Search

The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.

Abstract Background In developing countries, overweight prevalence is increasing while underweight prevalence is still high. This situation is known as the double nutrition burden. Both underweight and overweight are related to increased risk of chronic non-communicable diseases, reduced well-being and quality of life. This study aims to compare the prevalence of overweight and underweight among Vietnamese adults in 2000 and 2005. Methods The study was based on two nationally representative surveys, the National Nutrition Survey 2000 (14,452 subjects) and the National Adult Obesity Survey 2005 (17,213 subjects). Adults aged 25-64 years were sampled to be nationally representative. Multiple multinomial logistic regression analysis was used to investigate the association of underweight and overweight with socio-economic indicators. Results The distribution of BMI across the population and population groups indicated a shift towards higher BMI levels in 2005 as compared to 2000. The nationwide prevalence of overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) was 6.6% and 0.4% respectively in 2005, almost twice the rates of 2000 (3.5% and 0.2%). Using the Asian BMI cut-off of 23 kg/m2 the overweight prevalence was 16.3% in 2005 and 11.7% in 2000. In contrast, the underweight prevalence (BMI < 18.5 kg/m2) of 20.9% in 2005 was lower than the rate of 25.0% in 2000. Women were more likely to be both underweight and overweight as compared to men in both 2000 and 2005. Urban residents were more likely to be overweight and less likely to be underweight as compared to rural residents in both years. The shifts from underweight to overweight were clearer among the higher food expenditure levels. Conclusions The double nutrition burden was clearly present in Vietnam. The distribution of BMI across the population groups generally indicated a shift towards higher BMI levels in 2005 as compared to 2000. The prevalence of overweight was increased while the declined level of undernutrition was still high in 2005. The shifts of underweight to overweight were most obvious among population groups with higher food expenditure levels.

Previous studies have reported the functional role, biochemical features and synthesis pathway of podophyllotoxin (PTOX) in plants. In this study, we employed combined morphological and molecular techniques to identify an endophytic fungus and extract PTOX derivatives. Based on the analysis of ITS sequences and the phylogenetic tree, the isolate was classified as Penicillium herquei HGN12.1C, with a sequence identity of 98.58%. Morphologically, the HGN12.1C strain exhibits white colonies, short-branched mycelia and densely packed hyphae. Using PacBio sequencing at an average read depth of 195×, we obtained a high-quality genome for the HGN12.1C strain, which is 34.9 Mb in size, containing eight chromosomes, one mitochondrial genome and a GC content of 46.5%. Genome analysis revealed 10 genes potentially involved in PTOX biosynthesis. These genes include VdtD, Pinoresinollariciresinol reductase (PLR), Secoisolariciresinol dehydrogenase (SDH), CYP719A23, CYP71BE54, O-methyltransferase 1 (OMT1), O-methyltransferase 3 (OMT3), 2-ODD, CYP71CU and CYP82D61. Notably, the VdtD gene in fungi shares functional similarities with the DIR gene found in plants. Additionally, we identified peltatin, a PTOX derivative, in the HGN12.1C extract. Docking analysis suggests a potential role for the 2-ODD enzyme in converting yatein to deoxypodophyllotoxin. These findings offer invaluable insights into the synthesis mechanism of PTOX in fungi, shedding light on the relationship between host plants and endophytes., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Objective: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years., Background: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely., Methods: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period., Results: Twenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods., Conclusions: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise., (© 2024 American Headache Society.)

Physical activity can worsen migraine, leading to reduced activity levels in adults with chronic migraine. This study investigated the change in average steps per day, as a surrogate marker of physical activity, in adults with chronic migraine successfully treated with monoclonal antibodies against calcitonin gene-related peptide or its receptor. Data were obtained from adults with chronic migraine, who were classified as responders to preventive treatment with monoclonal antibodies. The primary endpoint was the difference in a mean number of steps per day between the 3 months prior to treatment initiation and the first 3 months after treatment initiation. The secondary endpoint was the correlation between the change in steps per day and the change in monthly migraine days. Twenty-two (20 females) participants with a median age of 48.5 years were enrolled. The median number of steps per day increased from 4421 at baseline to 5241 after treatment (P = 0.039). We found a positive correlation between the increase in steps per day and the treatment response (P = 0.013). In conclusion, an increase in physical activity, based on steps per day, positively correlated with treatment response to monoclonal antibodies. Automatically registered daily step count data might be used to monitor physical activity as a response to preventive treatment in adults with chronic migraine., (© 2024. The Author(s).)

Background: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab., Methods: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration., Results: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo ( p  = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p  = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p  = 0.026) and a simultaneous increase in heart rate (AUC, p  < 0.001) during the first hour after administration compared to placebo., Conclusion: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade., Trial Registration: ClinicalTrials.gov: Identifier NCT05889455., Competing Interests: Declaration of conflicting interestsWe declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BR reports personal fees from AbbVie/Allergan, Eli Lilly, Lundbeck, Novartis and Teva, as well as research grants from Novartis and Lundbeck, all outside of the submitted work. BR reports serving as junior associate editor of The Journal of Headache and Pain, and associate editor of Frontiers In Neurology. TPD has nothing to disclose. HA reports personal fees from Lundbeck and Teva, outside of the submitted work. JS and TMT are full-time employees and shareholders of Novartis Pharma AG, Basel, Switzerland. MA reports receiving personal fees from AbbVie, Amgen, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals, all outside of the submitted work. MA reports serving as associate editor of The Journal of Headache and Pain, and associate editor of Brain.

