible precursor signs of positive patient outcomes after ECT.

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP).

BACKGROUND: Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS. OBJECTIVES/HYPOTHESIS: The aim of our study was to compare the efficacy of 10 Hz rTMS and iTBS in treatment-resistant unipolar depression on response rates (50% decrease of MADRS scores at one month from baseline) and change in quality of life during a 6-month follow-up. In addition, we investigated whether some clinical features at baseline were associated with the response in the different groups. METHOD: Sixty patients were randomized in a double-blind, controlled study at the University Hospital Center of Nantes, and received 20 sessions of either rTMS or iTBS applied to the left dorsolateral prefrontal cortex targeted by neuronavigation. Statistical analysis used Fischer's exact test and Chi-square test as appropriate, linear mixed model, and logistic regression (occurrence of depressive relapse and factors associated with the therapeutic response). RESULTS: Included patients showed in mean more than 3 antidepressants trials. Response rates were 36.7% and 33.3%, and remission rates were 18.5% and 14.8%, in the iTBS and 10 Hz rTMS groups respectively. Both groups showed a similar significant reduction in depression scores and quality of life improvement at 6 months. We did not find any clinical predictive factor of therapeutic response in this sample. CONCLUSION: Our study suggests the clinical interest of iTBS stimulation (which is more time saving and cost-effective as conventional rTMS) to provide long-lasting improvement of depression and quality of life in highly resistant unipolar depression.

Impact of COVID-19 on thrombus composition and response to thrombolysis: Insights from a monocentric cohort population of COVID-19 patients with acute ischemic stroke.

BACKGROUND: Resistance to fibrinolysis, levels of procoagulant/antifibrinolytic neutrophil extracellular traps (NETs), and the severity of acute ischemic stroke (AIS) are increased by COVID-19. Whether NETs are components of AIS thrombi from COVID-19 patients and whether COVID-19 impacts the susceptibility of these thrombi to thrombolytic treatments remain unknown, however. OBJECTIVES: We aimed to characterize AIS thrombi from COVID-19 patients by immunohistology and to compare their response to thrombolysis to that of AIS thrombi from non-COVID-19 patients. PATIENTS/METHODS: For this monocentric cohort study, 14 thrombi from COVID-19 AIS patients and 16 thrombi from non-COVID-19 patients, all recovered by endovascular therapy, were analyzed by immunohistology or subjected to ex vivo thrombolysis by tissue-type plasminogen (tPA)/plasminogen. RESULTS: COVID-19 AIS thrombi were rich in neutrophils and contained NETs, but not spike protein. Thrombolysis assays revealed a mean resistance profile to tPA/plasminogen of COVID-19 AIS thrombi similar to that of non-COVID-19 AIS thrombi. The addition of DNase 1 successfully improved thrombolysis by potentiating fibrinolysis irrespective of COVID-19 status. Levels of neutrophil, NETs, and platelet markers in lysis supernatants were comparable between AIS thrombi from non-COVID-19 and COVID-19 patients. CONCLUSIONS: These results show that COVID-19 does not impact NETs content or worsen fibrinolysis resistance of AIS thrombi, a therapeutic hurdle that could be overcome by DNase 1 even in the context of SARS-CoV-2 infection.

Glenzocimab does not impact glycoprotein VI-dependent inflammatory haemostasis.

Not available.

Modeling Large Vessel Occlusion Stroke for the Evaluation of Endovascular Therapy According to Thrombus Composition.

More than 40% of endovascular therapy (EVT) fail to achieve complete reperfusion of the territory of the occluded artery in patients with acute ischemic stroke (AIS). Understanding factors influencing EVT could help overcome its limitations. Our objective was to study the impact of thrombus cell composition on EVT procedures, using a simulation system for modeling thrombus-induced large vessel occlusion (LVO) in flow conditions. In an open comparative trial, we analyzed the behavior of size-standardized platelet-rich and red blood cells (RBC)-rich thrombi during simulated stent retriever-mediated EVT procedures. Sixteen simulated EVT procedures were performed (8 RBC- vs. 8 platelet-rich thrombi). Platelet-rich thrombi were associated with a higher number of stent retriever passes (p = 0.03) and a longer procedure duration (p = 0.02) compared to RBC-rich thrombi. Conversely, RBC-rich thrombi released more embolic fragments than platelet-rich thrombi (p = 0.004). Both RBC-rich and platelet-rich thrombi underwent drastic compaction after being injected into the in vitro circulation model, and histologic analyses showed that these EVT-retrieved thrombi displayed features comparable to those previously observed in thrombi from patients with AIS patients having LVO, including a marked structural dichotomy between RBC- and platelet-rich areas. Our results show that the injection of in vitro-produced thrombi in artificial cerebrovascular arterial networks is suitable for testing recanalization efficacy and the risk of embolization of EVT devices and strategies in association with thrombus cell composition.

