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Abstract: Antiseizure medications and drugs for psychiatric diseases are frequently used in combination. In this context, pharmacokinetic interactions between these drugs may occur. The vast majority of these interactions are primarily observed at a metabolic level and result from changes in the activity of the cytochrome P450 (CYP). Carbamazepine, phenytoin, and barbiturates induce the oxidative biotransformation and can consequently reduce the plasma concentrations of tricyclic antidepressants, many typical and atypical antipsychotics and some benzodiazepines. Newer antiseizure medications show a lower potential for clinically relevant interactions with drugs for psychiatric disease. The pharmacokinetics of many antiseizure medications is not influenced by antipsychotics and anxiolytics, while some newer antidepressants, namely fluoxetine, fluvoxamine and viloxazine, may inhibit CYP enzymes leading to increased serum concentrations of some antiseizure medications, including phenytoin and carbamazepine. Clinically relevant pharmacokinetic interactions may be anticipated by knowledge of CYP enzymes involved in the biotransformation of individual medications and of the influence of the specific comedication on the activity of these CYP enzymes. As a general rule, these interactions can be managed by careful evaluation of clinical response and, when indicated, individualized dosage adjustments guided by measurement of drugs serum concentrations, especially if pharmacokinetic interactions may cause any change in seizure control or signs of toxicity. Further studies are required to improve predictions of pharmacokinetic interactions between antiseizure medications and drugs for psychiatric diseases providing practical helps for clinicians in the clinical setting.

A utilização da água para determinado propósito não deve prejudicar os diversos usos possíveis, entre os quais figuram as atividades de consumo humano, produção agropecuária, recreativas e a preservação da diversidade biológica. Este estudo objetivou coletar dados secundários (dados qualidade da água – IQA) da Cetesb – Companhia Ambiental do Estado de São Paulo - Brasil, em dois pontos distintos na região de Jaboticabal e compará-los com dados também secundários da Corporación Autónoma Regional de Cundinamarca – CAR - Dirección de Recursos Naturales República de Colombia - obtidos em rios da Colômbia. Verifica-se que os parâmetros e os pesos utilizados para determinar o IQA, no Brasil e na Colômbia, são bastante parecidos. Ao comparamos quanto à localização dos rios estudados, é importante salientar que os rios da Colômbia estão em altitudes maiores que os rios do Brasil, quesito que pode influenciar na avaliação de alguns parâmetros do IQA.

Abstract: Cenobamate is a novel antiseizure medication (ASM) commercially available in Europe and in the U.S. for the treatment of focal seizures in adults. The mechanisms responsible for its antiseizure activity include enhancement of the inactivated state of voltage-gated sodium channels with blockade of the persistent sodium current and positive allosteric modulation of GABAA receptors at a non-benzodiazepine binding site. Cenobamate has a high oral bioavailability that is not influenced by food intake. The terminal half-life is 50-60 hours, allowing for once-daily dosing. Cenobamate is a CYP2C19 inhibitor and an inducer of CYP3A4 and CYP2B6, and consequently, it can cause a number of drug-drug interactions. Efficacy and safety have been evaluated in two randomized, double-blind, placebo-controlled adjunctive therapy trials in adults with focal seizures. In both trials, cenobamate decreased significantly the frequency of focal seizures, with relatively high seizure freedom rates. Adverse events most commonly reported in double-blind trials included dizziness, somnolence, headache, fatigue, and diplopia. The occurrence of three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) during early clinical development led to the conduction of a Phase 3 open-label long-term safety study in a total of 1339 patients. In this study, no serious idiosyncratic adverse reactions were observed using a start-low and go-slow approach. Further studies are required to determine whether the clinical activity profile of cenobamate extends to protection against other seizure types and to evaluate its efficacy and safety profile in special patient groups such as infants, children, the elderly, and patients with comorbid conditions.

We report the first known occurrence of South American sea lion (Otaria flavescens) twins on the South American coast. In January 2021 a female pregnant with dizygotic male and female fetuses was found dead in southern Brazil. The timing of the stranding event suggests that the pregnancy was near-term. However, the total body length and weight of fetuses suggested poor development and growth, which could be due to the advanced age of the mother and/or poor nutrition of the individual during pregnancy. The female fetus was larger and heavier than the male and could have been implanted and developed earlier.

