MAB-MIG: registry of the spanish neurological society of erenumab for migraine prevention.

BACKGROUND: Erenumab was approved in Europe for migraine prevention in patients with ≥ 4 monthly migraine days (MMDs). In Spain, Novartis started a personalized managed access program, which allowed free access to erenumab before official reimbursement. The Spanish Neurological Society started a prospective registry to evaluate real-world effectiveness and tolerability, and all Spanish headache experts were invited to participate. We present their first results. METHODS: Patients fulfilled the ICHD-3 criteria for migraine and had ≥ 4 MMDs. Sociodemographic and clinical data were registered as well as MMDs, monthly headache days, MHDs, prior and concomitant preventive treatment, medication overuse headache (MOH), migraine evolution, adverse events, and patient-reported outcomes (PROs): headache impact test (HIT-6), migraine disability assessment questionnaire (MIDAS), and patient global improvement change (PGIC). A > 50% reduction of MMDs after 12 weeks was considered as a response. RESULTS: We included 210 patients (female 86.7%, mean age 46.4 years old) from 22 Spanish hospitals from February 2019 to June 2020. Most patients (89.5%) suffered from chronic migraine with a mean evolution of 8.6 years. MOH was present in 70% of patients, and 17.1% had migraine with aura. Patients had failed a mean of 7.8 preventive treatments at baseline (botulinum toxin type A-BoNT/A-had been used by 95.2% of patients). Most patients (67.6%) started with erenumab 70 mg. Sixty-one percent of patients were also simultaneously taking oral preventive drugs and 27.6% were getting simultaneous BoNT/A. Responder rate was 37.1% and the mean reduction of MMDs and MHDs was -6.28 and -8.6, respectively. Changes in PROs were: MIDAS: -35 points, HIT-6: -11.6 points, PIGC: 4.7 points. Predictors of good response were prior HIT-6 score < 80 points (p = 0.01), ≤ 5 prior preventive treatment failures (p = 0.026), absence of MOH (p = 0.039), and simultaneous BoNT/A treatment (p < 0.001). Twenty percent of patients had an adverse event, but only two of them were severe (0.9%), which led to treatment discontinuation. Mild constipation was the most frequent adverse event (8.1%). CONCLUSIONS: In real-life, in a personalized managed access program, erenumab shows a good effectiveness profile and an excellent tolerability in migraine prevention in our cohort of refractory patients.

Reversible CO2 Addition to a Si=O Bond and Synthesis of a Persistent SiO2 -CO2 Cycloadduct Stabilized by a Lewis Donor-Acceptor Ligand.

The donor-stabilized sila-ß-lactone 1 reacts with CO2 via a remarkable reversible [2+2]-cycloaddition reaction to form the spiro-cyclic silicon carbonate derivative 2. Furthermore, photolysis of 2 under pressure of CO2 affords the first persistent SiO2 -CO2 cycloadduct 3, presenting a Si2 O4 -like structure, which is stabilized by a Lewis donor-acceptor type ligand. As predicted by theoretical calculations, in marked contrast to the thermodynamically stable SiO2 dimer, the SiO2 -CO2 mixed cycloadduct 3 is labile and readily releases CO2 .

Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral ß-amino acids.

We report a one-pot synthesis of chiral ß2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure ß-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring.

Exceptionally Strong Electron-Donating Ability of Bora-Ylide Substituent vis-à-vis Silylene and Silylium Ion.

Electropositive boron-based substituent (phosphonium bora-ylide) with an exceptionally strong π- and σ-electron donating character dramatically increases the stability of a new type of N-heterocyclic silylene 2 featuring amino- and bora-ylide-substituents. Moreover, the related silylium ion 4 and transition-metal-silylene complexes, with trigonal-planar geometries around the silicon center, are also well stabilized. Therefore, the N,B-heterocyclic silylene 2 can be used as a strongly electron-donating innocent ligand in coordination chemistry similarly to N-heterocyclic carbenes.

A Fairly Stable Crystalline Silanone.

Silanones 2 substituted by bulky amino- and phosphonium ylide substituents have been synthesized and isolated in crystalline form. Thanks to the steric protection and the strong electron-donating ability of the substituents, silanones 2 are persistent and only slowly dimerizes at room temperature (t1/2 =0.5 or 5 h). Structural and theoretical analysis of 2 indicate a short Si=O bond (1.533 Å) and an enhanced polarization toward the O atom compared to Me2 Si=O owing to the strong π-electron donation from the phosphonium ylide substituent.

