Anticoagulation during extracorporeal membrane oxygenation: A narrative review.

Extracorporeal Membrane Oxygenation (ECMO) is a technology that offers organ support for critically ill patients with respiratory and/or cardiac failure. Despite improvements in recent years in technology and the biocompatibility of circuits, patients on ECMO remain at high risk of hematologic complications, such as bleeding or thrombosis. Anticoagulation is required in most cases to limit the risk of clotting, but questions persist regarding the optimal anticoagulation strategy. More precisely, there is still debate around the best anticoagulation agent and monitoring tools as well as on the transfusion thresholds and appropriate corrective measures when faced with complications. This narrative review provides an overview of hemostasis on ECMO and the impact of circuit size and coating. The benefits and downsides of unfractionated heparin (UHF) and Direct Thrombin Inhibitors (DTIs) as anticoagulation agents are reviewed. Finally, commonly available coagulation tests (activated clotting time, activated partial thrombin time, anti-Xa, and viscoelastic tests) and their limitations are addressed. In conclusion, future research is needed to determine the best anticoagulation strategy for patients on ECMO.

Symptom burden guiding invasive electrophysiological study in paroxysmal supraventricular tachycardia: The believe SVT registry.

BACKGROUND AND OBJECTIVE: Patients with palpitations clinically suggestive of paroxysmal supraventricular tachycardia (PSVT) are often managed conservatively until ECG-documentation of the tachycardia, leading to high impact on life quality and healthcare resource utilization. We evaluated results of electrophysiological study (EPS), and ablation when appropriate, among these patients, with special focus on gender differences in management. METHODS: BELIEVE SVT is a European multicenter, retrospective registry in tertiary hospitals performing EPS in patients with palpitations, without ECG-documentation of tachycardia or preexcitation, and considered highly suggestive of PSVT by a cardiologist or cardiac electrophysiologist. We analyzed clinical characteristics, results of EPS and ablation, complications, and clinical outcomes during follow-up. RESULTS: Six-hundred eighty patients from 20 centers were included. EPS showed sustained tachycardia in 60.9% of patients, and substrate potentially enabling AVNRT in 14.7%. No major/permanent complications occurred. Minor/transient complications were reported in 0.84% of patients undergoing diagnostic-only EPS and 1.8% when followed by ablation. During a 3.4-year follow-up, 76.2% of patients remained free of palpitations recurrence. Ablation (OR: 0.34, P < .01) and male gender (OR: 0.58, P = .01) predicted no recurrence. Despite a higher female proportion among patients with recurrence, (77.2% vs 63.5% among those asymptomatic during follow-up, P < .01), 73% of women in this study reported no recurrence of palpitations after EPS. CONCLUSIONS: EPS and ablation are safe and effective in preventing recurrence of nondocumented palpitations clinically suggestive of PSVT. Despite a lower efficacy, this strategy is also highly effective among women and warrants no gender differences in management.

Nucleated red blood cells as a biomarker for mortality in infants and neonates requiring veno-arterial extracorporeal membrane oxygenation for cardiac disease.

INTRODUCTION: Nucleated red blood cells (NRBC) are rare in the peripheral circulation of healthy individuals and their presence have been associated with mortality in adults and very low birth weight newborns, however, its value as a biomarker for mortality in infants requiring veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) has yet to be studied. We sought to determine if NRBC can serve as a biomarker for ECMO mortality and inpatient mortality in infants requiring V-A ECMO. METHODS: A single-center retrospective chart review analyzing infants <1 year of age requiring VA ECMO due to myocardial dysfunction or post-cardiotomy between January 1, 2011 to June 30, 2020. RESULTS: One hundred two patients required VA ECMO. Sixty-five patients required ECMO post-cardiotomy, 19 for perioperative deterioration, and 18 for myocardial dysfunction. Fifty-one patients (50%) died (21 died on ECMO, 30 died post-ECMO decannulation). Multivariable analysis found Age <60 days (OR 13.0, 95% CI 1.9-89.6, p = 0.009), NRBC increase by >50% post-ECMO decannulation (OR 17.1, 95% CI 3.1-95.1, p = 0.001), Single Ventricle (OR 9.0, 95% CI 1.7-47.7, p = 0.01), and lactate at ECMO decannulation (OR 3.0, 95% CI 1.3-7.1, p = 0.011) to be independently associated with inpatient mortality. ROC curves evaluating NRBC pre-ECMO decannulation as a biomarker for mortality on ECMO (AUC 0.80, 95% CI 0.68-0.92, p ⩽ 0.001) and post-ECMO decannulation (AUC 0.75, 95% CI 0.65-0.84, p ⩽ 0.001) show NRBC to be an accurate biomarker for mortality. CONCLUSIONS: Greater than 50% increase in NRBC post-ECMO decannulation is associated with inpatient mortality. NRBC value pre-ECMO decannulation may be a useful biomarker for mortality while on ECMO and post-decannulation.