La Hipercolesterolemia familiar(HF)es una enfermedad genética de carácter Autosómico Dominante,poco frecuente,generado por la mutación en el cromosoma 19.Es la primera causa de Enfermedad Cardiovascular Prematura.Las mutaciones patogénicas que generan la HF se relacionan con el receptor de LDL(LDLr),la apolipoproteina B-100(Apo- B100)y la proteína convertasa subtilisina/kexina tipo9(PCSK9),que produce elevación del colesterol y alteración de la vía del LDLr en el 80% de los casos diagnosticados de HF(5).Presentamos un reporte de caso de cuatro pacientes que pertenecen a la misma familia,quienes presentan mutaciones patogénicas de diferente compromiso a nivel cardiovascular y sistémico que ha afectado de manera negativa su cotidianidad. Discusión:El reporte de caso que presentamos se fundamenta en la sospecha de HF según los criterios de Holanda.En éstos pacientes se reconoce mutación del gen LDLr que se relaciona con HF.Sin embargo, no ha sido ampliamente estudiada.Se encuentra en el estudio de Chmara que se realizó en Polonia por primera vez se reporta la variante ac 11G>T.En Colombia, el estudio López encuentro tres mutaciones identificadas como la variante a c.11G>A, la variante n c.416A>G y la variante c.1187G>A.(8) Conclusión:La HF en nuestro medio es poco frecuente y con gran impacto social,en la mayoría de los casos genera síntomas clínicos y aumento del riesgo cardiovascular desde una edad temprana.Es importante resaltar en la diagnóstico oportuno y el conocimiento pro el personal de salud,para generar una calidad de vida adecuada a los pacientes y evitar que aumente el Riesgo Cardiovascular.

Increased anandamide levels via fatty acid amide hydrolase (FAAH) inhibition can decrease the pronociceptive responses and inflammatory mediators in animal models of migraine. Here, we profile the pharmacological activity of the FAAH inhibitor JZP327A, a chiral 1,3,4-oxadiazol-2(3H)-one compound, in the mediation of spontaneous and nocifensive behaviour in the animal models of migraine based on nitroglycerin (NTG) administration. JZP327A (0.5 mg/kg, i.p.) or vehicle was administered to male rats 3 h after NTG (10 mg/kg, i.p.) or NTG vehicle injection. The rats were then exposed to the open field test and an orofacial formalin test 1 h later. The levels of endocannabinoids and lipid-related substances, and the expression of pain and inflammatory mediators were evaluated in cranial tissues and serum. The findings show that JZP327A did not affect NTG-induced changes in the spontaneous behaviour of rats, while it inhibited NTG-induced hyperalgesia at the orofacial formalin test. Furthermore, JZP327A dramatically decreased the gene expression of calcitonin gene-related peptide (CGRP), tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the trigeminal ganglia and medulla-pons, while it did not change endocannabinoids or lipids levels nor CGRP serum levels in the same tissues. These data suggest an anti-hyperalgesic role for JZP327A in the NTG model, which is mediated by the inhibition of the inflammatory cascade of events. This activity does not seem mediated by a change in the levels of endocannabinoids and lipid amides.

Hybridization is widespread and constitutes an important source of genetic variability and evolution. In animals, its role in generating novel and independent lineages (hybrid speciation) has been strongly debated, with only a few cases supported by genomic data. The South American fur seal (SAfs) Arctocephalus australis is a marine apex predator of Pacific and Atlantic waters, with a disjunct set of populations in Peru and Northern Chile [Peruvian fur seal (Pfs)] with controversial taxonomic status. We demonstrate, using complete genome and reduced representation sequencing, that the Pfs is a genetically distinct species with an admixed genome that originated from hybridization between the SAfs and the Galapagos fur seal ( Arctocephalus galapagoensis ) ~400,000 years ago. Our results strongly support the origin of Pfs by homoploid hybrid speciation over alternative introgression scenarios. This study highlights the role of hybridization in promoting species-level biodiversity in large vertebrates.