Importance: Treatment of erythema and flushing in rosacea is challenging. Calcitonin gene-related peptide (CGRP) has been associated with the pathogenesis of rosacea, raising the possibility that inhibition of the CGRP pathway might improve certain features of the disease., Objective: To examine the effectiveness, tolerability, and safety of erenumab, an anti-CGRP-receptor monoclonal antibody, for the treatment of rosacea-associated erythema and flushing., Design, Setting, and Participants: This single-center, open-label, single-group, nonrandomized controlled trial was conducted between June 9, 2020, and May 11, 2021. Eligible participants included adults with rosacea with at least 15 days of either moderate to severe erythema and/or moderate to extreme flushing. No concomitant rosacea treatment was allowed throughout the study period. Visits took place at the Danish Headache Center, Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark. Participants received 140 mg of erenumab subcutaneously every 4 weeks for 12 weeks. A safety follow-up visit was performed at week 20. Data analysis occurred from January 2023 to January 2024., Intervention: 140 mg of erenumab every 4 weeks for 12 weeks., Main Outcomes and Measures: The primary outcome was mean change in the number of days with moderate to extreme flushing during weeks 9 through 12, compared with the 4-week run-in period (baseline). The mean change in number of days with moderate to severe erythema was a secondary outcome. Adverse events were recorded for participants who received at least 1 dose of erenumab. Differences in means were calculated with a paired t test., Results: A total of 30 participants (mean [SD] age, 38.8 [13.1] years; 23 female [77%]; 7 male [23%]) were included, of whom 27 completed the 12-week study. The mean (SD) number of days with moderate to extreme flushing was reduced by -6.9 days (95% CI, -10.4 to -3.4 days; P < .001) from 23.6 (5.8) days at baseline. The mean (SD) number of days with moderate to severe erythema was reduced by -8.1 days (95% CI, -12.5 to -3.7 days; P < .001) from 15.2 (9.1) days at baseline. Adverse events included transient mild to moderate constipation (10 participants [33%]), transient worsening of flushing (4 participants [13%]), bloating (3 participants [10%]), and upper respiratory tract infections (3 participants [10%]), consistent with previous data. One participant discontinued the study due to a serious adverse event (hospital admission due to gallstones deemed unrelated to the study), and 2 participants withdrew consent due to lack of time., Conclusions and Relevance: These findings suggest that erenumab might be effective in reducing rosacea-associated flushing and chronic erythema (participants generally tolerated the treatment well, which was consistent with previous data), and that CGRP-receptor inhibition holds potential in the treatment of erythema and flushing associated with rosacea. Larger randomized clinical trials are needed to confirm this finding., Trial Registration: ClinicalTrials.gov Identifier: NCT04419259.

Introduction: Migraine is a complex neurological disorder that affects a significant portion of the global population. As traditional pharmacological approaches often fall short in alleviating symptoms, the development of innovative therapies has garnered significant interest. This text aims to summarize the current pharmacological options for managing migraine and to explore the potential impact of novel therapies., Areas Covered: We focused on conventional treatments, emerging therapies, and novel compounds in clinical development, including therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic therapies, and other options. English peer-reviewed articles were searched in PubMed, Scopus, and ClinicalTrials.gov electronic databases., Expert Opinion: Several novel treatment options for migraine have become available in recent years. Emerging pharmacological therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic interventions, and other emerging treatment modalities, may prove to be valuable for the treatment of migraine. Further research, clinical trials, and substantiated evidence are necessary to validate the efficacy, safety, and long-term outcomes of these therapeutic options.

Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene-related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene-related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms., Objectives: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback., Methods: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey., Results: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant., Conclusion: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.H. has received honoraria for lecturing and/or writing from Allergan, Novartis, Teva, Lundbeck, and Eli Lilly. He serves as Associate Editor of Headache. A.A. and A.P. received compensation for speaking activities and consulting fees from Novartis, Teva Pharma, Eli-Lilly.E.T. has received personal fees for lectures/advisory boards: Novartis, Eli Lilly, Abbvie, TEVA, Roche, Lundbeck, Pfizer, Biogen. Consultant for and owner of stocks and IP in Man & Science. Stocks and IP in Nordic Brain Tech. Non-personal research grants from several sources, including EU, Norwegian Research Council, Dam foundation, KlinBeForsk. Commissioned research (non-personal): Lundbeck, Pfizer.Ente Ospedaliero Cantonale (employer) received compensation for C.Z.’s speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Genzyme, Lundbeck, Merck, Novartis, Teva Pharma, Roche.M.V., T.P.D., M.M.K., M.F., S.S. I.G.W., C.G. declare no conflict of interest.

Background: Stigmatization and trivialization of headache confront individuals with headache disorders, but the degree to which media may contribute is incompletely understood., Objective: The objective of this study was to quantify the frequency of disparaging metaphorical use of the words "headache" and "migraine" in articles and summaries of major publications., Methods: This longitudinal study analyzed a dataset of 1.3 million articles and summaries written by authors and editors of 38 major publications. Data cover written publications from 1998 up to 2017. The use of the words "headache" or "migraine" in articles and summaries by major publications was rated by two authors (P.Z. and A.V.) as either "metaphorical" or "medical" based on their contextual application. Pearson's chi-squared test was applied to assess differences in the frequency of metaphorical use of "headache" in comparison to "migraine." Secondary outcomes were the source of publication and time of publication., Results: A total of 6195 and 740 articles included the words "headache" or "migraine," respectively; 7100 sentences contained the word "headache" and 1652 sentences contained the word "migraine." Among a random sample of 1000 sentences with the word "headache," there was a metaphorical use in 492 (49.2% [95% CI, 46.1-52.3]) sentences. Among a random sample of 1000 sentences with the word "migraine," there was a metaphorical use in 45 (4.5% [95% CI, 3.2-5.8]) sentences. The five most prevalent sources were CNN, Fox News, The New York Times, The Guardian, and The Washington Post. There was an overall increase in the number of articles containing the words "headache" or "migraine" from database inception until analysis (1998 up to 2017). The database included no articles containing either "headache" or "migraine" in 1998; in 2016, this number was 1480 articles., Conclusions: In this longitudinal study, major publications applied a metaphorical use of "headache" about half of the time. The metaphorical use of "headache" is 11-fold greater than the metaphorical use of "migraine" in the same media sample. These depictions may contribute to the trivialization of headache and the stigmatization of individuals with headache disorders. Studies with individuals affected by headache disorders are needed to clarify potential influences., (© 2024 American Headache Society.)