A 4H+/4e- Electron-Coupled-Proton Buffer Based on a Mononuclear Cu Complex.

In this research article, we describe a 4H+/4e- electron-coupled-proton buffer (ECPB) based on Cu and a redox-active ligand. The protonated/reduced ECPB (complex 1: [Cu(8H+/14e-)]1+), consisting of CuI with 2 equiv of the ligand (catLH4: 1,1'-(4,5-dimethoxy-1,2-phenylene)bis(3-(tert-butyl)urea)), reacted with H+/e- acceptors such as O2 to generate the deprotonated/oxidized ECPB. The resulting compound, (complex 5: [Cu(4H+/10e-)]1+), was characterized by X-ray diffraction analysis, nuclear magnetic resonance (1H-NMR), and density functional theory, and it is electronically described as a cuprous bis(benzoquinonediimine) species. The stoichiometric 4H+/4e- reduction of 5 was carried out with H+/e- donors to generate 1 (CuI and 2 equiv of catLH4) and the corresponding oxidation products. The 1/5 ECPB system catalyzed the 4H+/4e- reduction of O2 to H2O and the dehydrogenation of organic substrates in a decoupled (oxidations and reductions are separated in time and space) and a coupled fashion (oxidations and reductions coincide in time and space). Mechanistic analysis revealed that upon reductive protonation of 5 and oxidative deprotonation of 1, fast disproportionation reactions regenerate complexes 5 and 1 in a stoichiometric fashion to maintain the ECPB equilibrium.

Electroactive Polymer-Based Spray Ionization for Direct Mass Spectrometric Analysis.

Electrochemically deposited electroactive polymer (EAP) films were investigated for their potential to enhance the performance of ambient ionization mass spectrometry (MS). Several EAPs of varying hydrophobicity were evaluated, including the superhydrophobic polymer poly[3,4-(2-dodecylethylenedioxy)thiophene] (PEDOT-C12). The EAPs were electropolymerized onto indium tin oxide-coated glass, placed in front of the inlet of a mass spectrometer, and charged to 3.5-4.5 kV. Analyte solutions were then applied to the surface, initiating ionization events. Analytes including peptides and small molecule pharmaceuticals were studied in 0.1% formic acid in methanol/water ("spray solvent") as well as in synthetic biological fluid matrices, using both EAP spray ionization (EAPSI) and paper spray ionization (PSI). Each EAPSI analysis required as little as 0.1 µL of solution, and the resulting sprays were stable and reproducible. The sensitivity, limit of detection (LOD), and limit of quantification (LOQ) were evaluated using bradykinin, cannabinol, and cannabidiol, which were prepared in pure solvents, artificial urine, and artificial saliva. The limits of detection and quantitation for EAPSI were improved relative to PSI by 1-2 orders of magnitude for analytes prepared in methanol/water and on the same order of magnitude as PSI for analytes prepared in artificial saliva and urine. This EAP-based spray ionization technique offers possibilities for rapid MS analysis with small sample sizes, high accuracy, and miniaturization of MS instruments.

Optimal lockdowns.

This paper provides a framework for understanding optimal lockdowns and makes three contributions. First, it theoretically analyzes lockdown policies and argues that policy makers systematically enact too strict lockdowns because their incentives are misaligned with achieving desired ends and they cannot adapt to changing circumstances. Second, it provides a benchmark to determine how strongly policy makers in different locations should respond to COVID-19. Finally, it provides a framework for understanding how, when, and why lockdown policy is expected to change.

Extracorporeal membrane oxygenation in the care of a preterm infant with COVID-19 infection: Case report.