Cyclic (Amino)(Phosphonium Bora-Ylide)Silanone: A Remarkable Room-Temperature-Persistent Silanone.

A silanone substituted by bulky amino and phosphonium bora-ylide substituents has been isolated in crystalline form. Thanks to the exceptionally strong electron-donating phosphonium bora-ylide substituent, the lifetime at room temperature of the silanone is dramatically extended (t1/2 =4 days) compared to the related (amino)(phosphonium ylide)silanone VI (t1/2 =5 h), allowing easier manipulation and its use as precursor of new valuable silicon compounds. The interaction of silanone with a weak Lewis acid such as MgBr2 increases further its stability (no degradation after 3 weeks at room temperature).

The Lightest Element Phosphoranylidene: NHC-Supported Cyclic Borylidene-Phosphorane with Significant B=P Character.

A borylidene-phosphorane, the lightest phosphoranylidene, which is stabilized by an N-heterocyclic carbene ligand, was synthesized and fully characterized. Experimental electron density analysis and DFT calculations indicate an enhanced ylene character (rather than an ylide character) with an exceptionally strong B→P π-back bonding related to the less electronegative boron compared to phosphorus.

Cyclic Amino(Ylide) Silylene: A Stable Heterocyclic Silylene with Strongly Electron-Donating Character.

An isolable heterocyclic silylene (4) with two different π-donating substituents, namely a classical amino group and a more electropositive and stronger carbon-based π-donating phosphonium ylide, was synthesized and fully characterized. The combination of these two different π-donating substituents confers high thermal stability and an unusual nucleophilic character on silylene 4. Therefore, silylene 4 behaves as a strong donor ligand toward transition metals with a donating character comparable to N-heterocyclic carbenes, in contrast to classical N-heterocyclic silylenes, which generally present a weak donating character.

Long-term safety of OnabotulinumtoxinA treatment in chronic migraine patients: a five-year retrospective study.

Background: Real-world studies have shown the sustained therapeutic effect and favourable safety profile of OnabotulinumtoxinA (BoNTA) in the long term and up to 4 years of treatment in chronic migraine (CM). This study aims to assess the safety profile and efficacy of BoNTA in CM after 5 years of treatment in a real-life setting. Methods: We performed a retrospective chart review of patients with CM in relation to BoNTA treatment for more than 5 years in 19 Spanish headache clinics. We excluded patients who discontinued treatment due to lack of efficacy or poor tolerability. Results: 489 patients were included [mean age 49, 82.8% women]. The mean age of onset of migraine was 21.8 years; patients had CM with a mean of 6.4 years (20.8% fulfilled the aura criteria). At baseline, patients reported a mean of 24.7 monthly headache days (MHDs) and 15.7 monthly migraine days (MMDs). In relation to effectiveness, the responder rate was 59.1% and the mean reduction in MMDs was 9.4 days (15.7 to 6.3 days; p < 0.001). The MHDs were also reduced by 14.9 days (24.7 to 9.8 days; p < 0.001). Regarding the side effects, 17.5% experienced neck pain, 17.3% headache, 8.5% eyelid ptosis, 7.5% temporal muscle atrophy and 3.2% trapezius muscle atrophy. Furthermore, after longer-term exposure exceeding 5 years, there were no serious adverse events (AE) or treatment discontinuation because of safety or tolerability issues. Conclusion: Treatment with BoNTA led to sustained reductions in migraine frequency, even after long-term exposure exceeding 5 years, with no evidence of new safety concerns.

Processing negative autobiographical memories in a foreign language.