To produce abundant cell culture samples to generate large, standardized image datasets of human induced pluripotent stem (hiPS) cells, we developed an automated workflow on a Hamilton STAR liquid handler system. This was developed specifically for culturing hiPS cell lines expressing fluorescently tagged proteins, which we have used to study the principles by which cells establish and maintain robust dynamic localization of cellular structures. This protocol includes all details for the maintenance, passage and seeding of cells, as well as Matrigel coating of 6-well plastic plates and 96-well optical-grade, glass plates. We also developed an automated image-based hiPS cell colony segmentation and feature extraction pipeline to streamline the process of predicting cell count and selecting wells with consistent morphology for high-resolution three-dimensional (3D) microscopy. The imaging samples produced with this protocol have been used to study the integrated intracellular organization and cell-to-cell variability of hiPS cells to train and develop deep learning-based label-free predictions from transmitted-light microscopy images and to develop deep learning-based generative models of single-cell organization. This protocol requires some experience with robotic equipment. However, we provide details and source code to facilitate implementation by biologists less experienced with robotics. The protocol is completed in less than 10 h with minimal human interaction. Overall, automation of our cell culture procedures increased our imaging samples' standardization, reproducibility, scalability and consistency. It also reduced the need for stringent culturist training and eliminated culturist-to-culturist variability, both of which were previous pain points of our original manual pipeline workflow., (© 2023. Crown.)

Background/aim: Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC., Case Report: A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later., Conclusion: SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Primordial germ cells (PGCs) have potential applications in genetic conservation, vaccination, tissue repair therapies, and genetic research. Chicken bone marrow-derived mesenchymal stem cells (cbMSCs) is a good candidate for co-culture with PGCs. However, there is no consensus on the optimal age of donors. In this study, we aimed to compare specific parameters of H'Mong cbMSCs obtained from day 14 th and 19 th embryos, and day 3 rd newborns. Isolated cbMSCs showed characteristics of MSCs. Cells had fibroblast-like morphology, plastic-adherent, expressed specific markers of MSCs and multilineage differentiation potential. The growth rate of cells from day 19 th embryos was higher than from other ages. Moreover, cells expressed markers of pluripotency such as Nanog , PouV , Sox2 , CVH , DAZL , and KIT , known for their role in maintaining stem cell self-renewal and pluripotency. As feeder cells, cbMSCs from three different ages promoted proliferation of H'Mong PGCs during co-culture. These results suggested that cbMSCs from different ages can be used for co-culture H'Mong PGCs which were further used for genetic preservation of H'Mong chicken or gene editing research., Competing Interests: The authors declare no conflicts of interest., (© 2024 Urmia University. All rights reserved.)

Background: The present study aimed to investigate whether levcromakalim, a K ATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody., Methods: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period., Results: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo ( p  < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo ( p  < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo ( p  < 0.001)., Conclusions: The induction of migraine attacks via opening of K ATP channels appears independent of CGRP receptor activation. Trial Registration: ClinicalTrials.gov, Identifier NCT05889442., Competing Interests: Declaration of conflicting interestsBR reports personal fees from AbbVie, Eli Lilly, Lundbeck, Novartis and Teva, as well as research grants from Novartis, all outside of the submitted work. BR reports serving as junior associate editor of The Journal of Headache and Pain, and associate editor of Frontiers In Neurology. TPD has nothing to disclose. BAC has nothing to disclose. FMA reports personal fees from Teva, AbbVie, Pfizer, Lundbeck, Novartis and Eli Lilly, all outside of the submitted work. FMA is the current President of the Danish Headache Society and a member of the Board of Directors in the European Headache Federation. FMA serves as associate editor for Frontiers In Pain Research, Frontiers In Neurology, Headache Medicine and Acta Neurologica Scandinavica; as junior associate editor for Cephalalgia, and as a member of the editorial board of the European Journal of Headache and Pain. HA reports personal fees from Lundbeck and Teva, outside of the submitted work. JS and TMT are full-time employees of Novartis Pharma AG, Basel, Switzerland. MA reports receiving personal fees from AbbVie, Amgen, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals, all outside of the submitted work. MA reports serving as associate editor of Cephalalgia, associate editor of The Journal of Headache and Pain and associate editor of Brain.