Coronavirus disease 2019 (COVID-19) was first reported to the World Health Organization (WHO) in December 2019 and has since unleashed a global pandemic, with over 518 million cases as of May 10, 2022. Neonates represent a very small proportion of those patients. Among reported cases of neonates with symptomatic COVID-19 infection, the rates of hospitalization remain low. Most reported cases in infants and neonates are community acquired with mild symptoms, most commonly fever, rhinorrhea and cough. Very few require intensive care or invasive support for acute infection. We present a case of a 2-month-old former 26-week gestation infant with a birthweight of 915 grams and diagnoses of mild bronchopulmonary dysplasia and a small ventricular septal defect who developed acute respiratory decompensation due to COVID-19 infection. He required veno-arterial extracorporeal membrane oxygenation support for 23 days. Complications included liver and renal dysfunction and a head ultrasound notable for lentriculostriate vasculopathy, extra-axial space enlargement and patchy periventricular echogenicity. The patient was successfully decannulated to conventional mechanical ventilation with subsequent extubation to non-invasive respiratory support. He was discharged home at 6 months of age with supplemental oxygen via nasal cannula and gastrostomy tube feedings. He continues to receive outpatient developmental follow-up. To our knowledge, this is the first case report of a preterm infant during their initial hospitalization to survive ECMO for COVID-19.

Efficacy and Safety of Topical Nitric Oxide-Releasing Berdazimer Gel in Patients With Molluscum Contagiosum: A Phase 3 Randomized Clinical Trial.

Importance: Molluscum contagiosum (MC) is a highly contagious skin condition. Lesions may persist for months to years, and no US Food and Drug Administration-approved medications are currently available in the US. Objective: To assess the efficacy and safety of berdazimer gel, 10.3%, a novel topical nitric oxide-releasing medication, in the treatment of MC. Design, Setting, and Participants: This was a multicenter, vehicle-controlled, double-blind, phase 3 randomized clinical trial (B-SIMPLE4) conducted in 55 clinics (mostly dermatology and pediatric) in the US from September 1, 2020, to July 21, 2021. Eligible participants were 6 months or older and had from 3 to 70 raised MC lesions. Patients with sexually transmitted MC or with MC only in the periocular area were excluded. Interventions: Patients were randomized to treatment with berdazimer gel, 10.3%, or vehicle gel, applied as a thin layer to all lesions once daily for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was complete clearance of all MC lesions at week 12. Safety and tolerability measures included adverse event frequency and severity, and assessment of local skin reactions and scarring. Data analyses were performed from August 31, 2021, to September 14, 2021. Results: A total of 891 participants were randomized, 444 to berdazimer, 10.3% (mean [range] age, 6.6 [0.9-47.5] years; 228 [51.4%] male; 387 [87.2%] White individuals), and 447 to vehicle (mean [range] age, 6.5 [1.3-49.0] years; 234 [52.3%] female; 382 [85.5%] White individuals). In the intention-to-treat population, 88.5% (393 patients) in the berdazimer group and 88.8% (397 patients) in the vehicle group had a lesion count performed at week 12. At week 12, 32.4% (144 patients) in the berdazimer group achieved complete clearance of MC lesions compared with 19.7% (88 patients) in the vehicle group (absolute difference, 12.7%; odds ratio, 2.0; 95% CI, 1.5-2.8; P < .001) with 14.4% (64 patients) of the berdazimer group discontinuing treatment because of MC clearance compared with 8.9% (40 patients) of the vehicle group. Adverse event rates were low. The most common adverse events were application-site pain and erythema, mostly mild in severity. Adverse events leading to discontinuation affected 4.1% (18 patients) of the berdazimer group and 0.7% (3 patients) of the vehicle group. The most common local skin reaction was mild to moderate erythema. Conclusions and Relevance: Use of berdazimer gel, 10.3%, for MC appears to demonstrate favorable efficacy and safety with low adverse event rates. Trial Registration: ClinicalTrials.gov Identifier: NCT04535531.

SB206, a Nitric Oxide-Releasing Topical Medication, Induces the Beginning of the End Sign and Molluscum Clearance.

