Effects of airborne pollutants on mitochondrial DNA Methylation

Background: Mitochondria have small mitochondrial DNA (mtDNA) molecules independent from the nuclear DNA, a separate epigenetic machinery that generates mtDNA methylation, and are primary sources of oxidative-stress generation in response to exogenous environments. However, no study has yet investigated whether mitochondrial DNA methylation is sensitive to pro-oxidant environmental exposures. Methods: We sampled 40 male participants (20 high-, 20 low-exposure) from each of three studies on airborne pollutants, including investigations of steel workers exposed to metal-rich particulate matter (measured as PM1) in Brescia, Italy (Study 1); gas-station attendants exposed to air benzene in Milan, Italy (Study 2); and truck drivers exposed to traffic-derived Elemental Carbon (EC) in Beijing, China (Study 3). We have measured DNA methylation from buffy coats of the participants. We measured methylation by bisulfite-Pyrosequencing in three mtDNA regions, i.e., the transfer RNA phenylalanine (MT-TF), 12S ribosomal RNA (MT-RNR1) gene and “D-loop” control region. All analyses were adjusted for age and smoking. Results: In Study 1, participants with high metal-rich PM1 exposure showed higher MT-TF and MT-RNR1 methylation than low-exposed controls (difference = 1.41, P = 0.002); MT-TF and MT-RNR1 methylation was significantly associated with PM1 exposure (beta = 1.35, P = 0.025); and MT-RNR1 methylation was positively correlated with mtDNA copy number (r = 0.36; P = 0.02). D-loop methylation was not associated with PM1 exposure. We found no effects on mtDNA methylation from air benzene (Study 2) and traffic-derived EC exposure (Study 3). Conclusions: Mitochondrial MT-TF and MT-RNR1 DNA methylation was associated with metal-rich PM1 exposure and mtDNA copy number. Our results suggest that locus-specific mtDNA methylation is correlated to selected exposures and mtDNA damage. Larger studies are needed to validate our observations

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn’s Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study

Background: Crohn’s disease (CD) significantly affects patients’ health-related quality of life and well-being. Aims: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients’ lives and identifies communication gaps between patients and health care professionals (HCPs). Methods: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. Results: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. Conclusion: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD

Genome-Wide Analysis of DNA Methylation and Fine Particulate Matter Air Pollution in Three Study Populations: KORA F3, KORA F4, and the Normative Aging Study

BACKGROUND: Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer and respiratory and cardiovascular diseases. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites. OBJECTIVES: We studied the association between DNA methylation and short-and mid-term air pollution exposure using genome-wide data and identified potential biological pathways for-additional investigation. METHODS: We collected whole blood samples from three independent studies-KORA F3 (2004-2005) and F4 (2006-2008) in Germany, and the Normative Aging Study (1999-2007) in the United States-and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Meta-analysis was performed to pool the study-specific results. RESULTS: Random-effect meta-analysis revealed 12 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (1 for 2-day average, 1 for 7-day, and 10 for 28-day) at a genome-wide Bonferroni significance level (p 0.05 and I-2< 0.5: the site from the 7-day average results and 3 for the 28-day average. Applying false discovery rate, p-value < 0.05 was observed in 8 and 1,819 additional CpGs at 7- and 28-day average PM2.5 exposure respectively. CONCLUSION: The PM-related CpG sites found in our study suggest novel plausible systemic pathways linking ambient PM exposure to adverse health effect through variations in DNA methylation

Preventive treatment patterns and treatment satisfaction in migraine: results of the OVERCOME (EU) study

Abstract Background Insights into the burden, needs and treatment of migraine from internet-based surveys in diverse real-world migraine populations are needed, especially at a time when novel preventive migraine medications are becoming part of the therapeutic armamentarium. The objectives of this analysis are to describe traditional preventive (orals and onabotulinum toxin A) treatment patterns in the OVERCOME (EU) study migraine cohort, as well as treatment patterns and patient satisfaction with current treatment in a subgroup of respondents eligible for migraine preventive medication. Methods The cross-sectional non-interventional OVERCOME (EU) study was conducted (October 2020–February 2021) via an online survey among adults (aged ≥ 18 years) resident in Germany or Spain. Participants, registered in existing online panels, who were willing to provide consent were considered. The migraine cohort included participants reporting headache/migraine in the past year, identified based on a validated migraine diagnostic questionnaire and/or self-reported physician diagnosis. A subgroup of survey respondents defined as eligible for migraine preventive medication at the point in time the cross-sectional survey was taken was also analysed. Variables assessed included sociodemographic and migraine-related clinical characteristics, preventive (traditional and calcitonin gene-related peptide monoclonal antibodies) treatment patterns and patient satisfaction with current treatment. Results are descriptive only. Results Of the 20,756 participants in the migraine cohort, 78.5% sought professional medical care, 50.8% received a migraine diagnosis and only 17.7% had ever used preventive medication. Half (53.3%) of participants currently using preventives took their most recent medication for six months or less. Most patients (73.9%) classified as eligible for preventive medication (based on headache frequency and/or at least moderate disability due to migraine) reported not using traditional preventives and many of those who did (66.8%) were not satisfied with their current standard of care. Conclusions Our findings highlight the low proportion of people diagnosed with migraine despite a higher rate of consultation and suggest the need for better access to treatment for people with migraine and new preventive therapies with improved efficacy and safety profiles to improve adherence and patient satisfaction

