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Objective: The aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis., Methods: We report methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core outcome set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach., Results: Our search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30)., Conclusions: The present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine., (© 2024. The Author(s).)

There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222-an investigational humanized monoclonal antibody directed against PACAP ligand-would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities., Methods: In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18-45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days' interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark., Results: In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P < 0.0001) compared to participants who received placebo + PACAP38 infusion. Secondary and explorative analysis revealed that PACAP38 infusion induced an increase in facial blood flow, heart rate and mild headache, and indicated that these PACAP38-induced responses were inhibited by Lu AG09222., Conclusions: This proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases., Trial Registration: ClinicalTrials.gov: NCT04976309. Registration date: July 19, 2021., (© 2023. The Author(s).)

Patients with transfusion-dependent beta (β)-thalassaemia experience a broad range of complications. ULYSSES, an epidemiological, multicentre, retrospective cross-sectional study, aimed to assess the prevalence and severity of treatment and disease complications, capture disease management and identify predictors of complications in patients with transfusion-dependent β-thalassaemia, treated in routine settings in Greece. Eligible patients were adults diagnosed with β-thalassaemia ≥12 months before enrolment and having received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion-free period ≥35 days in the 24 weeks before enrolment. Primary data were collected at a single visit and through chart review. Between Oct 21, 2019, and Jun 15, 2020, 201 eligible patients [median (interquartile range, IQR) age 45.7 (40.2-50.5) years; 75.6% > 40 years old; 64.2% female] were enrolled, a mean (standard deviation) of 42.9 (7.8) years after diagnosis. Median (IQR) age at diagnosis and RBC transfusion initiation were 0.8 (0.4-2.8) and 1.3 (1.0-5.0) years, respectively. From diagnosis to enrolment, patients had developed a median of six (range: 1-55) complications; 19.6% were grade ≥3. The most represented complications were endocrine/metabolic/nutrition disorders (91.5%), surgical/medical procedures (67.7%) and blood/lymphatic system disorders (64.7%). Real-world data generated by ULYSSES underscore the substantial complication burden of transfusion-dependent β-thalassaemia patients, routinely managed in Greece., Competing Interests: Antonis Kattamis has received grants from Novartis and Bristol Myers Squibb/Celgene; consulting fees from Agios Pharmaceuticals, Amgen, Bristol Myers Squibb/Celgene, Crispr/Vertex, Ionis Pharmaceuticals, Novartis and Vifor; honoraria from Novartis, Bristol Myers Squibb/Celgene, Chiesi and Crispr/Vertex; and meeting/travel support from Bristol Myers Squibb/Celgene.Sophia Delicou has received consulting fees, honoraria and meeting/travel support from Novartis and Bristol Myers Squibb.Foteini Petropoulou has received grants and/or study funding from Genesis Pharma, Protagonist Therapeutics and Celgene; consulting fees from Bristol Myers Squibb; and has attended advisory board meetings for Bristol Myers Squibb.Michael D. Diamantidis has received study funding/grants from Genesis Pharma, Ionis Pharmaceuticals, Novartis, Forma Therapeutics Inc., Synteract and Vifor International Inc.; honoraria from Genesis Pharma, Uni‐Pharma, Bristol Myers Squibb and Abbvie; meeting/travel support from Demo Company, Bristol Myers Squibb and Genesis Pharma; and has attended advisory board meetings for Bristol Myers Squibb.Loukia Evliati has received study funding from Genesis Pharma.Panagiotis Viktoratos is an employee of Bristol Myers Squibb.Alexandra Kourakli has received study funding/grants from Bristol Myers Squibb; consulting fees from Forma Therapeutics Inc.; honoraria from Novartis, Bristol Myers Squibb and Elpen; meeting/travel support from Glaxo and Rafarm; and has attended advisory board meetings for Genesis, Gilead and Agios.Ersi Voskaridou, Evangelos Klironomos, Ioannis Lafiatis, Stylianos Lafioniatis, Eleni Kapsali, Kiki Karvounis‐Marolachakis, Despoina Timotheatou and Chrysoula Deligianni have no disclosures to declare., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) provoked cluster headache attacks in individuals with episodic cluster headache during their active phase and individuals with chronic cluster headache. In this study, we investigated whether infusions of PACAP and VIP caused alterations in plasma levels of VIP and their potential contribution to induced cluster headache attacks., Methods: Participants received either PACAP or VIP infusion for 20 min on 2 separate days with an interval of at least 7 days in between. Blood collection was performed at T 0 , T 20 , T 30 , and T 90 . Plasma levels of VIP were measured using a validated radioimmunoassay method., Results: Blood samples were collected from participants with episodic cluster headache in the active phase (eCHA, n = 14), remission (eCHR, n = 15), and from participants with chronic cluster headache (cCH, n = 15). Baseline levels of VIP did not differ among the three groups ( p = 0.1161). During PACAP infusion, mixed-effects analysis revealed a significant increase in plasma levels of VIP in eCHA ( p = 0.0300) and eCHR ( p = 0.0058) but not in cCH ( p = 0.2930). We found no difference in the increase of plasma VIP levels between patients who developed PACAP38- or VIP-induced attacks., Conclusion: Cluster headache attacks induced by PACAP38 or VIP infusion are not associated with changes in plasma levels of VIP. Further studies are needed to investigate the role of VIP and the parasympathetic system in cluster headache., Clinical Trial Registration: The parent study is registered at ClinicalTrials.gov (NCT03814226)., Competing Interests: MA reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals during the conduct of the study. MA reported serving as Associate Editor of Cephalalgia, Associate Editor of The Journal of Headache and Pain, and Associate Editor of Brain. AS and LP are currently employed at Lundbeck. The opinions expressed in this manuscript are solely their own and do not express the views or opinions of Lundbeck. RJ reported fees from lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan and that she has been or is investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck. She is also director of Danish Headache Center, Lifting The Global Burden of Headache and director of Master of Headache Disorders at University of Copenhagen. She has received research funding from the University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation, and Tryg Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deligianni, Pellesi, Chaudhry, Haulund Vollesen, Snoer, Hannibal, Jensen and Ashina.)