The use of a foreign language has been introduced in the clinical setting as a form of emotional distance to help deal with negative experiences. However, the evidence of foreign language reducing emotionality during processing negative events is still scarce. This study aims to test whether the description and processing of a traumatic or highly emotional event in a foreign language could modulate the strength of the connection between traumatic symptomatology and emotional reaction. For this purpose, a sample of 128 healthy participants completed a series of questionnaires via an online platform. Firstly, their levels of distress, arousal and valence were assessed in their native language. Secondly, they were assigned to either the native language or the foreign language group and described a negative childhood event in the assigned language (English or Spanish), followed by five questions for processing the event. Next, their emotionality was assessed again in their native language. Finally, a questionnaire of traumatic stress symptoms and an avoidance scale were completed. Results showed that the relationship between traumatic symptomatology and emotionality was moderated by the language of processing the negative event. Specifically, traumatic symptomatology was more strongly associated with distress and arousal change when the processing task was performed in the native language. These findings suggest the influence of a foreign language on emotional reactivity when a negative experience is processed, which could be an essential tool in the treatment of disorders related to stress and trauma.

Languages and Psychotherapy: The Effect of Foreign Language on Fear Extinction.

BACKGROUND: Using a foreign language can influence emotion modulation, but whether different psychotherapy processes would be affected by a foreign language is still unclear. The current study explored the foreign language effect on the extinction of fear. METHOD: During the conditioning phase, part of the neutral stimuli presented to the participants were associated with a threat, while they performed a countdown task in their native language. In the extinction phase, participants performed the same task either in their native/foreign language and were informed that the threat would no longer appear. We collected self-reports of fear, and pupil dilation and electrodermal activity as physiological measures of arousal. RESULTS: Extinction was successful, indicated by greater self-reported fear and pupil dilation during the threat condition compared to neutral in the conditioning phase, but no significant differences during extinction. Although the foreign language group presented higher arousal, fear extinction occurred regardless of the linguistic context. CONCLUSIONS: Fear extinction via verbal instructions is equally effective in a foreign and a native language context. These results indicate that evidence should be continue to be gathered on the role of foreign languages using basic paradigms with clinical applications.

A community of marine bacteria with potential to biodegrade petroleum-based and biobased microplastics.

The biodegradability conditions for both, petroleum-based plastics and bioplastics needs to be evaluated under environmentally realistic conditions. We assessed the biodegradability of low-density polyethylene and biobased polyethylene terephthalate microplastic films by a consortium of marine bacteria during 45 days. Bacterial growth and pH were higher in the samples inoculated with bacteria, compared to the controls. Fourier Infrared spectroscopy-Attenuated Total Reflectance and scanning electron microscopy indicated changes in the chemical functional groups, and the presence of fractures and biofilms in the surface of both plastics exposed to the bacterial community, respectively. The chemical oxygen demand further indicated signs of biodegradation of both polymers. Specific groups of bacteria showed preference for each type of microplastic. Overall, our results show signs of biodegradation, or at least biodeterioration and biofragmentation, of both types of plastics, when subjected to the selected bacterial community. Biobased PET was no more prone to biodegradation than conventional, petroleum-based LDPE.

Behavioral Activation through Virtual Reality for Depression: A Single Case Experimental Design with Multiple Baselines.

Behavioral activation (BA) is a structured psychotherapeutic approach for the treatment of major depressive disorder (MDD), which aims at increasing the engagement in activities that might bring enjoyment and meaning to patients' lives. Although a growing body of evidence supports the effectiveness of BA, enhancing the motivation and activity level of depressed patients is often challenging. In the present study, we explored the effectiveness of a brief BA treatment supported by virtual reality (VR) to facilitate the visualization and anticipation of four pleasurable activities that we tried to re-introduce in the patients' daily routine. To do so, we conducted a single-case experimental design with multiple baselines in a sample of patients with moderate to severe depressive symptoms. Three overlap analyses across participants and across behaviors were conducted to calculate the rate of improvement of each patient after the delivery of the intervention. Across the three overlap indices, the participants generally showed moderate-to-large improvements in the level of daily activity, as well as in the time spent planning and/or engaging in one or more activities scheduled during the intervention. Furthermore, most patients also reported a moderate-to-large reduction in daily depressive symptoms and improved mood. Overall, the promising results of the present study suggest that the proposed VR-based BA intervention might represent a valid approach to behaviorally activate depressed patients. The barriers and future lines of research of this innovative field are discussed.

Scientists' warning against the society of waste.