Purpose: To compare corneal tomographic parameters between Hispanic White and non-Hispanic White patients using Pentacam data., Methods: This retrospective study evaluated preoperative Pentacam data from 641 patients 50 years or older who underwent surgery for senile cataract and self-identified as Hispanic or non-Hispanic White. Patients of non-White race or multiethnic groups, or a history of surgery, trauma, or any abnormality of the cornea or anterior segment were excluded. Cornea and anterior segment parameters, as measured with Pentacam, were then compared between Hispanics and non-Hispanics., Results: There were 352 Hispanic White and 289 non-Hispanic White patients. These included 231 men and 410 women, with a mean age of 69.5 ± 8.2 years. There were no significant differences between Hispanics and non-Hispanics in front or back keratometry or amount of front astigmatism. However, Hispanics had a greater amount of back astigmatism (0.36 ± 0.19 vs 0.32 ± 0.17 diopter, P = 0.04). Moreover, there was a statistically significant difference in front steep axis of the left eyes between Hispanics and non-Hispanics (97.8 ± 47.9 vs 108.2 ± 48.9 deg, P = 0.01), and a marginally significant difference in front steep axis of the right eyes (81.0 ± 48.2 vs 73.5 ± 49.9 deg, P = 0.06). Hispanics also had a lower vertex pachymetry (548.1 ± 34.5 vs 553.4 ± 37.4 μm, P = 0.04) and a smaller anterior chamber volume (134.7 ± 39.0 vs 146.1 ± 39.9 mm 3 , P < 0.001)., Conclusions: There are some differences in cornea and anterior segment parameters between Hispanics and non-Hispanics 50 years or older who underwent surgery for senile cataract. However, such differences may not be clinically significant., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab., Methods: This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months., Results: In total, 100 patients (erenumab: n = 60, fremanezumab: n = 40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n = 36, fremanezumab: n = 26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p  = 0.558). There was no wearing-off within the erenumab ( p  = 0.194) or the fremanezumab ( p  = 0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p  = 0.573)., Conclusions: There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks., Competing Interests: Declaration of conflicting interestsAMF, LVL, SY, CKC and BAC have no conflicts of interests to report. TPD reports personal fees from Teva, outside of the submitted work. FMA has received Honoria or personal fees from Pfizer, Teva, Novartis, Lundbeck, AbbVie and Eli Lilly for lecturing or participating in advisory boards; is principal investigator for phase IV trials sponsored by Novartis and by Teva; serves as president of Danish Headache Society and board member of the European Headache Federation; serves as associate editor for Acta Neurologica Scandinavica, Frontiers in Neurology, Frontiers in Pain Research and Headache Medicine; serves as junior associate editor for Cephalalgia and Cephalalgia Reports; and is a member of the editorial board of The Journal of Headache and Pain.

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.)

Migraine is an evolving, and sometimes lifelong disorder. The prevalence of episodic migraine peaks among individuals aged in their late 30s, implying a tendency for the disorder to remit with increasing age thereafter, whereas chronic migraine is more likely to persist into later life. Diagnosis and treatment of migraine in older adults, defined as individuals aged 60 years or older, is rendered more complex by increasing probabilities of atypical clinical features and comorbidities, with patients' comorbidities sometimes limiting their therapeutic options. However, the changing clinical presentation of migraine over an individual's lifespan is not well characterised. The neurobiological basis of remission in older adults remains unclear, although vascular, neuronal, and hormonal changes are likely to be involved. Long-term longitudinal studies of individuals with migraine would be particularly informative, with the potential not only to suggest new research directions, but also to lead to the identification of novel therapeutic agents. Although several novel migraine medications are becoming available, their effectiveness, tolerability, and safety often remain uncertain in older adults, who have commonly been excluded from the evaluation of these agents in randomised controlled trials, or who constitute only a small proportion of study populations. There is a need to recognise these limitations in the available evidence, and the specific, and often unmet, clinical needs of older adults with migraine, not least because older adults constitute an increasing proportion of populations worldwide., Competing Interests: Declaration of interests HA has received travel fees, honoraria, and personal fees from Teva for participating in advisory boards. MTG has received personal fees as a speaker or advisory board member for, or non-financial support from, Teva, Novartis, AbbVie, Pfizer, and Casasco. BJ has received honoraria as an advisory board member or speaker for Allergan/AbbVie, Eli Lilly, Lundbeck, Care Pharmacy, and Teva; and has been the principal investigator for an Allergan (AbbVie) trial. BJ is President of the Australian and New Zealand Headache Society. SS reports grants, personal fees, and non-financial support from Abbott, Allergan/AbbVie, AstraZeneca, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Pfizer, Teva, and Uriach. SS serves as president elect of the European Stroke Organisation and second vice president of the European Headache Federation. SS serves as associate editor of the Journal of Headache and Pain, section chief editor of Headache and Neurogenic Pain in Frontiers of Neurology, and assistant editor for Stroke. MJL has received honoraria as a consultant or speaker for Eli Lilly, Teva, AbbVie, Sanofi-Aventis, SK pharm, and YuYu Pharma; has been the principal investigator or co-investigator in trials sponsored by Eli Lilly, Novartis, Teva (Otsuka), Allergan, Lundbeck, Biohaven, Yuhan Company, Ildong Pharm, Samjin Pharm, and DongA ST; and has received research support from the National Research Foundation of Korea. MJL is an associate editor of Cephalalgia. KCB reports consulting activities unrelated to this Review or topic of research for Eli Lilly and Allergan/AbbVie. FMA has received honoraria for delivering lectures or participating on advisory boards for Pfizer, Teva, Lundbeck, Novartis, and Eli Lilly. FMA serves as associate editor for the journals Headache Medicine, Acta Neurologica Scandinavica, Frontiers in Neurology, and Frontiers in Pain Research. FMA serves as president of the Danish Headache Society and a member of the Board of Directors of the European Headache Federation. MA is a consultant, speaker, or scientific advisor for AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva; and a primary investigator for ongoing Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva trials. MA serves as associate editor of Cephalalgia, associate editor of the Journal of Headache and Pain, and associate editor of Brain. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To explore and critically appraise the evidence supporting the role of estrogen withdrawal in menstrual migraine., Main Body: Menstrual migraine, impacting about 6% of reproductive-age women, manifests as migraine attacks closely related to the menstrual cycle. The estrogen withdrawal hypothesis posits that the premenstrual drop in estrogen levels serves as a trigger of migraine attacks. Despite its wide acceptance, the current body of evidence supporting this hypothesis remains limited, warranting further validation. Estrogen is believed to exert a modulatory effect on pain, particularly within the trigeminovascular system - the anatomic and physiologic substrate of migraine pathogenesis. Nevertheless, existing studies are limited by methodologic inconsistencies, small sample sizes, and variable case definitions, precluding definitive conclusions. To improve our understanding of menstrual migraine, future research should concentrate on untangling the intricate interplay between estrogen, the trigeminovascular system, and migraine itself. This necessitates the use of robust methods, larger sample sizes, and standardized case definitions to surmount the limitations encountered in previous investigations., Conclusion: Further research is thus needed to ascertain the involvement of estrogen withdrawal in menstrual migraine and advance the development of effective management strategies to address unmet treatment needs., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: Following the promising pre-marketing placebo-controlled randomized clinical trials of fremanezumab, post-marketing studies are necessary to verify efficacy and tolerability in various real-world settings. The present study assessed real-world efficacy and safety of fremanezumab., Methods: A 3-month, single-center, prospective, observation study of adults with chronic migraine who were treated with monthly subcutaneous injections of 225 mg fremanezumab in Denmark. The primary outcome was defined as proportion of patients who achieved ≥30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. Among secondary outcomes were ≥50 and ≥75% responder rates and the proportion of patients reporting adverse events., Results: A total of 91 patients with chronic migraine were enrolled and received at least one dose of fremanezumab of whom 89 patients (98%) completed the 3-months treatment period. At baseline, the mean (SD) number of monthly headache days was 24.3 ± 5.8 and mean number of MMDs was 18.5 ± 7.4. The number of patients who achieved ≥30% reduction in MMDs from baseline to weeks 9-12 was 58 (65%), while 45 (51%) and 21 (24%) had ≥50 and 75% reduction in MMD, respectively. Twenty-one patients (23%) reported adverse event, in which the most common were constipation (4.4%), fatigue (4.4%) and dizziness (3.3%). No serious adverse events were reported., Conclusion: In adult chronic migraine patients with previous failure of conventional oral migraine preventives, fremanezumab was found to be effective and well-tolerated., Competing Interests: TD reports personal fees from Teva, outside of the submitted work. FA has received Honoria or personal fees from Pfizer, Teva, Novartis, Lundbeck and Eli Lilly for lecturing or participating in advisory boards; is principal investigator for phase IV trials sponsored by Novartis and by Teva; serves as president of Danish Headache Society and board member of the European Headache Federation; serves as associate editor for Acta Neurol Scand, Front Neurol, Front Res Pain, and Headache Medicine; serves as junior associate editor for Cephalalgia and Cephalalgia Reports; member of the editorial board of J Headache Pain. 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 Cullum, Chaudhry, Do and Amin.)