Made available in DSpace on 2022-04-28T19:45:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Agencia Nacional de Investigación e Innovación Trophic niche width and individual specialization among marine predators are often subjected to seasonal constraints. Differences are expected to arise for sexually dimorphic species exposed to distinct ecological opportunities, as well as intrinsic differences in physiological abilities or energetic requirements. We assess seasonal and sexual differences in isotopic niche overlap and width and analyze inter-individual foraging variation throughout the year of the South American fur seal (Arctocephalus australis). We obtained chronologically ordered δ13C and δ15N data from vibrissae of 25 males and 24 females from southern Brazil and Uruguay. There were significant differences between sexes for both isotopes with males showing higher values (δ13C = − 14.5 ± 0.5‰; δ15N = 18.9 ± 1.2‰) than females (δ13C = − 15.2 ± 0.5‰; δ15N = 17.8 ± 1.2‰), but not among seasons or years. A very small isotopic niche overlap found between sexes (1.1–9.5%), with limited seasonal variation, likely resulted from differences in prey consumption and foraging habitats. Compared to other seasons, females had a wider isotopic niche in spring. While males showed seasonal stability in the foraging niche, females showed some small variation, which is probably influenced by central place foraging. Both sexes had considerable interindividual variation in estimated dietary composition and had different proportions of potential prey contribution at the population level. These findings enlighten the knowledge of South American fur seal trophic ecology, and how they may seasonally and spatially shift their foraging strategies according to their distinct life histories. It ultimately reflects in a small niche partitioning and possibly low intraspecific competition at the species northernmost area of occurrence in the western South Atlantic. Programa de Pós-Graduação em Oceanografia Biológica Instituto de Oceanografia Universidade Federal do Rio Grande (FURG) Laboratório de Ecologia e Conservação da Megafauna Marinha (ECOMEGA) Instituto de Oceanografia Universidade Federal do Rio Grande (FURG) Departamento de Ecología y Evolución Facultad de Ciencias Universidad de la República Programa de Pós-Graduação em Biodiversidade de Ambientes Costeiros Instituto de Biociências Universidade Estadual Paulista (UNESP) Laboratório de Estratigrafia e Paleontologia Instituto de Biociências Universidade Estadual Paulista (UNESP) Centro Universitario Regional del Este Universidad de la República Programa de Pós-Graduação em Biodiversidade de Ambientes Costeiros Instituto de Biociências Universidade Estadual Paulista (UNESP) Laboratório de Estratigrafia e Paleontologia Instituto de Biociências Universidade Estadual Paulista (UNESP)

35 pages, 3 figures.-- Open access, Marine mammals can play important ecological roles in aquatic ecosystems, and their presence can be key to community structure and function. Consequently, marine mammals are often considered indicators of ecosystem health and flagship species. Yet, historical population declines caused by exploitation, and additional current threats, such as climate change, fisheries bycatch, pollution and maritime development, continue to impact many marine mammal species, and at least 25% are classified as threatened (Critically Endangered, Endangered or Vulnerable) on the IUCN Red List. Conversely, some species have experienced population increases/recoveries in recent decades, reflecting management interventions, and are heralded as conservation successes. To continue these successes and reverse the downward trajectories of at-risk species, it is necessary to evaluate the threats faced by marine mammals and the conservation mechanisms available to address them. Additionally, there is a need to identify evidence-based priorities of both research and conservation needs across a range of settings and taxa. To that effect we: (1) outline the key threats to marine mammals and their impacts, identify the associated knowledge gaps and recommend actions needed; (2) discuss the merits and downfalls of established and emerging conservation mechanisms; (3) outline the application of research and monitoring techniques; and (4) highlight particular taxa/populations that are in urgent need of focus, S.E.N. acknowledges funding from the Natural Environment Research Council (NE/L002434/1). S.E.N. and B.J.G. also acknowledge support from the European Union (INDICIT; EU grant agreement no. 110661/ 2018/ 794561/ SUB/ENV. C2). E.C. has a doctoral fellowship from the World Wildlife Foundation - Education for Nature. M.I.D.C. was supported by the UK Department for Business and Industrial Strategy (BEIS; project number OESEA-16-78). D.J.F.R. was supported by National Capability funding from the UK Natural Environment Research Council (NERC) to the Sea Mammal Research Unit (SMRU) (grant no. SMRU1001). A.B.O. acknowledges funding from the Office of Naval Research (award no. N000141613017). D.M.P. was supported by the Whale Habitat Professorship Endowment Fund, Marine Mammal Institute, Oregon State University. K.A.S. was supported by a Royal Society of New Zealand Te Aparangi Rutherford Discovery Fellowship

The phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here, we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genus Arctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 and 2.5 Ma. Otaria diverged first, followed by Phocarctos and then four major lineages within Arctocephalus. However, we found Zalophus to be nonmonophyletic, with California (Zalophus californianus) and Steller sea lions (Eumetopias jubatus) grouping closer than the Galapagos sea lion (Zalophus wollebaeki) with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family. [Hybridization; ILS; phylogenomics; Pleistocene; Pliocene; monophyly.]

Autosomal dominant Müller cell dystrophy is a rare condition we described in 1991. It is characterized by a striking sheen appearance on the retinal surface with progressive retinal changes leading to disorganization and atrophy with a decreased b-wave electroretinograms.We examined 45 members of a 4-generation family. Fifteen subjects from three generations were found with the disease, without gender predilection. Seven patients underwent ophthalmic examination including fundus examination, intravenous fluorescein angiogram, spectral-domain optical coherence tomography, and electroretinogram. Six patients have a 30-year follow-up. Histopathology examination was performed on eyes of the eldest patient. Whole exome sequencing was done in four affected subjects.Findings include a decreased visual acuity, abnormal cellophane-like sheen of the vitreoretinal interface, a "plush" nerve fiber layer, and characteristic macular changes. Electroretinogram showed a selective b-wave diminution. Intravenous fluorescein angiogram presented perifoveal hyperfluorescence and capillary leakage. Spectral-domain optical coherence tomography revealed cavitations involving inner and later outer retinal layers with later disorganization. Histopathologic findings included Müller cell abnormalities with cystic disruption of inner retinal layers, pseudoexfoliation in anterior segment, and amyloidosis of extraocular vessels. Pedigree analysis suggests an autosomal dominant inheritance with late onset. DNA analysis demonstrated a previously undescribed heterozygous missense p.Glu109Val mutation in transthyretin.To the best of our knowledge, this is the first family reported with this disorder. Our data support the hypothesis that autosomal dominant Müller cell dystrophy is a distinct retinal dystrophy affecting Müller cells. Mutations in transthyretin gene may manifest as a predominantly retinal disorder.

The Atlantic spotted dolphin (Stenella frontalis) is endemic to tropical, subtropical, and warm temperate waters of the Atlantic Ocean. Throughout its distribution, both geographic distance and environmental variation may contribute to population structure of the species. In this study, we follow a seascape genetics approach to investigate population differentiation of Atlantic spotted dolphins based on a large worldwide dataset and the relationship with marine environmental variables. The results revealed that the Atlantic spotted dolphin exhibits population genetic structure across its distribution based on mitochondrial DNA control region (mtDNA-CR) data. Analyses based on the contemporary landscape suggested, at both the individual and population level, that the population genetic structure is consistent with the isolation-by-distance model. However, because geography and environmental matrices were correlated, and because in some, but not all analyses, we found a significant effect for the environment, we cannot rule out the addition contribution of environmental factors in structuring genetic variation. Future analyses based on nuclear data are needed to evaluate whether local processes, such as social structure and some level of philopatry within populations, may be contributing to the associations among genetic structure, geographic, and environmental distance.

The aim of this study was to assess lipid disorders in children from five ethnic groups, both urban and indigenous, from northern and central Mexico. We measured the lipid profile to determine the ability of the body mass index (BMI) to discriminate an abnormally high lipid level using receiving operating characteristics (ROC). We analyzed the association and interaction of obesity and ethnicity with lipid disorders using generalized linear models in 977 children. The highest prevalence of lipid disorders (high TG, high TC, high LDL, high APOB, and dyslipidemia) was found in central Mexico-Mexico City and urban northern Mexico. The BMI performed better at predicting low HDL in Seris, a northern indigenous group (0.95, CI: 0.69–0.85), and Mexico City (0.75, CI: 0.69–0.82), and high LDL in Puebla (central Mexico, 0.80, CI: 0.69–0.85). Obesity significantly (p < 0.05) increases lipid disorders by around two times (OR~2) for almost all lipid markers. Obesity and ethnic interaction increase the lipid disorders by more than five times for different lipid markers and ethnic groups (high total cholesterol OR = 5.31; low HDL OR = 5.11, and dyslipidemia OR = 5.68). Lipid disorders are not restricted to children with high BMIs, but obesity exacerbates these. The emerging lipid disorder risk depends on the ethnic group.