Acute Treatment Patterns, Migraine Burden, and Healthcare Resource Use in People With Migraine: Results From the OVERCOME (EU) Observational Study

Abstract Introduction The ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) European Union (EU) is part of an overarching population-based study program that also includes the United States and Japan. Here, we report data on the migraine/severe headache burden and the use of acute medication and healthcare resources in Spain and Germany. Methods OVERCOME (EU) was an online, non-interventional, cross-sectional survey conducted in adults in Spain and Germany between October 2020 and February 2021. A total migraine cohort was established based on health survey participants who reported headache/migraine in the last 12 months AND identified as having migraine based on modified International Classification of Headache Disorders, third edition criteria OR self-reported physician diagnosis. Data were analyzed for the total migraine cohort and the subcohort with moderate to severe headache attacks, with average pain severity ≥ 5 points, pain duration ≥ 4 h, and at least moderate disability due to migraine [Migraine Disability Assessment (MIDAS) score ≥ 11] over the past 3 months. Results Pain of moderate or severe intensity was the most frequent symptom in the total migraine cohort (n = 19,103/20,756; 92.0%). Proportions of participants reporting severe disability (MIDAS Grade IV), poorer quality of life (QoL; Migraine-Specific QoL Questionnaire), and higher interictal burden (Migraine Interictal Burden Scale-4), generally increased with number of headache days (HDs)/month. Most participants (92.5%) reported current acute migraine/severe headache medication use, although only 39.0% were using triptans. In the moderate to severe attacks subcohort (n = 5547), 48.4% were using triptans, with nonsteroidal anti-inflammatory drugs the most common acute medication. The moderate to severe attacks subcohort also reported poorer QoL and greater pain and disability with increasing HDs/month, although severe interictal burden was reported for ~ 60% of participants regardless of HDs/month. Treatment satisfaction (six-item migraine Treatment Optimization Questionnaire) in those using triptans was generally poor in both total and subcohorts. Conclusion High migraine-related burden levels were reported, despite use of acute medication. Although triptans are recommended for moderate to severe migraine attacks in Spanish and German guidelines, less than half of participants were using triptans; treatment satisfaction in those using triptans was generally poor. New tailored treatment options may help address unmet needs in current acute treatment

Burden and unmet needs in migraine patients: results from the OVERCOME (Spain) study

Introduction This analysis aimed to evaluate demographics, migraine-related disability, symptoms, diagnosis and healthcare consultation, work productivity, and treatment patterns according to headache frequency in adults with migraine in the OVERCOME (ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE) (Spain) study. Methods Data were obtained from an observational, cross-sectional, web-based survey conducted between October 2020-February 2021 in Spain. Eligible participants were adult members of online survey panels living in Spain who were able to read and write Spanish and fulfilled the International Classification of Headache Disorders, third edition (ICHD-3) criteria for migraine or had a self-reported physician diagnosis. Results In total, 10,229 patients comprised the Spanish sample. Only 56.2% of respondents had a confirmed healthcare professional (HCP) diagnosis of migraine, despite almost all meeting modified ICHD-3 criteria. Pain severity, migraine-related disability, and interictal burden increased with increasing number of headache days per month. Migraine impacted on respondents' work productivity, with increases in presenteeism, work productivity loss, and daily activity impairment at higher headache frequencies. Over the past year, 66.2% of all HCP visits were specifically due to migraine, most commonly with a general practitioner or pharmacist. A subgroup of 1277 patients (12.5% of the total survey population) met eligibility criteria for migraine preventive medications, of whom only 36.6% were currently taking a preventive. Conclusions Results of the OVERCOME (Spain) survey reveal the substantial burden of migraine, which is directly linked to headache frequency. However, most patients experiencing frequent headaches and eligible for migraine preventives are currently not taking them. Findings highlight the importance of addressing unmet needs for people with migraine in Spain.Funding. This work was supported by Eli Lilly and Company. The Rapid Service Fee was funded by the sponsor. Acknowledgements. The authors would like to thank the participants of this study for their contribution