Cancer is among the leading causes of death worldwide, with no effective and safe treatment to date. This study is the first to co-conjugate the natural compound cinchonain Ia, which has promising anti-inflammatory activity, and L-asparaginase (ASNase), which has anticancer potential, to manufacture nanoliposomal particles (CALs). The CAL nanoliposomal complex had a mean size of approximately 118.7 nm, a zeta potential of -47.00 mV, and a polydispersity index (PDI) of 0.120. ASNase and cinchonain Ia were encapsulated into liposomes with approximately 93.75% and 98.53% efficiency, respectively. The CAL complex presented strong synergistic anticancer potency, with a combination index (CI) < 0.32 in two-dimensional culture and 0.44 in a three-dimensional model, as tested on NTERA-2 cancer stem cells. Importantly, the CAL nanoparticles demonstrated outstanding antiproliferative efficiency on cell growth in NTERA-2 cell spheroids, with greater than 30- and 2.5-fold increases in cytotoxic activity compared to either cinchonain Ia or ASNase liposomes, respectively. CALs also presented extremely enhanced antitumor effects, reaching approximately 62.49% tumor growth inhibition. Tumorized mice under CALs treatment showed a survival rate of 100%, compared to 31.2% in the untreated control group ( p < 0.01), after 28 days of the experiment. Thus, CALs may represent an effective material for anticancer drug development.

Introduction: Worldwide, far from all of those who would benefit make use of headache services, largely because of clinical, social, and political barriers to access. Identifying the factors contributing to low healthcare utilization can generate evidence to guide health policy. Our purpose here is better to characterize healthcare utilization patterns in Denmark., Methods: The Headache in Denmark (HINDER) study is a nationwide cross-sectional survey of people with headache, conducted using SurveyXact (Rambøll Group A/S, Copenhagen). Healthcare utilization was assessed in a study sample generated by population screening and recruitment. Data collection occurred over two weeks, from September 23 rd until October 4 th , 2021. The questions enquired into disease characteristics, management, burden, medication intake and healthcare utilization., Results: The number of participants included in the HINDER panel was 4,431, with 2,990 (67.5%: 2,522 [84.3%] female, 468 [15.7%] male; mean age 40.9 ± 11.6 years) completing the survey. One quarter of participants (27.7%) disagreed or strongly disagreed that they were able to manage their headache attacks. Most participants (81.7%) agreed or strongly agreed that their headache was a burden in their everyday lives. The most reported acute medications, by 87.2% of participants, were simple analgesics; of note, 8.6% reported using opioids for their headache. One quarter of participants (24.4%) had never consulted a medical doctor for their headache; one in six (16.5%: more than two thirds of the 24.4%) had never done so despite agreeing or strongly agreeing that their headache was a burden in their everyday lives. Two thirds (65.3%) of participants overall, and almost three quarters (72.4%) of those with weekly headache, had tried one or more complementary or alternative therapies outside conventional medical care., Conclusions: Our findings are indicative of inadequate delivery of headache care in a country that provides free and universal coverage for all its residents. The implications are twofold. First, it is not sufficient merely to make services available: public education and increased awareness are necessary to encourage uptake by those who would benefit. Second, educational interventions in both pre- and postgraduate settings are necessary, but a prerequisite for these is a resetting of policy priorities, properly to reflect the very high population ill-health burden of headache., (© 2023. The Author(s).)

Background: Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate., Objective: In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification., Discussion: Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack., Conclusions: Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on., Video Link: Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 ., (© 2023. The Author(s).)