Habitat fragmentation could alter ecological traits including species trophic habits. Here, we used carbon and nitrogen stable isotope ratios to establish differences in isotopic niche width and food resource use between forest fragments and the continuous forest for the phyllostomid frugivorous bat Artibeus lituratus. Using mist nests, we captured bats from two forest fragments and two sites in continuous forest, and sampled from each individual captured three body tissues with contrasting turnover rates (skin, muscle, and liver). Samples were collected between February and March (austral summer) and between August and September (austral winter). In addition, in each sampling site and season we collected potential food resources (fruits and insects) consumed by our A. lituratus. Our findings indicate that A. lituratus had a predominantly omnivorous diet, with high consumption of insects during summer in forest fragments. The increasing consumption of insects in these fragments seems to have led to a wider isotopic niche, in relation to the continuous forest. Because A. lituratus is typically a seed disperser, changes in trophic habits in the forest fragments from frugivory to insectivory may diminish their role in forest regeneration. Abstract in Portuguese is available with online material.

Individual specialisation could affect several ecological and evolutionary processes. Assessing isotopic data from different tissues of a single individual (multi‐tissue approach) represents a common method to estimate individual trophic specialisation (ITS). However, a neglected problem with this approach is that isotopic values of two tissues from a single individual are not statistically independent, and hence, an underestimation of the within‐individual component of variance should be theoretically expected. In this study, we evaluate this potential problem by comparing ITS estimations as currently calculated (uncorrected ITS) against ITS estimations based on a new method that considers the non‐independence problem (corrected ITS). We used unpublished δ¹⁵N and δ¹³C data for nine fish species, together with previously published δ¹⁵N and δ¹³C data for eight other vertebrate species, to estimate (and compare) components of variance and ITS values, using uncorrected and corrected isotopic data. In addition, for each species, we used a Monte Carlo resampling routine to test the null hypothesis that all individuals sample equally from the population diet distribution. We found that the use of uncorrected δ¹⁵N values provided an average ITS estimation which is, depending on the overlap among tissues turnover rates, 14%–35% (fish dataset) and 17%–40% (all species dataset) lower than estimations based on corrected values. Similarly, the use of uncorrected δ¹³C values provided an average ITS estimation which is 12%–29% (fish dataset) and 21%–45% (all species dataset) lower than corrected estimations. The implications of these results in an ecological context are of great significance. For instance, the fish dataset showed that while uncorrected estimations indicate that three (δ¹³C) or four (δ¹⁵N) species are trophic specialists at the individual level, a moderate correction in isotopic values indicate that none (δ¹³C) or only one (δ¹⁵N) species is a trophic specialist at that level. Noticeably, this last result is much more congruent with dietary data obtained from stomach content analysis. Given the several pros of the multi‐tissue approach, such as its reduced operative costs, we suggest not to abandon this method, but to cope with the non‐independence problem by using the correction proposed here or, at least, by selecting body tissues with a minimal overlap in their turnover rates.

El objetivo de este libro es ofrecer un espacio de reflexión y posibles respuestas a fenómenos relacionados con la convergencia entre el ojo y la medicina. Lo anterior se realiza mediante el diálogo entre estudiantes y profesionales con diferentes campos y niveles de formación, con el objeto de lograr un saber transdisciplinar del ojo, un órgano dotado de variedad de metáforas, significados y funcionalidades. El presente texto recopila a manera de working papers y apuntes de sesión el resultado de un viaje por el ojo humano, un viaje que atraviesa el arte, la medicina, la literatura y la espiritualidad. Esperamos lo disfrute y que tenga la luminosidad precisa para el asombro.