The metabolism of contemporary industrialized societies, that is their energy and material flows, leads to the overconsumption and waste of natural resources, two factors often disregarded in the global ecological equation. In this Discussion article, we examine the amount of natural resources that is increasingly being consumed and wasted by humanity, and propose solutions to reverse this pattern. Since the beginning of the 20th century, societies, especially from industrialized countries, have been wasting resources in different ways. On one hand, the metabolism of industrial societies relies on non-renewable resources. On the other hand, yearly, we directly waste or mismanage around 78% of the total water withdrawn, 49% of the food produced, 31% of the energy produced, 85% of ores and 26% of non-metallic minerals extracted, respectively. As a consequence, natural resources are getting depleted and ecosystems polluted, leading to irreversible environmental changes, biological loss and social conflicts. To reduce the anthropogenic footprint in the planet, and live in harmony with other species and ourselves, we suggest to shift the current economic model based on infinite growth and reduce inequality between and within countries, following a degrowth strategy in industrialized countries. Public education to reduce superfluous consumption is also necessary. In addition, we propose a set of technological strategies to improve the management of natural resources towards circular economies that, like ecosystems, rely only upon renewable resources.

Dysregulation of Lysyl Oxidases Expression in Diabetic Nephropathy and Renal Cell Carcinoma.

Lysyl oxidases (LOXs) are amino oxidase enzymes that catalyze the oxidative deamination of lysine and hydroxylysine residues to form allysine, the first step towards the development of the final cross-linking reaction in collagens, a crucial macromolecule that reinforces extracellular matrices. Basement membranes are specialized extracellular matrices that are essential components of the glomerular filtration barrier, which also support tubular epithelial cells. Lysyl oxidases are post-translational enzymes indispensable for tissue architecture, participating actively in the development and function of kidneys. The differential expression and dysregulation of these enzymes promote diabetic nephropathy, one of the major complications observed in end-stage renal diseases. In addition, these enzymes act as transcription factors that trigger the epithelial-mesenchymal transition responsible for the generation of different cancers. In the kidney, the expression studies in physiological conditions identified LOXL1 and LOXL2 as constituent proteins of glomerular basement membranes. Besides, LOX and LOXL2 are upregulated in fibrosis and renal cell carcinoma. The current review summarizes the physiological expression of LOXs enzymes in the nephrons, including glomerulus and tubules. Their roles in renal diseases are particularly highlighted in diabetic nephropathy and renal cell carcinoma, two pathophysiological conditions where these enzymes have been demonstrated to participate. The focus of the present study is to describe and discuss the current understanding in this field. The current potential of LOXs enzymes as a biomarker and pharmacological target to kidney diseases that involves extracellular matrix cross-linking enzymes is also discussed. LOXs isoforms and their capacity as therapeutic targets could be used for diagnostic and prognostic purposes and in treating these renal complications.

Atmospheric Deposition Impact on Bacterial Community Composition in the NW Mediterranean.

Atmospheric deposition is a source of inorganic nutrients and organic matter to the ocean, and can favor the growth of some planktonic species over others according to their nutrient requirements. Atmospheric inputs from natural and anthropogenic sources are nowadays increasing due to desertification and industrialization, respectively. While the impact of mineral dust (mainly from the Saharan desert) on phytoplankton and bacterial community composition has been previously assessed, the effect of anthropogenic aerosols on marine bacterial assemblages remains poorly studied. Since marine bacteria play a range of roles in the biogeochemical cycles of inorganic nutrients and organic carbon, it is important to determine which taxa of marine bacteria may benefit from aerosol fertilization and which not. Here, we experimentally assessed the effect of Saharan dust and anthropogenic aerosols on marine bacterioplankton community composition across a spatial and temporal range of trophic conditions in the northwestern Mediterranean Sea. Results from 16S rDNA sequencing showed that bacterial diversity varied significantly with seasonality and geographical location. While atmospheric deposition did not yield significant changes in community composition when all the experiments where considered together, it did produce changes at certain places and during certain times of the year. These effects accounted for shifts in the bacterial community's relative abundance of up to 28%. The effect of aerosols was overall greatest in summer, both types of atmospheric particles stimulating the groups Alphaproteobacteria, Betaproteobacteria, and Cyanobacteria in the location with the highest anthropogenic footprint. Other bacterial groups benefited from one or the other aerosol depending on the season and location. Anthropogenic aerosols increased the relative abundance of groups belonging to the phylum Bacteriodetes (Cytophagia, Flavobacteriia, and Sphingobacteriia), while Saharan dust stimulated most the phytoplanktonic group of Cyanobacteria and, more specifically, Synechococcus.

