The potential of lasmiditan in migraine

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT1F) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatmentrelated side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans

Drug delivery nanosystems for the localized treatment of glioblastoma multiforme

[EN] Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood-brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood-brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma.This research was funded by an Ussher start-up funding award (School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin) and the European Union’s Horizon 2020 research and innovation program under Grant agreement No. 708036.Nam, L.; Coll Merino, MC.; Erthal, L.; De La Torre-Paredes, C.; Serrano, D.; Martínez-Máñez, R.; Santos-Martinez, M.... (2018). Drug delivery nanosystems for the localized treatment of glioblastoma multiforme. Materials. 11(5). https://doi.org/10.3390/ma11050779S115Goodenberger, M. L., & Jenkins, R. B. (2012). Genetics of adult glioma. Cancer Genetics, 205(12), 613-621. doi:10.1016/j.cancergen.2012.10.009Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., … Kleihues, P. (2007). 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Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood − brain barrier using MRI-guided focused ultrasound. Journal of Controlled Release, 189, 123-132. doi:10.1016/j.jconrel.2014.06.031Mead,

Headache, depression and anxiety: associations in the Eurolight project.

Headache disorders and psychiatric disorders are both common, while evidence, mostly pertaining to migraine, suggests they are comorbid more often than might be expected by chance. There are good reasons for establishing whether they are: symptoms of comorbid illnesses may summate synergistically; comorbidities hinder management, negatively influencing outcomes; high-level comorbidity indicates that, where one disease occurs, the other should be looked for. The Eurolight project gathered population-based data on these disorders from 6624 participants.Eurolight was a cross-sectional survey sampling from the adult populations (18-65 years) of 10 EU countries. We used data from six. The questionnaire included headache-diagnostic questions based on ICHD-II, the Headache-Attributed Lost Time (HALT) questionnaire, and HADS for depression and anxiety. We estimated odds ratios (ORs) to show associations between migraine, tension-type headache (TTH) or probable medication-overuse headache (pMOH) and depression or anxiety.pMOH was most strongly associated with both psychiatric disorders: for depression, ORs (vs no headache) were 5.5 [2.2-13.5] (p < 0.0001) in males, 5.5 [2.9-10.5] (p < 0.0001) in females; for anxiety, ORs were 10.4 [4.9-21.8] (p < 0.0001) and 7.1 [4.5-11.2] (p < 0.0001). Migraine was also associated with both: for depression, ORs were 2.1 [1.3-3.4] (p = 0.002) and 1.8 [1.1-3.1] (p = 0.030); for anxiety 4.2 [2.8-6.3] (p < 0.0001) and 2.4 [1.7-3.4] (p < 0.0001). TTH showed associations only with anxiety: ORs 2.5 [1.7-3.7] (p < 0.0001) for males, 1.5 [1.1-2.1] (p = 0.021) for females. Participants with migraine carried 19.1 % probability of comorbid anxiety, 6.9 % of depression and 5.1 % of both, higher than the representative general-population sample (14.3, 5.6 and 3.8 %). Probabilities in those with MOH were 38.8, 16.9 and 14.4 %; in TTH, they did not exceed those of the whole sample. Comorbid psychiatric disorder did not add to headache-attributed productive time losses, but weak associations existed (R (2)  = 0.020-0.082) for all headache types between lost productive time and probabilities of depression and, less so, anxiety.In this large study we confirmed that depression and especially anxiety are comorbid more than by chance with migraine, and showed the same is true, but more strongly, with MOH. Arguably, migraine patients and, more certainly, MOH patients should be screened with HADS in pursuit of best outcomes

