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BackgroundIn daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort.MethodsThis is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment.ResultsOf 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: − 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054–0.975]; p = 0.049).ConclusionsIn real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.

ObjectiveTo evaluate the frequency and headache-related impact response to monoclonal antibodies against calcitonin gene-related peptide (CGRP) in a clinical sample of refractory migraine patients.MethodsWe included migraine patients with ≥ 8 headache days/month that had failed at least three preventive medications. Demographic, medical and migraine history were collected. Patients completed an electronic headache diary including headache days/month, migraine days/month, headache pain intensity (0–3 numerical scale), use of analgesics and completed Patient-Reported Outcome questionnaires at baseline and after 12 weeks. Patients were classified into ≥ 50%, ≥ 75% and 100% responders according to the improvement in frequency.ResultsWe included 155 patients (109 erenumab and 46 galcanezumab). After 12 weeks, headache frequency decreased − 9.1 headache days/month and − 8.5 migraine days/month from baseline. A 39.5% had a ≥ 50% headache days/month reduction and a 51.6% ≥ 50% migraine days/month reduction. In the ≥ 50% migraine days/month-responders group, frequency reduction was − 13,9 migraine days/month from baseline and showed clear improvements for all patient-reported outcomes. A 14.2% and 26.5% had a ≥ 75% response in headache and migraine days/month, respectively, and 11.0% showed a 100% migraine days/month reduction. Patients who were not on other preventive medications had less severe disability and higher ratio of migraine over headache days/month were more likely of being a ≥ 50% migraine days/month-responder. We did not record any severe adverse events, being the most common constipation (20.0%), fatigue (7.1%) and a transient increase in blood pressure (5.2%).ConclusionsIn real-world clinical practice, monoclonal antibodies against CGRP proved to be effective treatments in resistant migraine patients.

BackgroundPatient-Reported Outcomes (PROs) have been developed to numerically quantify disability, impact and quality of life. They have been widely used in migraine clinical trials. However, we still do not know which PRO more accurately reflects preventive treatment response from a patient’s perspective or which one may help us with treatment decisions in clinical practice. They have been used to enforce the efficacy results in clinical trials and real-world evidence so far. The aim of this study was to analyze which PROM is (1) better correlated with all primary efficacy endpoints and (2) which one is better associated with treatment continuation with CGRP-mAbs at week-12, which is usually the moment when this decision is made.MethodsPatients with migraine who had received 3 administrations of CGRP-mAbs were evaluated in this prospective cohort study. Primary efficacy outcomes considered: a change in migraine days (MMD), headache days (MHD), pain intensity (INT), acute medication days (AMD) and 50% responder rate. The Spearman coefficient (rs) was the measure used for quantify the strength of the correlation between PROMs and treatment efficacy outcomes changes. A stepwise logistic regression identified which PROM was independently associated with treatment continuation at week-12.Results263 patients completed 12 weeks of treatment. The efficacy outcomes and PROMs scores were statistically significantly reduced at week-12 for all patients. The role function-restrictive (RFR) domain of the Migraine-Specific Quality of Life (MSQ) questionnaire was statistically significantly correlated with all primary efficacy outcomes. Relative changes in MSQ total score (OR[95%]: 0.840[0.619-0.973]; p=0.037) and Patient Global Impression of Change (PGIC) scale (OR[95%]: 15.569[6.254-31.533]; p<0.001) were the PROMs associated with treatment continuation as independent factors at week-12.ConclusionsChanges in MSQ questionnaire and PGIC scale at week-12 were the PROMs with higher association with CGRP-mAbs response from a patient’s perspective and medical decision-taking.