espanolLas hembras lactantes de los otaridos difieren en la duracion y frecuencia de sus viajes de alimentacion, lo que puede afectar a la duracion y frecuencia de los episodios de lactancia de las crias y, en consecuencia, a su crecimien-to, a menos que las hembras modifiquen la densidad energetica de la leche y/o la cantidad total de leche suministrada en funcion de la duracion del viaje. Para comprobar la validez de esta hipotesis en los leones marinos sudamericanos, medimos dos componentes del patron de cuidado maternal (la duracion de los viajes de alimentacion y la duracion del tiempo en tierra) y tres componentes del comportamiento de buceo (tiempo de buceo, tiempo en el fondo y numero de inmersiones por hora) de las hembras lactantes en dos colonias diferentes de Uruguay y Argentina, asi como la composi-cion y densidad energetica de su leche y la tasa de crecimiento de sus crias. Las duraciones de los viajes de alimentacion y del tiempo en tierra de las hembras dependieron del sexo y peso de las crias, mientras que la densidad energetica de la leche dependio de la masa corporal de la hembra y la duracion de los viajes de alimentacion. Por el contrario, las tres variables de buceo no estuvieron relacionadas con la masa corporal de la hembra ni con el sexo de la cria. El crecimiento de las crias tambien fue independiente de la duracion del viaje de alimentacion y del tiempo en tierra, siendo el sexo de las crias la unica variable significativa. Esto sugiere que las diferencias individuales en el comportamiento de alimenta-cion de las hembras juegan un papel menor en la determinacion de las tasas de crecimiento de las crias durante las tres semanas inmediatamente posteriores al parto EnglishChanges in the duration and frequency of foraging trips by female otariids may result in changes in the du-ration and frequency of lactation bouts and hence influence pup growth rate, unless females modify milk energy density and/or the total amount of milk delivered depending on the trip duration. To test this hypothesis on South American sea lions, we measured two attendance pattern components (foraging trip and haul-out duration) and three diving behaviour components of nursing females (dive time, bottom time and number of dives per h) at two different rookeries in Uruguay and Argentina, the composition and energy density of their milk, and the growth rate of their pups. Female foraging trip and haul-out durations depended on pup sex and weight, whereas milk energy density depended on female body mass and foraging trip durations. By contrast, the three dive variables were independent of female body mass or pup sex. Pup growth was also independent of the foraging trip and haul-out duration, with pup sex as the only significant variable. This suggests that individual differences in female foraging behaviour play a minor role in determining pup growth rates during the first three weeks after birth

El hogar infantil vecinal del barrio popular de Kennedy en Pereira, a causa de la pandemia por el Covid-19 tuvo que cerrar sus puertas a los niños de dos a cinco años, lo que limitó la educación a la virtualidad. Por esta razón, las clases que antes se desarrollaban durante toda la semana pasaron a ser llamadas telefónicas semanales de control, actividades en casa y una clase virtual los viernes de una hora. En el caso de la clase que dirige la profesora Juli Quiceno, de los diecisiete niños que conforman el grupo, solo asisten cinco. Asimismo, hay un muy bajo cumplimiento de las tareas. Situación que se debe especialmente a la falta de involucramiento de los padres en las actividades y educación de sus hijos. Al respecto, es importante aclarar que el hogar infantil vecinal hace parte de las iniciativas del instituto colombiano de bienestar familiar (ICBF) para asegurar que los menores de edad de bajos recursos tengan una educación básica.

We thank Dr. Bruzzone for her interest in our article.1 We agree that participation in the study per se could have impacted outcomes. In particular, as pointed out in our Discussion, patients in the control group were also administered the questionnaire, and therefore, they might have been sensitized to report adverse effects that otherwise could have been neglected. We also agree that screening for adverse effects should be part of the routine management of people with epilepsy. Ideally, this should be supplemented by other measures aimed at raising awareness about the impact of adverse effects on quality of life, and about the strategies that can be applied to optimize drug treatment according to individual needs.