Headache yesterday in Europe

BACKGROUND: Surveys enquiring about burden of headache over a prior period of time (eg, 3 months) are subject to recall bias. To eliminate this as far as possible, we focused on presence and impact of headache on the preceding day (“headache yesterday”). METHODS: Adults (18-65 years) were surveyed from the general populations of Germany, Italy, Lithuania, Luxembourg and the Netherlands, from a work-force population in Spain and from mostly non-headache patient populations of Austria, France and UK. A study of non-responders in some countries allowed detection of potential participation bias where initial participation rates were low. RESULTS: Participation rates varied between 11% and 59% (mean 27%). Non-responder studies suggested that, because of participation bias, headache prevalence might be overestimated in initial responders by up to 2% (absolute). Across all countries, 1,422 of 8,271 participants (15-17%, depending on correction for participation bias) had headache yesterday lasting on average for 6 hours. It was bad or very bad in 56% of cases and caused absence from work or school in 6%. Among those who worked despite headache, 20% reported productivity reduced by >50%. Social activities were lost by 24%. Women (21%) were more likely than men (12%) to have headache yesterday, but impact was similar in the two genders. CONCLUSIONS: With recall biases avoided, our findings indicate that headache costs at least 0.7% of working capacity in Europe. This calculation takes into account that most of those who missed work could make up for this later, which, however, means that leisure and social activities are even more influenced by headache

A genome-wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway

Iron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity of all RNA polymerases contributes to the down-regulation of many mRNAs, tRNAs and rRNAs. Opposite to the general expression pattern, many genes including components of the iron deficiency response, the mitochondrial retrograde pathway and the general stress response display a remarkable increase in both transcription rates and mRNA levels upon iron limitation, whereas genes encoding ribosomal proteins or implicated in ribosome biogenesis exhibit a pronounced fall. This expression profile is consistent with an activation of the environmental stress response. The phosphorylation stage of multiple regulatory factors strongly suggests that the conserved nutrient signaling pathway TORC1 is inhibited during the progress of iron deficiency. These results suggest an intricate crosstalk between iron metabolism and the TORC1 pathway that should be considered in many disorders.This work was supported by predoctoral contracts from the Spanish Ministry of Science, Innovation and Universities (MICINN) to AMR and LRA; a fellowship from the “Generalitat de Catalunya” (Spain) to SMM; European Union Funds (FEDER) and MICINN grants BIO2017-87828-C2-1-P to SP, BIO2017-87828-C2-2-P to MATR, BFU2016-77728-C3-3-P to JEPO, and BFU2015-71978-REDT to SP and JEPO; and Regional Government of Valencia PROMETEOII 2015/006 grant to JEPO

Surgical management of enchondroma with joint transfer: a case report

The enchondromas are the most common benign bone tumor in the hands, mainly in young patients and its treatment is surgical in most cases due to its possible complications avoided through different procedures such as joint transfer, which allows to maintain a good quality of life for the patient. We present the case of a 42-year-old woman who came to the clinic for blunt trauma in the right hand where she was incidentally diagnosed with enchondroma on the third finger of the proximal interphalangeal joint of the right hand. Articular transfer of the proximal interphalangeal joint was performed. Second toe on the right, at 6 weeks corroborates correct evolution with bone consolidation of the articular transfer grade III and donor zone grade II, without infection complications, the correct recovery of the extensor movement range of this joint improving so their state of life should be the main objective of these procedures

Eleven-month longitudinal study of antibodies in SARS-CoV-2 exposed and naïve primary health care workers upon COVID-19 vaccination

