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Drug discovery in epilepsy began with the finding of potassium bromide by Sir Charles Locock in 1857. The following century witnessed the introduction of phenotypic screening tests for discovering antiseizure medications (ASMs). Despite the high success rate of developing ASMs, they have so far failed in eliminating drug resistance and in delivering disease‐modifying treatments. This emphasizes the need for new drug discovery strategies in epilepsy. RNA‐based drugs have recently shown promise as a new modality with the potential of providing disease modification and counteracting drug resistance in epilepsy. RNA therapeutics can be directed either toward noncoding RNAs, such as microRNAs, long noncoding RNAs (ncRNAs), and circular RNAs, or toward messenger RNAs. The former show promise in sporadic, nongenetic epilepsies, as interference with ncRNAs allows for modulation of entire disease pathways, whereas the latter seem more promising in monogenic childhood epilepsies. Here, we describe therapeutic strategies for modulating disease‐associated RNA molecules and highlight the potential of RNA therapeutics for the treatment of different patient populations such as sporadic, drug‐resistant epilepsy, and childhood monogenic epilepsies. [ABSTRACT FROM AUTHOR]

Background and Aim: The DanEoE is a previously described population‐ and register‐based cohort of 236 adult patients with eosinophilic esophagitis (EoE) in a well‐defined Danish region with a population of 580 000 and free medical treatment. The aim of the study was to compare the phenotype and treatment response between EoE patients with complications to patients without complications at diagnosis. Methods: A retrospective cross‐sectional study of the DanEoE cohort's 236 adult EoE patients diagnosed between 2007 and 2017 in the North Denmark Region. Patients were divided into a group who had had complications (dilated or food bolus obstruction [FBO]) before or at the diagnosis, and a group without. Results: At the diagnostic endoscopy, 61% had never had a complication, and 39% had either had FBO (n = 77) or been dilated (n = 15). The complicated group had the same mean age at symptom debut (37 [SD = 16] vs 37 [SD = 17] years, P = 1.0), but were diagnosed significantly later with a resulting longer diagnostic delay (13 [SD = 13] vs 7.9 [SD = 11] years, P = 0.01). Almost half of all patients were never treated to symptomatic remission (uncomplicated 40%, complicated 49%). The histological remission was not secured in the majority (uncomplicated 68%, complicated 70%). Despite this, <15% of patients with previous FBO experienced this after the diagnosis. Conclusion: In the population‐based DanEoE cohort, results indicated that the complicated EoE phenotype was a patient with a 5‐year longer diagnostic delay. In the current study, the complication status did not predict the treatment response. This population‐based DanEOE cohort study indicates that the complicated eosinophilic esophagitis phenotype is a patient with a 5‐year longer diagnostic delay. [ABSTRACT FROM AUTHOR]

Drug concentrations in peripheral blood are often used to evaluate whether death was caused by drug intoxication. In some cases, peripheral blood is not available, and analytical results of alternative matrices should instead be used in the toxicological evaluation. However, reference concentrations of alternative matrices are few, which makes interpretation of results a challenge. In this study, concentrations of selected benzodiazepines, opioids, illicit drugs, and other commonly used drugs in postmortem femoral blood, cardiac blood, brain tissue, and muscle tissue are presented. Alternative matrix‐to‐femoral blood drug concentration ratios and correlations of blood and alternative matrix drug concentrations were calculated to examine which of the investigated alternative matrices were most suited to use for toxicological evaluation in cases where peripheral blood is not available. The results showed that concentrations in cardiac blood, brain tissue, and muscle tissue could be useful in the postmortem evaluation of most of the 19 selected analytes. In most cases, analytes were detected in all the alternative matrices. The median concentration ratios for the selected analytes in brain tissue, cardiac blood, and muscle tissue relative to femoral blood ranged from 0.57 to 3.42, 0.59 to 1.87, and 0.67 to 7.04, respectively. Overall, cardiac blood provided the concentrations most comparable with femoral blood concentrations, indicating that cardiac blood can be useful in cases where femoral blood is not available. However, the measured concentrations should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Antimicrobial agents are used extensively off‐label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild‐type E. coli and S. delphini infections in mink. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is part of the pathophysiology in Alzheimer's disease (AD). AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD‐associated genes are expressed in glial cells. The hormone and neuropeptide Glucagon‐Like Peptide‐1 (GLP‐1) was originally developed for treatment of type 2 diabetes but has equally important effects in weight loss control and provides cardiovascular benefits. The potential for applying a licensed therapeutic option with a well‐established safety profile is currently being investigated in two phase 3a randomized, placebo‐controlled trials with semaglutide in people with early Alzheimer's disease (evoke/evoke+). Here, we investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and compare the identified pathways with human gene signatures in AD brain tissue. Method: Mice were treated daily subcutaneously with semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15‐17. RNA‐sequencing and immunohistochemistry was performed to assess transcriptional and morphological changes in the hippocampus at Day 19 and Day 28 (Day 2 and 11 post‐LPS, respectively). RNA‐sequencing analyses included differentially expressed gene analysis, weighted gene co‐regulated network analysis, pathway analysis and gene set enrichment analysis on published human AD datasets. Result: Semaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co‐expressed inflammatory genes in LPS/semaglutide‐treated mice (p<0.01 vs LPS+vehicle treated mice) on Day 28. Pathway analysis was consistent with an overall dampening of inflammatory processes in mice treated with LPS and semaglutide. The mouse LPS model mirrored the transcriptional signatures identified in people with AD in data of human hippocampal subtype transcriptional signatures, suggesting that semaglutide could potentially alleviate homologous inflammatory molecular processes in humans. A single nucleus RNA‐sequencing study in mice is ongoing to further elucidate the molecular effects of semaglutide on neuroinflammation and will be presented at the conference. Conclusion: In an LPS‐induced neuroinflammation mouse model, subcutaneously semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could be a novel mechanism through which semaglutide, may affect neuronal integrity and function relevant for AD pathophysiology. [ABSTRACT FROM AUTHOR]