Assessment of adulthood in the living Spanish population based on ossification of the medial clavicle epiphysis using ultrasound methods.

It is a fact that in recent years requests have greatly increased to obtain estimates of the legal age of undocumented individuals alleged to be minors who have been forced to enter different European Community countries for socioeconomic reasons or due to war. Spain is one of the countries most affected by this illegal immigration because of its proximity to North Africa. Therefore, it has become necessary to develop new standards which help provide a response to the demands of the justice administration. In recent years, the Superior Justice Court has rejected several pieces of expert evidence on the grounds that the age intervals therein were not sufficiently reliable and that the radiographic techniques used to determine age were invasive, potentially causing harm to the alleged minor. These sentences have caused interest in this field of work to increase within the scientific community. As a result, in order to improve age predictions and, above all, reduce minors' exposure to radiation, this study was created for completion on the Spanish population, using the ultrasound scan as a diagnostic technique. Used as a study sample were the ultrasound images of the proximal sternal epiphysis of the clavicle among 221 individuals of both sexes, of ages ranging from 5 to 30 years. All of the images were classified into 4 stages of fusion, in accordance with the development of metaphyseal closure proposed by Schulz et al. in 2008. The results show differences among the 4 proposed groups for each of the stages of fusion, with the results found in Stage II being especially important because, for both sexes, they would imply that the patient studied has reached an age of over 18 years, which is the legal age of adulthood in Spain, as established by the Spanish Constitution of 1978. Though further research is still recommended, these results, coupled with the use of ultrasound as a non-invasive diagnostic technique, could help solve some of the problems currently arising in justice courts.

Languages and Psychotherapy: The Effect of Foreign Language on Fear Extinction / Lenguas y Psicoterapia: El Efecto de la Lengua Extranjera en la Extinción del Miedo

Background: Using a foreign language can influence emotion modulation, but whether different psychotherapy processes would be affected by a foreign language is still unclear. The current study explored the foreign language effect on the extinction of fear. Method: During the conditioning phase, part of the neutral stimuli presented to the participants were associated with a threat, while they performed a countdown task in their native language. In the extinction phase, participants performed the same task either in their native/foreign language and were informed that the threat would no longer appear. We collected self-reports of fear, and pupil dilation and electrodermal activity as physiological measures of arousal. Results: Extinction was successful, indicated by greater self-reported fear and pupil dilation during the threat condition compared to neutral in the conditioning phase, but no significant differences during extinction. Although the foreign language group presented higher arousal, fear extinction occurred regardless of the linguistic context. Conclusions: Fear extinction via verbal instructions is equally effective in a foreign and a native language context. These results indicate that evidence should be continue to be gathered on the role of foreign languages using basic paradigms with clinical applications.(AU)

Antecedentes: Usar un idioma extranjero puede influir la modulación de las emociones, pero no está claro si su uso podría influir diferentes procesos psicoterapéuticos. Este estudio explora el efecto de la lengua extranjera en la extinción del miedo. Método: Durante el condicionamiento, parte de los estímulos presentados se asociaron a amenaza, mientras los participantes realizaban una tarea de cuenta regresiva en un contexto de lengua nativa. En la fase de extinción, se realizó la misma tarea en su lengua nativa/extranjera, y se informó de que ya no habría amenaza. Se recogieron autoinformes de miedo, así como dilatación de pupila y actividad electrodérmica como medidas fisiológicas de excitación. Resultados: La extinción fue satisfactoria, como muestran una mayor dilatación pupilar y los autoinformes de miedo al comparar las condiciones de amenaza y neutral en la fase de condicionamiento, y no encontrar diferencias significativas durante la extinción. Aunque el grupo de lengua extranjera presentó una mayor excitación, la extinción del miedo ocurre independientemente del contexto lingüístico. Conclusiones: La extinción del miedo mediante instrucciones verbales es igualmente eficaz en contexto de lengua extranjera y nativa. Estos resultados invitan a seguir reuniendo pruebas sobre el papel de las lenguas extranjeras mediante paradigmas con aplicaciones clínicas.(AU)