Understanding how a subset of expressed genes dictates cellular phenotype is a considerable challenge owing to the large numbers of molecules involved, their combinatorics and the plethora of cellular behaviours that they determine 1,2 . Here we reduced this complexity by focusing on cellular organization-a key readout and driver of cell behaviour 3,4 -at the level of major cellular structures that represent distinct organelles and functional machines, and generated the WTC-11 hiPSC Single-Cell Image Dataset v1, which contains more than 200,000 live cells in 3D, spanning 25 key cellular structures. The scale and quality of this dataset permitted the creation of a generalizable analysis framework to convert raw image data of cells and their structures into dimensionally reduced, quantitative measurements that can be interpreted by humans, and to facilitate data exploration. This framework embraces the vast cell-to-cell variability that is observed within a normal population, facilitates the integration of cell-by-cell structural data and allows quantitative analyses of distinct, separable aspects of organization within and across different cell populations. We found that the integrated intracellular organization of interphase cells was robust to the wide range of variation in cell shape in the population; that the average locations of some structures became polarized in cells at the edges of colonies while maintaining the 'wiring' of their interactions with other structures; and that, by contrast, changes in the location of structures during early mitotic reorganization were accompanied by changes in their wiring., (© 2023. The Author(s).)

Objective: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine., Methods: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period., Results: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale., Conclusion: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache., (© 2022. The Author(s).)

In clinical practice, patients with cluster headache often ask questions or mention information that they have seen or heard on the Internet. Because YouTube (www.youtube.com) is the second most visited Web site worldwide and offers a plethora of video content, we found it timely to ascertain the quality of information on cluster headache that is freely available on YouTube. We conducted an inquiry on YouTube on January 24, 2022, with the search term "cluster headache." Eligible YouTube videos included those with ≥10,000 views and content related to cluster headache. We assessed the quality and reliability of the videos with the Global Quality Scale and DISCERN, respectively. The search strategy identified 644 videos of which 134 were eligible for inclusion. The sources of the included videos were categorized as "healthcare professional/institution" (n = 45), "personal experience" (n = 52), and "other" (n = 37). According to the Global Quality Scale, 70 (52%) were low quality, 34 (25%) were of moderate quality, and 30 (22%) were of high quality. According to DISCERN, 104 (78%) were of low reliability, 28 (21%) were of moderate reliability, and 2 (1%) were of high reliability. The quality and reliability of cluster headache-related information on YouTube has room for improvement, even the content provided by healthcare providers. These findings should incentivize stakeholders, for example, government services, professional societies, healthcare providers, to provide accessible and better information on cluster headache., (© 2022 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Introduction: Large numbers of people with headache who would benefit are not reached by headache services. Among the causes are poor or disorganized provision of headache services, but reluctance to seek healthcare has frequently been identified as a significant barrier. We conducted a national survey of people with headache to assess the extent of this problem in Denmark, a country with well organized, highly resourced, and readily accessible services., Methods: We conducted a nationwide cross-sectional survey of adults ≥ 18 years old in Denmark reporting at least one headache day in the last year. We used social media (Facebook) to publicize and drive a recruitment campaign. The survey investigated five items: (1) disease burden, (2) social life, (3) presenteeism, (4) social support, and (5) healthcare utilization., Results: We included 6,567 respondents from May 2021 to June 2021; 70.2% were female, 39.8% male, and mean age was 43.2 ± 13.4 years. Of the respondents, 54.2% reported headache at least once a week, 33.4% reported headache a couple of times a month, and 12.4% reported headache a couple of times a year. Two-thirds of respondents (66.6%) reported that headache limited their social lives occasionally or frequently. Most respondents (86.8%) reported going to work or attending educational activities occasionally or more frequently even though they had headache. Half of the respondents (49.5%) experienced lack of understanding of their headaches from people occasionally or more frequently. Almost half of respondents (43.7%) had never consulted a medical doctor for their headache; even of those with weekly headache, more than a quarter (28.3%) had never done so in their lifetimes., Conclusions: Headache disorders continue to be a problem, even in a high-income country with free and easily accessible headache services. Further studies are needed to investigate and clarify why even people with the highest burden are hesitant to seek and make use of widely available headache services., (© 2022. The Author(s).)

Introduction: Accessibility of treatment with monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) signaling pathway is impeded by regulatory restrictions. Affected individuals may seek out other services including non-pharmacological therapies. Thus, we found it timely to ascertain the use of non-pharmacological therapies in individuals with treatment-resistant migraine eligible for and naïve to treatment with CGRP-signaling targeting monoclonal antibodies., Methods: We conducted a single-center cross-sectional observational study of patients eligible for and naïve to treatment with monoclonal antibodies targeting CGRP or its receptor. We recorded demographical information (gender, age, educational level, employment status, and income), disease burden (frequency of headache days and migraine days), previous use of preventive pharmacological medications for migraine, and use of non-pharmacological therapies over the past 3 months including frequency of interventions, costs, and patient-reported assessment of efficacy on a 6-point scale (0: no efficacy, 5: best possible efficacy)., Results: We included 122 patients between 17 June 2019 and 6 January 2020; 101 (83%) were women and the mean age was 45.2 ± 13.3 years. One-third ( n = 41 [34%]) had used non-pharmacological therapy within the past 3 months. Among these participants, the median frequency of different interventions was 1 (IQR: 1-2), the median number of monthly visits was 2.3 (IQR: 1.3-4), mean and median monthly costs were 1,086 ± 1471, and 600 (IQR: 0-1200) DKK (1 EUR = ~7.5 DKK), respectively, and median patient-reported assessment of the efficacy of interventions was 2 (IQR: 0-3)., Conclusion: Even in a high-income country with freely accessible headache services and universal healthcare coverage, there was a non-negligible direct cost in parallel with low satisfaction for non-pharmacological therapies among patients at a tertiary headache center., Competing Interests: SS reports grants, personal fees and/or non-financial support from Allergan, Novartis, Teva, Eli Lilly, AstraZeneca, Abbott, Medscape, Pfizer, Bayer, Medtronic, Starmed, Bristol-Meyer-Squibb, Daiichi-Sankyo, Lundbeck, Uriach and Neurodiem Ology Medical Education. RG-G reports Honoraria for conferences, consulting or educational activities: Novartis, Allergan/ Abbvie, Teva, Lilly, Lundbeck, Tecnifar, Pfizer, FLOAT, CMBE. Research grants: Fundação para a Ciência e Tecnologia (project 29675, MigN2Treat, 02/SAICT/2017), Novartis-Sociedade Portuguesa de Cefaleias and Learning-Health, Luz Saúde (Research group LiON, Luz Innovation on Neurosciences). DU reports grants, personal fees and/or non-financial support from Allergan, Novartis, Teva, Eli Lilly. FA has received honoraria and personal fees from Teva, Lundbeck, Novartis, Eli Lilly for lecturing or participating in advisory boards. 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 © 2022 Rundblad, Cullum, Sacco, Gil-Gouveia, Uludüz, Do and Amin.)