The beginning of the end (BOTE) sign has been proposed to describe well-recognized clinical signs of inflammation (including erythema, induration, and scale) that predict imminent resolution of molluscum contagiosum (MC). This phenomenon has never been prospectively studied. An integrated analysis of two prospective, 12-week, randomized, double-blind clinical trials of topical nitric oxide-releasing SB206 gel evaluated an association between BOTE sign and MC lesion reduction. Of 707 randomized patients, ~80% exhibited BOTE signs regardless of treatment assignment. At week 12, MC lesion counts decreased from baseline by 50.7% for baseline BOTE+ versus 29.1% for BOTE- (P = 0.0015) vehicle-treated patients compared with a 63.3% decrease for baseline BOTE+ versus 51.7% for BOTE- (P = 0.0194) SB206-treated patients. Among vehicle-treated patients, 48 (22.3%) who were never BOTE+ had an 18.5% reduction from baseline in MC lesion counts versus a 34.0% reduction in 165 patients (76.7%) who experienced BOTE at any time, suggesting that the projected duration of lesion clearance for patients with 18-20 MC lesions is 15 months for BOTE- versus 6 months for BOTE+ patients. Patients who were both BOTE+ and treated with SB206 had the greatest reduction in MC lesion count. SB206 may trigger BOTE signs and shorten the duration of MC infection. The two studies whose data are analyzed in this study are registered at ClinicalTrials.gov with the identifiers NCT03927703 and NCT03927716.

Enabling Conducting Polymer Applications: Methods for Achieving High Molecular Weight in Chemical Oxidative Polymerization in Alkyl- and Ether-Substituted Thiophenes.

Polythiophenes (PTs) constitute a diverse array of promising materials for conducting polymer applications. However, many of the synthetic methods to produce PTs have been optimized only for the prototypical alkyl-substituted example poly(3-hexylthiophene) (P3HT). Improvement of these methods beyond P3HT is key to enabling the widespread application of PTs. In this work, P3HT and two ether-substituted PTs poly(2-dodecyl-2H,3H-thieno[3,4-b][1,4]dioxine) (PEDOT-C12) and poly(3,4-bis(hexyloxy)thiophene) (PBHOT) are synthesized by the FeCl3-initiated oxidative method under different conditions. Polymerization was carried out according to a common literature procedure ("reverse addition") and a modified method ("standard addition"), which differ by the solvent system and the order of addition of reagents to the reaction mixture. Gel-permeation chromatography (GPC) was performed to determine the impact of the different methods on the molecular weights (Mw) and degree of polymerization (Xw) of the polymers relative to polystyrene standards. The standard addition method produced ether-substituted PTs with higher Mw and Xw than those produced using the reverse addition method for sterically unhindered monomers. For P3HT, the highest Mw and Xw were obtained using the reverse addition method. The results show the oxidation potential of the monomer and solution has the greatest impact on the yield and Xw obtained and should be carefully considered when optimizing the reaction conditions for different monomers.

Polar Ocean Observations: A Critical Gap in the Observing System and Its Effect on Environmental Predictions From Hours to a Season.

There is a growing need for operational oceanographic predictions in both the Arctic and Antarctic polar regions. In the former, this is driven by a declining ice cover accompanied by an increase in maritime traffic and exploitation of marine resources. Oceanographic predictions in the Antarctic are also important, both to support Antarctic operations and also to help elucidate processes governing sea ice and ice shelf stability. However, a significant gap exists in the ocean observing system in polar regions, compared to most areas of the global ocean, hindering the reliability of ocean and sea ice forecasts. This gap can also be seen from the spread in ocean and sea ice reanalyses for polar regions which provide an estimate of their uncertainty. The reduced reliability of polar predictions may affect the quality of various applications including search and rescue, coupling with numerical weather and seasonal predictions, historical reconstructions (reanalysis), aquaculture and environmental management including environmental emergency response. Here, we outline the status of existing near-real time ocean observational efforts in polar regions, discuss gaps, and explore perspectives for the future. Specific recommendations include a renewed call for open access to data, especially real-time data, as a critical capability for improved sea ice and weather forecasting and other environmental prediction needs. Dedicated efforts are also needed to make use of additional observations made as part of the Year of Polar Prediction (YOPP; 2017-2019) to inform optimal observing system design. To provide a polar extension to the Argo network, it is recommended that a network of ice-borne sea ice and upper-ocean observing buoys be deployed and supported operationally in ice-covered areas together with autonomous profiling floats and gliders (potentially with ice detection capability) in seasonally ice covered seas. Finally, additional efforts to better measure and parameterize surface exchanges in polar regions are much needed to improve coupled environmental prediction.