Does the transcranial direct current stimulation improve dual-task postural control in young healthy adults?

Some studies have suggested that postural balance improved after a single session of transcranial direct current stimulation (tDCS), whereas others have found minimal, if any, effects on postural performance. To address the issue of replication in tDCS studies, we re-tested the anodal tDCS effects of left dorsolateral prefrontal cortex while performing a dual-task by increasing the attentional demands associated with more challenging proprioceptive conditions. Twenty-four young adults (mean age: 21.3 ± 1.2 years) were randomly divided into two groups (a "real tDCS" vs. a "sham tDCS" group) were asked to maintain a quiet stance on a force platform. Eight trials were conducted, with eyes open and eyes closed, standing on a firm and foam surface and performing a simple and dual-task (backward counting). The postural performance was assessed by various centre-of-pressure parameters before and immediately after a 20-min tDCS session. No main effect of group and no interaction considering this factor were observed, regardless of the centre-of-pressure variables (all p values > 0.1). No evidence of a more efficient postural control emerged after a tDCS session. Beyond promising research on tDCS to maximize cognitive and behavioural enhancement, the current results indicate that caution needs to be taken when drawing firm conclusions, at least in young healthy adults.

DNA Content in Ischemic Stroke Thrombi Can Help Identify Cardioembolic Strokes Among Strokes of Undetermined Cause.

BACKGROUND AND PURPOSE: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. METHODS: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). RESULTS: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P<0.001) and poorer in GPVI (0.104 versus 0.117 ng/mg, P=0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63-0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. CONCLUSIONS: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03268668.

Protective Effect of ApoA1 (Apolipoprotein A1)-Milano in a Rat Model of Large Vessel Occlusion Stroke.

Background and Purpose- Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods- In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results- The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline (P=0.034 and P=0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation (P=0.001 and P=0.02, respectively). Conclusions- ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview- An online visual overview is available for this article.

Translation and Cultural Adaptation of PROactive Instruments for COPD in French and Influence of Weather and Pollution on Its Difficulty Score.

Introduction: The recently developed daily and clinical visit PROactive physical activity in COPD (PPAC) instruments are hybrid tools to objectively quantify the level of physical activity and the difficulties experienced in everyday life. Our aim was to translate these instruments for the French-speaking chronic obstructive pulmonary disease (COPD) community worldwide and evaluate the influence of weather and pollution on difficulty score. Methods: The translation procedure was conducted following the guidelines for cross-cultural adaptation process. The translated clinical visit (C-PPAC) was tested among COPD patients in France. A retest was conducted after an interval of at least 2 weeks. The C-PPAC difficulty score was then tested to see how sensitive it was to the influence of weather and outdoor pollution. Results: One hundred and seventeen COPD patients (age 65±9 years; FEV1: 51±20%) from 9 regions in France were included. The French version of C-PPAC was found comprehensible by the patients with an average score of 4.8/5 on a Likert-scale. It showed good internal consistency with Cronbach's α>0.90 and a good test retest reliability with an intraclass correlation coefficient of ≥0.80. The difficulty score was negatively correlated with duration of daylight (ρ=-0.266; p<0.01) and influenced by the intensity of rainfall (light vs. heavy rainfall: 68±16 vs. 76±14 respectively, p=0.045). The score was lower in patients receiving long term oxygen therapy (60±15 vs. 71±15, p<0.01), but not correlated with the pollution indices. Conclusion: The French versions of the questionnaires of the PPAC instruments are accepted and comprehensible to COPD patients. The difficulty score of C-PPAC is sensitive to duration of daylight and rainfall. Such weather factors must be taken into consideration when evaluating the physical activity behavior using these tools in COPD.

Cost-utility analysis of transcranial direct current stimulation (tDCS) in non-treatment-resistant depression: the DISCO randomised controlled study protocol.

INTRODUCTION: Depression is among the most widespread psychiatric disorders in France. Psychiatric disorders are associated with considerable social costs, amounting to €22.6 billion for treatment and psychotropic medication in 2011. Treatment as usual (TAU), mainly consisting of pharmacotherapy and psychotherapy, is effective for only a third of patients and in most cases fails to prevent treatment resistance and chronicity. Transcranial direct current stimulation (tDCS) consists in a non-invasive and painless application of low-intensity electric current to the cerebral cortex through the scalp. Having proved effective in depressed patients, it could be used in combination with TAU to great advantage. The objective is to compare, for the first time ever, the cost-utility of tDCS-TAU and of TAU alone for the treatment of a depressive episode that has been refractory to one or two drug treatments. METHODS AND ANALYSIS: This paper, based on the DISCO study protocol, focuses on the design of a prospective, randomised, controlled, open-label multicentre economic study to be conducted in France. It will include 214 patients with unipolar or bipolar depression, assigning them to two parallel arms: group A (tDCS-TAU) and group B (TAU alone). The primary outcome is the incremental cost-effectiveness ratio, that is, the ratio of the difference in cost between each strategy to the difference in their effects. Their effects will be expressed as numbers of quality-adjusted life-years, determined through administration of the EuroQol Five-Dimension questionnaire over a 12-month period to patients (EQ-5D-5L). Expected benefits are the reduction of treatment resistance and suicidal ideation as well as social and professional costs of depression. Should depression-related costs fall significantly, tDCS might be considered an efficient treatment for depression. ETHICS AND DISSEMINATION: This protocol has been approved by a French ethics committee, the CPP--Est IV (Comité de Protection des Personnes-Strasbourg). Data are to be published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: RCB 2018-A00474-51; NCT03758105.