Background: Clinical trials have shown that erenumab is effective and well-tolerated for the preventive treatment of chronic migraine. To extend the results from clinical trials, we assessed the real-world efficacy and safety of erenumab in patients with chronic migraine from the outpatient clinic at the Danish Headache Center., Methods: A 52-week, single-center, prospective, observation study of erenumab in adults with chronic migraine who are eligible for treatment with monoclonal antibodies against CGRP or its receptor in Denmark. The primary outcome was defined as proportion of patients who achieved ≥ 30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12., Results: A total of 300 adult patients with chronic migraine were enrolled and received at least one dose of erenumab. At baseline, the mean (SD) number of monthly headache days was 23 ± 4.9 and mean number of MMDs was 16.8 ± 6.4. Of 300 enrolled patients, 273 (91.0%) patients completed 12 weeks of treatment, and 119 (39.7%) completed 52 weeks of treatment. The number of patients who achieved ≥ 30% reduction in MMDs from baseline to weeks 9-12 was 195 (71.4%) of 273 patients. Sustained ≥ 30% reduction in MMDs at all assessment periods throughout the 52-week treatment period was achieved by 102 (34%) of 300 patients. Adverse events occurred in 220 (73.3%) out of 300 patients. The most common adverse event was constipation. Treatment discontinuation due to lack of tolerability occurred in 41 (13.7%) patients., Conclusions: Among adult patients with chronic migraine and previous failure of medications for migraine prevention, erenumab was found to be effective and well-tolerated., (© 2022. The Author(s).)

Purpose of Review: To review the latest advances in migraine management with a focus on medications specifically developed for the treatment of migraine., Recent Findings: Randomized clinical trials demonstrated the efficacy of calcitonin gene-related peptide (CGRP) mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist gepants for acute abortion and prevention of migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is another signaling molecule of interest and represents a potential new drug class of mechanism-based migraine medications. Drugs targeting PACAP are currently undergoing clinical trials, and the coming years will reveal whether this class of drugs will expand our therapeutic armamentarium., Summary: Here, we summarize the role of CGRP and PACAP in migraine pathophysiology and discuss novel therapies targeting the CGRP and PACAP signaling pathways., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A major barrier to adequate headache care is the relative lack of formal education and training of healthcare professionals. Concerted efforts should be made to pinpoint major gaps in knowledge in healthcare professionals to facilitate better educational policies in headache training. The aim of this study was to identify deficiencies and barriers in headache training among residents in neurology in Denmark., Methods: We conducted a national cross-sectional survey of residents in neurology in Denmark from April 2019 to September 2019. The survey included questions on participant demographics, knowledge of and barriers in headache disorders, guidelines and diagnostic tools usage, contact with primary and tertiary care, medication overuse, and non-pharmacological interventions. Furthermore, respondents were asked to provide a ranked list from most to least interesting for six sub-specializations/disorders, i.e., cerebrovascular disease, dementia, epilepsy, headache, multiple sclerosis, Parkinson's disease., Results: Sixty (40%) out of estimated a population of ~ 150 resident across Denmark accepted the invitation. Of these, 54/60 (90%) completed the survey. Although two-thirds, 35/54 (65%), of the respondents had prior formalized training in headache disorders, we identified gaps in all explored domains including diagnosis, management, and referral patterns. Particularly, there was an inconsistent use of guidelines and diagnostic criteria from the Danish Headache Society (2.74 (± 1.14)), the Danish Neurological Society (3.15 (± 0.86)), and the International Classification of Headache Disorders (2.33 (± 1.08)); 1: never/have not heard of, 4: always. Headache was ranked second to last out of six sub-specializations in interest., Conclusions: Overall knowledge on headache disorders amongst neurology residents in Denmark do not meet the expectations set out by national and international recommendations. Stakeholders should make strategic initiatives for structured education in headache for improved clinical outcomes in parallel with costs reduction through resource optimization., (© 2022. The Author(s).)

Objective: In this narrative review, we summarize clinical and experimental data on the effect of light in migraine and discuss future prospects., Background: Effective nonpharmacological treatment of hypersensitivity to light in migraine is an unmet clinical need. Current management strategies primarily consist of seeking a dark room and avoiding light exposure. Advances in the past 2 decades have improved our understanding of the underlying pathophysiology of how migraine is influenced by light. This may provide promising avenues for novel approaches in clinical management., Methods: We searched MEDLINE for articles published from database inception up to September 1, 2021. We used the search term "migraine" with the search terms "light," "photophobia," "treatment," "trigger," "circadian rhythm," "environment," and/or "pathophysiology.", Results: Light is commonly reported as a trigger factor of migraine attacks, however, early manifestation of photophobia and false attribution is likely the actual cause based on data deriving from retrospective, prospective, and experimental studies. The most common photophobia symptoms in migraine are exacerbation of headache by light and abnormal sensitivity to light with the underlying neural pathways likely being dependent on ongoing activity in the trigeminovascular system. Clinical studies and experimental models have identified mediators of photophobia and uncovered narrow wavebands of the light spectrum that may reduce pain intensity during a migraine attack. Consequently, novel devices have undergone exploratory clinical trials with promising results., Conclusion: False attribution is likely the reason why light is commonly reported as a trigger factor of migraine attacks, and a prospective confirmation is required to prevent unnecessary avoidance. The observation that individuals with migraine are not equally photophobic to all wavebands of the light spectrum opens the potential for innovative pain management strategies. In this context, using human-centric lighting (also called integrative lighting) to mimic the natural daylight cycle and avoid harmful wavebands through modern technology may prove beneficial. Future research should identify direct and indirect consequences of light and other environmental factors in migraine to fill out knowledge gaps and enable evidence-based care strategies within institutions, work environments, and other settings., (© 2022 American Headache Society.)