MCRDR Knowledge-Based 3D Dialogue Simulation in Clinical Training and Assessment.

Dialogue-based simulation is a real-world practice technique for medical and clinical education that provides students with an opportunity to train using hands-on experiences without putting actual patients being put at risk. In this paper, a 3D interactive dialogue-based training and assessment system that supports the detailed development of clinical trial competency for medical students in a distributed virtual environment was proposed. For clinical training, MCRDR-based natural language understanding to realize the semantic representation of written dialog from the most relevant inference results was applied, and on the basis of this, a convolutional neural network model was also used to make the generated inference more exact and reliable. For clinical assessment, the dialogue-driven competency method was used to encompass medical knowledge, communication skill as well as professionalism skill based on the collected dialogue information. Finally, the potential of the created system was demonstrated with several clinical cases. The preliminary results indicate that the system demonstrates the potential of providing efficient training and flexible assessment, while saving time, improving practical skills and making students more confident.

Humanized mouse model of Rasmussen's encephalitis supports the immune-mediated hypothesis.

Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ- and granzyme B-expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.

Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials.

OBJECTIVE: The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200-600 mg/day) in adults (ages 16-70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo-controlled trials (SP667, SP754 [NCT00136019], SP755 [NCT00220415]). METHODS: Patients with POS (≥2 years' duration, ≥2 previous antiepileptic drugs [AEDs]) uncontrolled by a stable dosing regimen of 1-3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment-emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs. RESULTS: One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by ≥5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in ≥1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600-mg/day groups, respectively (vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7-2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% [51/334] vs 3.9% [5/129] placebo), lamotrigine (19.2% [56/291] vs 4.3% [5/117]), and levetiracetam (10.1% [28/278] vs 3.9% [4/103]). CONCLUSIONS: The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration.

Efficacy of lacosamide by focal seizure subtype.

The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a 50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment.

Development of lacosamide for the treatment of partial-onset seizures.

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug-drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy.

Comparative three-dimensional structure of the trabecular bone in the talus of primates and its relationship to ankle joint loads generated during locomotion.

The trabecular structure of the ankle bone in small to medium-bodied (60-5000 g) primates of distinct locomotor types was analyzed using high-resolution X-ray computed tomography. There are large inter-, intraspecific, and regional (medial vs. lateral) variations in the trabecular architecture of the talar body. Body mass has no effect on the bone volume fraction or on the fabric anisotropy. However, both the number and thickness of trabeculae seem to be body mass-dependent. All taxa show anisotropic trabecular bone, but the degree of anisotropy and elongation values vary, notably across the locomotion categories. The fabric orientation in the talar body indicates that, practically, all taxa studied display a generally consistent pattern of orientation restricted primarily to a dorsoplantar direction. We have observed a mediolateral difference in the bone volume fraction in most primates who are proficient or frequent climbers. This could reflect a specific reinforcement of the trabecular structure in response to the loads engendered in habitually sustained foot inversion. In contrast, tali of primates who are proficient or frequent leapers rather exhibit a different three-dimensional distribution of the material, which consists of a more anisotropic trabecular structure. This could reflect stronger unidirectional and stereotypical-loading conditions generated at the ankle joints during a leap. Finally, it appears that the talar trabecular bone structure has a good potential for predicting locomotion in extinct species. We have analyzed the trabecular bone structure of the talus of some Eocene European primates (Adapis, Leptadapis, and Necrolemur) and compared the functional signal of the external versus internal talar anatomy in these fossils.

Early-life stress is associated with gender-based vulnerability to epileptogenesis in rat pups.