We evaluated the kinetics of antibody responses to Two years into the COVID-19 pandemic and 1 year after the start of vaccination rollout, the world faced a peak of cases associated with the highly contagious Omicron variant of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) and nucleocapsid (N) antigens over five cross-sectional visits (January-November 2021), and the determinants of pre-booster immunoglobulin levels, in a prospective cohort of vaccinated primary health care workers in Catalonia, Spain. Antibodies against S antigens after a full primary vaccination course, mostly with BNT162b2, decreased steadily over time and were higher in pre-exposed (n = 247) than naive (n = 200) individuals, but seropositivity was maintained at 100% (100% IgG, 95.5% IgA, 30.6% IgM) up to 319 days after the first dose. Antibody binding to variants of concern was highly maintained for IgG compared to wild type but significantly reduced for IgA and IgM, particularly for Beta and Gamma. Factors significantly associated with longer-term antibodies included age, sex, occupation, smoking, adverse reaction to vaccination, levels of pre-vaccination SARS-CoV-2 antibodies, interval between disease onset and vaccination, hospitalization, oxygen supply, post COVID and symptomatology. Earlier morning vaccination hours were associated with higher IgG responses in pre-exposed participants. Symptomatic breakthroughs occurred in 9/447 (2.01%) individuals, all among naive (9/200, 4.5%) and generally boosted antibody responses. Additionally, an increase in IgA and/or IgM seropositivity to variants, and N seroconversion at later time points (6.54%), indicated asymptomatic breakthrough infections, even among pre-exposed. Seropositivity remained highly stable over almost a year after vaccination. However, gradually waning of anti-S IgGs that correlate with neutralizing activity, coupled to evidence of an increase in breakthrough infections during the Delta and Omicron predominance, provides a rationale for booster immunization

Quality indicators in radiation oncology: proposal of the Spanish Society of Radiation Oncology (SEOR) for a continuous improvement of the quality of care in oncology.

Purpose Current cancer treatment options include surgical intervention, radiotherapy, and chemotherapy. The quality of the provision of each of them and their effective coordination determines the results in terms of benefit/risk. Regarding the radiation oncology treatments, there are not stabilised quality indicators to be used to perform control and continuous improvement processes for healthcare services. Therefore, the Spanish Society of Radiation Oncology has undertaken a comprehensive project to establish quality indicators for use with the information systems available in most Spanish healthcare services. Methods A two-round Delphi study examines consensus of several possible quality indicators (n = 28) in daily practice. These indicators were defined after a bibliographic search and the assessment by radiation oncology specialists (n = 8). They included aspects regarding treatment equipment, patient preparation, treatment, and follow-up processes and were divided in structure, process, and outcome indicators. Results After the evaluation of the defined quality indicators (n = 28) by an expert panel (38 radiation oncologist), 26 indicators achieved consensus in terms of agreement with the statement. Two quality indicators did not achieve consensus. Conclusions There is a high degree of consensus in Spanish Radiation Oncology specialists on which indicators in routine clinical practice can best measure quality. These indicators can be used to classify services based on several parameters (patients, equipments, complexity of the techniques used, and scientific research). Furthermore, these indicators allow assess our current situation and set improvements’ objectives.pre-print241 K

Ancient DNA of the pygmy marmoset type specimen Cebuella pygmaea (Spix, 1823) resolves a taxonomic conundrum

The pygmy marmoset, the smallest of the anthropoid primates, has a broad distribution in Western Amazonia. Recent studies using molecular and morphological data have identified two distinct species separated by the Napo and Solimões-Amazonas rivers. However, reconciling this new biological evidence with current taxonomy, i.e., two subspecies, Cebuella pygmaea pygmaea (Spix, 1823) and Cebuella pygmaea niveiventris (Lönnberg, 1940), was problematic given the uncertainty as to whether Spix's pygmy marmoset (Cebuella pygmaea pygmaea) was collected north or south of the Napo and Solimões-Amazonas rivers, making it unclear to which of the two newly revealed species the name pygmaea would apply. Here, we present the first molecular data from Spix's type specimen of Cebuella pygmaea, as well as novel mitochondrial genomes from modern pygmy marmosets sampled near the type locality (Tabatinga) on both sides of the river. With these data, we can confirm the correct names of the two species identified, i.e., C. pygmaea for animals north of the Napo and Solimões-Amazonas rivers and C. niveiventris for animals south of these two rivers. Phylogenetic analyses of the novel genetic data placed into the context of cytochrome b gene sequences from across the range of pygmy marmosets further led us to reevaluate the geographical distribution for the two Cebuella species. We dated the split of these two species to 2.54 million years ago. We discuss additional, more recent, subdivisions within each lineage, as well as potential contact zones between the two species in the headwaters of these rivers