Purpose of Review: In this review, we summarize updates in the diagnostic approach of headaches with the aim of facilitating the distinction between primary and secondary etiology in headaches., Recent Findings: In the USA, headache is the fifth most common complaint in the emergency department, but only a minority will have a secondary etiology. Initial suspicion and diagnostic workup of secondary headache relies on a patient's medical history due to a scarcity of validated biomarkers. A special interest group under the International Headache Society recently synthesized information on red flags (information that indicates a secondary etiology) and green flags (information that indicates a primary etiology). A systematic diagnostic approach using red flags and green flags can help reduce unnecessary testing and shift attention to patient care. Going forward, further validation of these concepts is needed to properly introduce them for clinical use., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objective: ClinicalTrials.gov is a centralized venue for monitoring clinical research and allows access to information on publicly and privately funded studies. To better recognize influential institutions in the field of headache, we identified major organizations conducting clinical trials in migraine research. Furthermore, we examined the frequency of different study designs. Methods: Utilizing the ClinicalTrials.gov application programming interface, we extracted studies including individuals with migraine from February 29, 2000, to July 28, 2020, for the following: (1) host organization, (2) study type, (3) primary purpose, (4) intervention model, and (5) allocation. Results: We included 921 entries encompassing 423 organizations. Thirty-two organizations produced ≥5 entries each and 40.0% of all entries. Most, 86%, were interventional studies while 13.6% were observational studies. The most common study design had a randomized allocation of participants. The most frequent primary purpose was treatment (62.4%) followed by prevention (13.0%). There were 56.9% parallel assignment models, 15.2% single group assignment models, and 12.4% crossover assignment models. Conclusion: A minority of organizations contribute to a significant number of registrations of clinical migraine trials, suggesting that clinical research in migraine is oligarchic. The most common study is interventional and randomized, with parallel assignment of participants with treatment as the primary purpose. This likely reflects the need to evaluate novel putative pharmacological medications., Competing Interests: PZ has received honorarium from Lundbeck Biopharmaceuticals, Board Vitals, and Fieve Clinical Research. He collaborates with Headache Science Incorporated without receiving financial support. He has ownership interest in Cymbeline LLC. The remaining author declares 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 © 2021 Zhang and Do.)

Background: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients., Findings: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213)., Conclusion: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out., (© 2021. The Author(s).)

Migraine is ranked as a leading cause of years lived with disability among all neurological disorders. Therapies targeting the calcitonin gene-related peptide (CGRP) signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists (gepants), are today approved for migraine prophylaxis with additional compounds expected to be introduced to the market soon. In this review, we consider other putative prophylactic migraine drugs in development, including compounds targeting G-protein coupled receptors, glutamate, ion channels, and neuromodulatory devices. Emergence of these new interventions could complement our current treatment armamentarium for migraine management., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources., Competing Interests: Declaration of interests MA is a consultant, speaker or scientific advisor for AbbVie, Allergan, Amgen, Alder, Biohaven, Eli Lilly, Lundbeck, Novartis, and Teva, and primary investigator for Alder, Amgen, Allergan, Eli Lilly, Lundbeck, Novartis and Teva trials. MA has no ownership interest and does not own stocks of any pharmaceutical company. MA serves as associate editor of Cephalalgia, and associate editor of the Journal of Headache and Pain. MA is president of the International Headache Society. DCB has served as a consultant to and received research funding from Amgen–Novartis, Allergan, Avanir, Biohaven, Eli Lilly, Promius–Dr Reddy's, and Teva. DCB is on the editorial board of Current Pain and Headache Reports. PP-R has received honoraria for participation in clinical trials and contribution to advisory boards or medical education from Allergan, Almirall, Amgen, Biohaven, Chiesi, Electrocore, Eli Lilly, Medscape, Novartis, and Teva. PP-R's headache research is supported by La Caixa Foundation, AGAUR, Instituto Investigacion Carlos III, Migraine Research Foundation, PERIS, EraNet Neuron, FEDER RIS3CAT, and Novartis. AÖ is on consultant or advisory boards for Allergan, Eli Lilly, Novartis, Teva–Amgen, and Abdi İbrahim İlaç. SS reports consultant, advisory board, or speaker fees for Abbott, Allergan, Eli Lilly, Medscape, Novartis, and Teva. SA reports personal fees from Allergan, Percept, Novartis, Teva, Satsuma, Amgen, Eli Lilly, Supernus, Theranica, Biohaven, and Promius, outside the submitted work. TJS is co-editor of the Journal of Headache and Pain, a director and trustee of Lifting The Burden, and reports personal fees from Eli Lilly, outside the submitted work. RBL serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache, has received research support from the National Institutes of Health, and receives support from the Migraine Research Foundation and the National Headache Foundation. RBL has reviewed for the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, serves as consultant, advisory board member, or has received honoraria from Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Boston Scientific, Dr Reddy's, Electrocore, Eli Lilly, eNeuraTherapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. RBL has received royalties from Wolff's Headache and Informa; and holds stock options in eNeura Therapeutics and Biohaven. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache., Background: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other., Methods: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus., Results: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago.", Conclusions: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags., (© 2020 American Headache Society.)