During development, the risk of developing mesial temporal lobe epilepsy (MTLE) increases when the developing brain is exposed to more than one insult in early life. Early life insults include abnormalities of cortical development, hypoxic-ischemic injury and prolonged febrile seizures. To study epileptogenesis, we have developed a two-hit model of MTLE characterized by two early-life insults: a freeze lesion-induced cortical malformation at post-natal day 1 (P1), and a prolonged hyperthermic seizure (HS) at P10. As early life stressors lead to sexual dimorphism in both acute response and long-term outcome, we hypothesized that our model could lead to gender-based differences in acute stress response and long-term risk of developing MTLE. Male and female pups underwent a freeze-lesion induced cortical microgyrus at P1 and were exposed to HS at P10. Animals were monitored by video-EEG from P90 to P120. Pre and post-procedure plasma corticosterone levels were used to measure stress response at P1 and P10. To confirm the role of sex steroids, androgenized female pups received daily testosterone injections to the mother pre-natally and post-natally for nine days while undergoing both insults. We demonstrated that after both insults females did not develop MTLE while all males did. This correlated with a rise in corticosterone levels at P1 following the lesion in males only. Interestingly, all androgenized females showed a similar rise in corticosterone at P1, and also developed MTLE. Moreover, we found that the cortical lesion significantly decreased the latency to generalized convulsion during hyperthermia at P10 in both genders. The cortical dysplasia volumes at adulthood were also similar between male and female individuals. Our data demonstrate sexual dimorphism in long-term vulnerability to develop epilepsy in the lesion + hyperthermia animal model of MTLE and suggest that the response to early-life stress at P1 contributes significantly to epileptogenesis in a gender-specific manner.

Long-term consequences of a prolonged febrile seizure in a dual pathology model.

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.

Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials.

BACKGROUND: Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool. OBJECTIVE: To provide insight into the clinical utility of lacosamide by performing a priori-defined and post hoc analyses on a large, pooled patient population. STUDY DESIGN: Pooled data from three randomized, double-blind, multicentre, placebo-controlled phase II/III trials. PATIENTS: Adult patients with partial-onset seizures with or without secondary generalization (N = 1294). INTERVENTION: Four- to six-week titration followed by 12-week maintenance treatment with lacosamide (Vimpat®) 200, 400 or 600 mg/day or placebo. MAIN OUTCOME MEASURE: A priori-defined primary efficacy variables for the pooled analysis were change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase; a priori-defined secondary efficacy variables were the proportion of patients achieving a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate), the proportion of Maintenance Phase completers remaining seizure free throughout the entire Maintenance Phase and the percentage of seizure-free days during the Maintenance Phase for patients entering the Maintenance Phase. The pooled analyses of the change in seizure frequency, and 50% and 75% responder rates were performed with an intent-to-treat (ITT) approach, including all patients receiving at least one dose of trial medication and having at least one post-baseline efficacy assessment. Similar analyses of the two primary efficacy variables and 75% responder rates were also performed using a modified ITT population (ITTm) that included ITT patients who entered the Maintenance Phase. Additional post hoc efficacy analyses were an evaluation of onset of efficacy and assessment of efficacy in patients grouped by prior surgical history and individual concomitant AED use. In addition, pharmacokinetic-pharmacodynamic modelling was performed, and safety data were assessed. RESULTS: In this pooled analysis of 1294 difficult-to-treat patients, all three dosages of lacosamide (200, 400 and 600 mg/day) showed a significant improvement compared with placebo for median percent seizure reduction (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day), as well as for 50% responder rate (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day). Evaluation of 75% responder rate in the phase II/III pooled population showed that a significantly higher proportion of patients randomized to lacosamide 400 or 600 mg/day achieved a ≥75% reduction in seizure frequency compared with placebo (ITT and ITTm; p < 0.001); statistical significance was not observed for lacosamide 200 mg/day (ITT and ITTm). A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%). The mean change from baseline in the percentage of seizure-free days in patients entering the Maintenance Phase for the phase II/III pool was 8.0%, 11.6% and 14.7% with lacosamide 200 (p = 0.077), 400 (p < 0.001) and 600 (p < 0.001) mg/day groups, respectively, compared with 6.1% in the placebo group. The onset of efficacy relative to placebo was evident by the first week of treatment with lacosamide. Efficacy was similar in lacosamide-treated patients reporting prior surgical intervention for epilepsy compared to lacosamide-treated patients with no prior surgical intervention. Lacosamide showed a reduction in seizures, regardless of the concomitant AEDs used. The preferred pharmacokinetic-pharmacodynamic model (E(max)) supported the therapeutic dose range of lacosamide, and no additional safety concerns were identified in the phase II/III pooled analysis. CONCLUSIONS: Results of these a priori-defined and post hoc pooled data analyses from phase II/III trials demonstrate that lacosamide effectively reduces seizures in patients at all three dosages evaluated with an early onset of efficacy, regardless of patient surgical history and concomitant AED regimen.