BackgroundMigraine is not routinely assessed at work, making impossible to realize its impact and the potential benefit of migraine-related health strategies. We aimed to assess epidemiology, work and economic impact of migraine in a workplace cohort of a tertiary hospital.MethodsCross-sectional analysis of a cohort of employees working in a Spanish tertiary hospital. Through a web questionnaire, we screened participants for migraine, collecting demographic data, work characteristics, work impairment due to headache (WPAI), treatments and healthcare resource utilization. We calculated direct and indirect costs for the hospital.ResultsSix hundred sixty-seven employees participated (8.8%). 71.2% (475/667) fulfilled criteria for migraine, being 76.8% (365/475) low-frequency episodic migraine (LFEM), 12.6% (60/475) high-frequency episodic migraine (HFEM) and 10.5% (50/475) chronic migraine (CM). Only 56.2% (267/475) were aware of suffering from migraine. Only 43.3% (26/60) of HFEM and 56.0% (28/50) of CM have been on preventive treatment in the last year. Migraine caused an overall economic loss for the hospital of 439,848.90 €/month, as a result of utilization of healthcare resources at the workplace (136,028.0 €/month) and indirect costs (absenteeism + presenteeism: 303,820.90 €/month). Specifically, only 110 participants (HFEM + CM) were responsible for half of indirect costs (165,017.2€/month).ConclusionsAlthough healthcare professionals have greater knowledge on health issues, migraine is underdiagnosed and undertreated, leading to a significant economic loss for the hospital. These results urge companies to assess migraine and promote stronger and migraine-specific health strategies at the workplace as a way to improve their own economic sustainability and the burden of migraine in their workforce.

Background Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. Objective To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. Methods This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. Results From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism ( p  < 0.001) and presenteeism ( p  < 0.001). Average savings in indirect costs per patient at M3 were absenteeism 105.4 euros/month and presenteeism 394.3 euros/month, similar for M6. Considering the monthly cost of anti-CGRP MAbs, the cost-benefit analysis showed savings of 159.8 euros per patient at M3, with an annual projected savings of 639.2 euros/patient. Both responders and partial responders (30–50% reduction in MHD) presented a positive cost-benefit balance. The overall savings of the cohort at M3/M6 compensated the negative cost-benefit balance for non-responders (< 30% reduction in MHD). Conclusion Anti-CGRP MAbs have a positive impact in the workforce significantly reducing absenteeism and presenteeism. In Spain, this benefit overcomes the expenses derived from their use already at 3 months and is potentially sustainable at longer term; also in patients who are only partial responders, prompting reconsideration of current reimbursement criteria and motivating the extension of similar cost-benefit studies in other countries.

BackgroundThere is a need to establish which are the more relevant headache-related outcomes that have an impact on our patient’s lives to accurately evaluate treatment response in daily clinical practice.ObjectiveThe aim of this study was to evaluate the relevance of clinical trial endpoints in clinical real-life disability improvement in response to migraine preventive treatment with OnabotulinumtoxinA.MethodsThis is an observational prospective study. We included patients with chronic migraine fulfilling ICHD-3beta/3 criteria. We prospectively collected data of 8 headache-related and acute medication use endpoints recommended by the Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine. We evaluated their impact on disability improvement after 6 months of treatment with OnabotulinumtoxinA. We defined as a responder in disability, patients with ≥50% MIDAS score reduction after 2 cycles of treatment following PREEMPT protocol. We performed an analysis to measure the impact of improvement in the evaluated outcome measures according to perceived disability in clinical practice.ResultsWe included 395 patients (85.1% women, mean age 46.7 ± 12.6 years). Mean headache frequency at baseline was 26.5 ± 5.2 headache days/month. After 6 months, 49.1% of patients were headache-related disability responders. From all outcome measures collected, variables independently associated to disability improvement were headache days reduction (p = 0.02) and ≥ 50% pain intensity reduction (p = 0.04). A ≥ 50% reduction in headache frequency or pain intensity showed similar influence on disability improvement after treatment.ConclusionsHeadache pain intensity is as important as frequency when evaluating the clinical response and impact on patient headache-related disability after migraine preventive treatment with OnabotulinumtoxinA.

Observations on \"macrobacteria\" inhabiting the reduced bottoms of two freshwater lagoons in central Chile are here presented. The new finding of morphologically diverse, colorless multicellular filamentous bacteria expands their known presence into Chilean continental freshwater environments and confirms their association with reduced habitats. Their morphologies and ecology appear to connect them to similar benthic marine findings and Precambrian microfossils, encouraging their exploration in similar systems around the world and guiding the search for biosignatures in extraterrestrial paleoenvironments.