Combined Measures of Psychomotor and Cognitive Alterations as a Potential Hallmark for Bipolar Depression.

OBJECTIVE: The current study aimed to examine whether specific features of psychomotor retardation (PMR) and cognitive functioning established different profiles in unipolar (UD) and bipolar depression (BD). METHODS: Two groups of age-matched patients with UD (n=54) and BD (n=20) completed the Montgomery-Asberg Depression Rating Scale (MADRS/60), the Montreal Cognitive Assessment (MoCA/30), and the Salpêtrière Retardation Rating Scale (SRRS/60). We analyzed the group effect and then performed intra-group analyses. RESULTS: The BD patients have higher SRRS score, and lower MoCA score than UD despite no difference on the level of depression between UD and BD. Our results show that PMR can be predicted by the level of depression in UD and by the cognitive alteration and onset of disease in BD. CONCLUSION: PMR is a relevant marker of depression. Our results highlight the importance of concomitant evaluation of psychomotor and cognitive functions in the distinction of UD and BD symptoms.

Acute ischemic stroke thrombi have an outer shell that impairs fibrinolysis.

OBJECTIVES: Thrombi responsible for large vessel occlusion (LVO) in the setting of acute ischemic stroke (AIS) are characterized by a low recanalization rate after IV thrombolysis. To test whether AIS thrombi have inherent common features that limit their susceptibility to thrombolysis, we analyzed the composition and ultrastructural organization of AIS thrombi causing LVO. METHODS: A total of 199 endovascular thrombectomy-retrieved thrombi were analyzed by immunohistology and scanning electron microscopy (SEM) and subjected to ex vivo thrombolysis assay. The relationship between thrombus organization and thrombolysis resistance was further investigated in vitro using thrombus produced by recalcification of citrated whole blood. RESULTS: SEM and immunohistology analyses revealed that, although AIS thrombus composition and organization was highly heterogeneous, AIS thrombi shared a common remarkable structural feature in the form of an outer shell made of densely compacted thrombus components including fibrin, von Willebrand factor, and aggregated platelets. In vitro thrombosis experiments using human blood indicated that platelets were essential to the formation of the thrombus outer shell. Finally, in both AIS and in vitro thrombi, the thrombus outer shell showed a decreased susceptibility to tissue plasminogen activator-mediated thrombolysis as compared to the thrombus inner core. INTERPRETATION: Irrespective of their etiology and despite their heterogeneity, intracranial thrombi causing LVO have a core shell structure that influences their susceptibility to thrombolysis.

Mitigation of monocyte driven thrombosis on cobalt chrome surfaces in contact with whole blood by thin film polar/hydrophobic/ionic polyurethane coatings.

Monocytes are active at the crossroads between inflammation and coagulation processes since they can secrete pro-inflammatory cytokines and express tissue factor (TF), a major initiator of coagulation. Cobalt-chrome (CoCr), a metal alloy, used as a biomaterial for vascular stents, has been shown to be potentially pro-thrombotic and pro-inflammatory. Research work with a polymer from a family of degradable-polar hydrophobic ionic polyurethanes (D-PHI), called HHHI, has been shown to exhibit anti-inflammatory responses from human monocytes. We have generated multifunctional polyurethane thin films (MPTF) based on the HHHI chemistry, as a thin coating for CoCr and have evaluated the reactivity of blood with MPTF-coated CoCr. The results showed that the coating of CoCr with MPTF derived from HHHI prevents thrombin generation, reduces coagulation activation, and suppresses fibrin formation in whole blood. Activation of monocytes was also suppressed at the surface of MPTF-coated CoCr and specifically the decrease in thrombin generation was accompanied by a significant decrease in TF and pro-inflammatory cytokine levels. Mass spectroscopy of the adsorbed proteins showed lower levels of fibrinogen, fibronectin and complement C3, C4, and C8 when compared to CoCr. We can conclude that MPTFs reduce the pro-thrombotic and pro-inflammatory phenotype of monocytes and macrophages on CoCr, and prevent clotting in whole blood.