Among healthcare workers (HCWs), SARS-CoV-2 vaccine hesitancy may be linked to a higher susceptibility to nocebo effects, i.e., adverse events (AEs) experienced after medical treatments due to negative expectations. To investigate this hypothesis a cross-sectional survey was performed with a self-completed questionnaire that included a tool (Q-No) for the identification of nocebo-prone individuals. A total of 1309 HCWs (67.2% women; 43.4% physicians; 28.4% nurses; 11.5% administrative staff; 16.6% other personnel) completed the questionnaires, among whom 237 (18.1%) had declined vaccination. Q-No scores were ≥15 in 325 participants (24.8%) suggesting nocebo-prone behavior. In a multivariate logistic regression model with Q-No score, age, gender, and occupation as independent variables, estimated odds ratios (ORs) of vaccination were 0.43 (i.e., less likely, p < 0.001) in participants with Q-No score ≥ 15 vs. Q-No score < 15, 0.58 in females vs. males ( p = 0.013), and 4.7 (i.e., more likely) in physicians vs. other HCWs ( p < 0.001), independent of age, which was not significantly associated with OR of vaccination. At least one adverse effect (AE) was reported by 67.5% of vaccinees, mostly local pain and flu-like symptoms. In a multivariate logistic regression model, with Q-No score, age, gender, and occupation as independent variables, estimated ORs of AE reporting were 2.0 in females vs. males ( p < 0.001) and 1.47 in physicians vs. other HCWs ( p = 0.017) independently of age and Q-No score, which were not significantly associated with OR of AE. These findings suggest that nocebo-prone behavior in HCWs is associated with SARS-CoV-2 vaccination hesitancy indicating a potential benefit of a campaign focused on nocebo-prone people.

Background: We aimed to explore patients' preferences for headache treatments with a self-administered questionnaire including the Q-No questionnaire for nocebo., Methods: Questionnaires from 514 outpatients naïve to neurostimulation and monoclonal antibodies were collected., Results: Patients assessed that the efficacy of a treatment is more important than safety or route of administration. They preferred to use an external neurostimulation device for both acute (67.1%) and preventive treatment (62.8%). Most patients preferred to take a pill (86%) than any other drug given parenterally for symptomatic pharmaceutical treatment. For preventive pharmaceutical treatment, most patients preferred to take a pill once per day (52%) compared to an injection either subcutaneously or intravenously each month (9% and 4%), or three months (15% and 11%). 56.6% of all participants scored more than 15 in Q-No questionnaire indicating potential nocebo behaviors that contributed significantly in their choices., Conclusion: These patient preferences along with efficacy and safety data may help physicians better choose the right treatment for the right person.

Background and Purpose: Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (ΔT), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification., Methods: Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR., Results: In total, 50 patients were included in the study. Culprit carotid arteries had higher ΔT compared with nonculprit (0.93±0.58 versus 0.58±0.35°C; P<0.001). The addition of ΔT to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768; Pdif=0.05)., Conclusions: Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination., (© 2014 American Heart Association, Inc.)

The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD.

Current research on the cytokine-mediated signalling towards the polarization and differentiation of a T-helper cell lineage lacks mechanistic insights on the transcriptional regulation of cytokine receptor genes. Here, we propose a new mechanism for the transcriptional regulation of the interferon gamma receptor 1 gene via long-range intrachromosomal interactions with the Ifnγ locus mediated by the protein CTCF. These interactions sustain the monoallelic expression of the differentially methylated IfnγR1 gene and are persistent on blockade of active transcription. Our findings suggest that regulatory elements for a cytokine gene locus can also positively regulate the transcription of its receptor.