Introduction Spontaneous reports of adverse drug reactions (ADRs) are a valuable supplement to clinical studies in informing about the safety of medications. This is especially relevant for pediatric populations, which are not often included in large-scale clinical trials. Objectives To evaluate patterns of pediatric ADRs to antiseizure medications (ASMs) reported to the Italian Spontaneous Reporting System (SRS) database during the period November 1, 2001─May 31, 2019. Methods Suspected ADRs ascribed to medications listed under ATC code N03, plus clobazam (code N05BA09), and affecting individuals below age 18 years were sourced from the Italian SRS database, categorized based on a modification of the MedDRA® high-level term, and analyzed using descriptive statistics. Results A total of 956 reports listing a total of 1806 ADRs ascribed to one or more ASMs were received for individuals in pediatric age. The most commonly reported ADRs were skin rashes (24.0% of all reports), epileptic seizures (12.6%), gastrointestinal disturbances (11.8%), and somnolence (10.6%). A more detailed analysis was conducted on 675 reports listing a single ASM as suspected drug and occurring in patients with a specified or presumed diagnosis of epilepsy. Adverse drug reaction patterns differed widely across ASMs. Skin rashes were the most commonly reported ADR for lamotrigine (62.3%), carbamazepine (50.3%), phenobarbital (42.3%), and oxcarbazepine (33.0%). Other most commonly reported ADRs were gastrointestinal symptoms for ethosuximide (44%), irritability/aggression for levetiracetam (25.0%), epileptic seizures for valproic acid (16.1%), fever (often associated with hypohidrosis) for topiramate (17.9%), and utilization error (mostly accidental drug administration) for clonazepam (34.6%). Conclusions Patterns of spontaneous ADR reports are indicative of major differences in safety profile among individual ASMs. Most, but not all, frequently reported ADRs were in line with findings from clinical trials and observational studies.

We describe the foraging ecology of South American fur seals (Arctocephalus australis) at Isla de Lobos, Uruguay, the northernmost colony of the species in the Atlantic. We use multiple approaches to investigate diet and behavior at sea. South American fur seal females are epi- or meso-pelagic divers that feed on vertically migrating prey of high-energy content (e.g., Argentine short-fin squid—Illex argentinus, anchovy—Engraulis anchoita and hake—Merluccius hubbsi). Fur seal females travel far to forage, focusing their efforts over the slope of the continental shelf. Different degrees of individual trophic specialization and foraging away from the coast reduce the overlap with coastal fisheries and may explain the growth of this population during the past 60 years.

Hybridization that results from breeding with non-conspecifics occurs when both isolating mechanism, pre-breeding recognition and post-breeding gene incompatibilities, fail. Behavior often works to prevent hybridization. Despite these mechanisms, hybridization has been documented in the fur seals, among species within the genus Arctocephalus. We report a case of a hybrid female from South American fur seal (Arctocephalus australis) and South American sea lion (Otaria flavescens), with her offspring. Mitochondrial DNA analysis indicated that mother lineage was from South American fur seal. Nuclear genetic data supported the admixture ancestry between both genera of both individuals, confirming the first intergeneric pinniped hybridization. In addition, relatedness coefficient for the hybrid female-pup pair confirms that the hybrid female was fertile and had produced a live, hybrid pup. Results trigger a discussion on the circumstances in which isolating mechanisms may be circumvented and insights into the importance of hybridization in speciation processes in mammals.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was

For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabolism is a major rate-limiting step hampering access to the systemic circulation after oral dosing. The transfer of orally administered, highly lipid-soluble drugs to the lymphatic system is mediated by their association with chylomicrons, large intestinal lipoproteins that are assembled in the enterocytes in the presence of long-chain triglycerides or long-chain fatty acids. Due to its very high lipophilicity, cannabidiol (CBD) has physicochemical features (e.g. logP = 6.3) consistent with an oral absorption mediated at least in part by transport via the intestinal lymphatic system. CBD also undergoes extensive first-pass hepatic metabolism. Formulation changes favoring diversion of orally absorbed CBD from the portal to the lymphatic circulation pathway can result in reduced first-pass liver metabolism, enhanced oral bioavailability, and reduced intra- and intersubject variability in systemic exposure. In this manuscript, we discuss (1) evidence for CBD undergoing hepatic first-pass liver metabolism and lymphatic absorption to a clinically important extent; (2) the potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of presystemic elimination in the liver; and (3) strategies by which innovative chemical and/or pharmaceutical delivery systems of CBD with improved bioavailability could be developed.