Intracytoplasmic sperm injection (ICSI) is a widely used assisted reproduction technique, but in cattle it faces major challenges due to inefficient oocyte activation after sperm microinjection. This study investigated different oocyte activation strategies and assessed the potential role of reducing agents glutathione (GSH), cysteamine (Cys) and dithiobutylamine (DTBA) to improve sperm head decondensation and embryo development following Piezo-ICSI. Haploid parthenogenetic activation using different ethanol concentrations (1%, 3%, 7% and 10%) failed to yield blastocysts, while diploid activation with ethanol or ionomycin combined with inhibitors significantly improved cleavage (43–55%) and blastocyst rates (14–27%), respectively. However, applying two ethanol pulses was detrimental, reducing both cleavage and blastocysts likely due to toxic overexposure. Sperm head decondensation compounds in Piezo-ICSI showed a high percentage of inactivated oocytes (75% GSH, 55% Cys and 40% DTBA). The highest male pronuclear formation rates were observed in the control without sperm head decondensation (21%) and with DTBA treatment (10%). Despite this, the treatment with Cys resulted in higher developmental potential to the blastocyst stage (22%) comparable to the control (24%). These data suggest that the inclusion of sperm head decondensing agents could represent a promising new strategy for enhancing the early in vitro development of ICSI-generated embryos. However, for this purpose, careful optimization of the concentration and incubation time of these decondensing compounds is essential.

Background Migraine is a complex neurological disorder with significant heterogeneity in its clinical presentation and molecular mechanisms. Calcitonin gene-related peptide (CGRP) has emerged as a key player in migraine pathophysiology, but challenges remain in its utilization as a biomarker. This study aimed to investigate salivary CGRP levels during migraine attacks across the frequency spectrum and explore associations with clinical variables. Methods A prospective longitudinal pilot study was conducted, recruiting migraine patients from an outpatient headache clinic. Salivary CGRP levels were measured at interictal, onset, post-2 h of onset and end-of-attack. Using generalized linear mixed models, we explored the effect of CGRP changes over the attack in presence of depressive symptoms (DS), acute attack treatment, and after three-months of erenumab treatment. Finally, patients were classified and compared according to their CGRP phenotype. Results A total of 44 migraine patients were included (90.9% women), with 80 migraine attacks analyzed. Salivary CGRP levels increased at the onset of migraine attacks. We observed statistically significant interactions between DS and both the linear (Est. [SE]: 19.4 [5.8], p  = 0.001) and quadratic terms of time (-19.1 [6.0], p  = 0.002). Additionally, a significant three-way interaction within the use of acute treated attack (linear-term: -18.5 [6.2], p  = 0.005; quadratic-term: 19.2 [6.8], p  = 0.005) was also found. Molecular phenotyping revealed that 72.7% (32/44) of patients presented only CGRP-dependent attacks, while 27.3% (12/44) presented non-CGRP-dependent migraine attacks. Patients with only CGRP-dependent attacks were associated with younger age, shorter disease evolution time, a higher proportion of aura, and fewer monthly headache days ( p  < 0.05). Exploratory analysis of erenumab treatment effects did not result in changes in CGRP levels during migraine attacks. Conclusions Our study underscores the dynamic nature of migraine at a molecular level and emphasizes the importance of integrating clinical variables, such as depressive symptoms, in understanding its pathophysiology. The identification of distinct migraine subtypes based on CGRP dependence suggests potential opportunities for personalized treatment approaches.

The recent discovery of a deep-water sulfur-cycling microbial biota in the ∼2.3-Ga Western Australian Turee Creek Group opened a new window to life's early history. We now report a second such subseafloor-inhabiting community from the Western Australian ∼1.8-Ga Duck Creek Formation. Permineralized in cherts formed during and soon after the 2.4- to 2.2-Ga “Great Oxidation Event,” these two biotas may evidence an opportunistic response to the mid-Precambrian increase of environmental oxygen that resulted in increased production of metabolically useable sulfate and nitrate. The marked similarity of microbial morphology, habitat, and organization of these fossil communities to their modern counterparts documents exceptionally slow (hypobradytelic) change that, if paralleled by their molecular biology, would evidence extreme evolutionary stasis. Significance An ancient deep-sea mud-inhabiting 1,800-million-year-old sulfur-cycling microbial community from Western Australia is essentially identical both to a fossil community 500 million years older and to modern microbial biotas discovered off the coast of South America in 2007. The fossils are interpreted to document the impact of the mid-Precambrian increase of atmospheric oxygen, a world-changing event that altered the history of life. Although the apparent 2-billion-year-long stasis of such sulfur-cycling ecosystems is consistent with the null hypothesis required of Darwinian evolution—if there is no change in the physical-biological environment of a well-adapted ecosystem, its biotic components should similarly remain unchanged—additional evidence will be needed to establish this aspect of evolutionary theory.