This paper is concerned with the impact of medical inadmissibility provisions in Canada's immigration law on applicants with disabilities. The paper draws on key informant interviews, policy analysis, and Ministry of Immigration data on medical inadmissibility findings. We follow the lead of recent mobilities scholarship to examine how the immigration system is enacted, reproduced, and contested over time. From this perspective, we see that recent court challenges to the statutory provisions have created additional procedural space for applicants to contest findings of inadmissibility. However, the legitimacy of excessive demand as a basis for exclusion remains firmly in place, while recent immigration policy changes signal an intensification of measures to limit the social reproductive costs of immigration. Les personnes handicapées, l'inadmissibilité pour motifs sanitaires et la politique d'immigration sélective Cet article s'intéresse aux effets des dispositions de la législation canadienne en matière d'immigration relatives à l'inadmissibilité pour motifs sanitaires des candidats ayant une incapacité. L'article se fonde sur des entretiens auprès d'informateurs clés, des analyses politiques et des données du ministère sur les décisions d'inadmissibilité pour motifs sanitaires. Les recherches récentes portant sur la mobilité forment le point de départ d'une exploration du mode de fonctionnement du système d'immigration, sa reproduction et sa remise en question au fil du temps. Vues sous cet angle, les contestations actuelles des dispositions légales devant les tribunaux ont permis de dégager un espace de procédure supplémentaire pour les candidats afin de contester les verdicts d'inadmissibilité. Cependant, la légitimité de la demande excessive en tant que motif d'interdiction perdure, tandis que les changements récents apportés à la politique d'immigration annoncent une intensification des mesures visant à limiter les coÛts sociaux de l'immigration. [ABSTRACT FROM AUTHOR]

The neural cell adhesion molecule (NCAM) directly interacts with the fibroblast growth factor receptor (FGFR). Both fibronectin type III (FN3) modules of NCAM are involved in this interaction. One of the NCAM–FGFR contact sites has been localized recently to the upper N-terminal part of the second NCAM FN3 module encompassing the F and G β-strands and the interconnecting loop region. Here, we investigated whether any of the six putative strand-loop-strand regions in the first NCAM FN3 module are involved in FGFR interactions. Peptide sequences encompassing these regions, termed encamins, were synthesized and tested for their ability to bind and activate FGFR. Encamins localized to the N-terminal part of the first FN3 module did not interact with FGFR, whereas encamins localized to the C-terminal part, termed EncaminA, C and E, bound to and activated FGFR. The encamins induced FGFR-dependent neurite outgrowth, and EncaminC and E promoted neuronal survival and enhanced pre-synaptic function. In conclusion, the interaction between NCAM and FGFR probably involves multiple contact sites at an interface formed by the two NCAM FN3 modules and FGFR, and encamins could constitute important pharmacological tools for the study of specific functional aspects of NCAM, including neuroprotection and modulation of plasticity. [ABSTRACT FROM AUTHOR]