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Abstract Background Epilepsy and other seizure disorders account for a high disease burden in Germany. As a timely diagnosis and accurate treatment are crucial, improving the management of these disorders is important. Outside of Germany, outpatient long-term video EEGs (ALVEEGs) have demonstrated the potential to support the diagnosis and management of epilepsy and other seizure disorders. This study aims to evaluate the implementation of ALVEEGs as a new diagnostic pathway in eastern parts of Germany to diagnose epilepsy and other seizure disorders and to assess if ALVEEGs are equally effective as the current inpatient-monitoring gold standard, which is currently only available at a limited number of specialized centers in Germany. Methods ALVEEG is a prospective, multicenter, randomized controlled equivalence trial, involving five epilepsy centers in the eastern states of Germany. Patients will be randomized into either intervention (IG) or control group (CG), using a permuted block randomization. The sample size targeted is 688 patients, continuously recruited over the trial. The IG will complete an ALVEEG in a home setting, including getting access to a smartphone app to document seizure activity. The CG will receive care as usual, i.e., inpatient long-term video-EEG monitoring. The primary outcome is the proportion of clinical questions being solved in the IG compared to the CG. Secondary outcomes include hospital stays, time until video EEG, time until diagnosis and result discussion, patients’ health status, quality of life and health competence, and number and form of epilepsy-related events and epileptiform activity. Alongside the trial, a process implementation and health economic evaluation will be conducted. Discussion The extensive evaluation of this study, including an implementation and health economic evaluation, will provide valuable information for health policy decision-makers to optimize future delivery of neurological care to patients affected by epilepsy and other seizure disorders and on the uptake of ALVEEG into standard care in Germany. Trial registration German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023.

Background Although there is now substantial evidence on the acute impacts of the COVID-19 pandemic on anxiety disorders, the long-term population impact of the pandemic remains largely unexplored. Aims To quantify a possible longitudinal population-level impact of the pandemic by projecting the prevalence of anxiety disorders through 2030 among men and women aged up to 95 years in Germany under scenarios with varying impacts of the pandemic on the incidence of anxiety disorders. Method We used a three-state illness–death model and data from the Global Burden of Disease Study to model historical trends of the prevalence and incidence of anxiety disorders. The German population projections determined the initial values for projections. The COVID-19 incidence rate data informed an additional incidence model, which was parameterised with a wash-in period, delay, wash-out period, incidence increase level and decay constant. Results When no additional increase in the incidence during the pandemic waves during 2020–2022 was assumed, it was estimated that 3.86 million women (9.96%) and 2.13 million men (5.40%) would have anxiety disorders in 2030. When increases in incidence following pandemic waves were assumed, the most extreme scenario projected 5.67 million (14.02%) women and 3.30 million (8.14%) men with the mental disorder in 2030. Conclusions Any increased incidence during the pandemic resulted in elevated prevalence over the projection period. Projection of anxiety disorder prevalence based on the illness–death model enables simulations with varying assumptions and provides insight for public health planning. These findings should be refined as trend data accumulate and become available.

BackgroundAdverse effects of chronically high levels of stress on physical and mental health are well established. In physicians, the effects of elevated stress levels exceed the individual level and include treatment errors and reduced quality of patient-doctor relationships. Breathing and mindfulness-based exercises have been shown to reduce stress and could serve as an immediate and easy-to-implement anti-stress intervention among physicians. Due to the heterogeneity of their effect on stress, we aim to evaluate the intervention effect of performing a short daily breathwork-based or mindfulness-based intervention on the everyday level of perceived stress in physicians in residence in Germany in a series of N-of-1 trials.MethodsStudy participants will choose between two short interventions, box breathing, and one guided more complex mindfulness-based breathing exercise. Each participant subsequently will be randomly allocated to a sequence of 1-week intervention (A) and control (B, everyday life) phases. Each N-of-1 trial consists of two two-week cycles (AB or BA), resulting in a total trial duration of 4 weeks (ABAB or BABA). Perceived levels of stress will be assessed daily via the StudyU App on the participant’s smartphone. Additionally, participants will be asked to complete a questionnaire at baseline and three months after completion of the study that contains questions about basic participant characteristics, lifestyle factors, individual living situations, and validated psychological questionnaires. Intervention effects will be estimated by Bayesian multi-level random effects models on the individual and population level.DiscussionThis study contributes to the development of short-term solutions to reduce work-related stress for physicians in residence. This is expected to benefit the individual and increase the quality of overall healthcare due to a reduction in treatment errors and an increase in the quality of doctor-patient relationships.Clinical trial registrationClinicalTrials.gov, identifier NCT05745545.

ObjectivesDepression is a major contributor of young people's burden of disease. In this study we aim to estimate the effect of elevated depressive symptoms on physical health-related quality of life.DesignWe used self-reported information from the prospective BELLA cohort study, which included adolescents selected from the general population in Germany. The baseline assessment (2003–2006) and the 1-, 2-, and 6-year follow-up waves provide the data basis.ParticipantsThe baseline study population consisted of 1,460 adolescents between the ages of 12 and 17 who, according to their caregivers, did not suffer from depression.VariablesThe primary outcome, as measured by the physical component score (PCS) of the SF-36 at a 6-year follow-up (range: 0–100), is physical health-related quality of life. The exposure of interest is depressive symptoms, as measured by the Center for Epidemiological Studies Depression Scale for Children (CES-DC) at baseline, 1-year follow-up and 2-year follow-ups (range: 0–60). We dichotomized the exposure into subthreshold (≤15) and elevated depressive symptoms (>15). For the main analyses we considered a cumulative index for elevated depressive symptoms across the three time points (range: 0–3). Considered confounders are sex, age, socioeconomic status, migrant background, social support, anxiety symptoms, physical activity, chronic diseases, and sleeping problems.Statistical methodsWe used multiple imputation to account for missing values. Within each imputed dataset, we applied inverse probability weighting (IPW) to estimate the effect of the cumulative index for elevated depressive symptoms at baseline, 1- and 2-year follow-up on physical health-related quality of life at 6-year follow-up. We derived 95% confidence intervals by bootstrapping.ResultsAfter adjusting with IPW, the effect of the cumulative index per one unit increase of elevated depressive symptoms on the physical component score was −1.71 (95% CI: −3.51 to −0.04). The adjusted effect estimates of single exposure of elevated depressive symptoms on physical health-related quality of life were −0.83 (95% CI: −3.69 to 1.87) at baseline, −2.96 (95% CI: −4.94 to −0.52) at 1-year follow-up and −1.32 (95% CI: −3.85 to 1.15) at 2-year follow-up.ConclusionFindings suggest that elevated depressive symptoms during adolescence decrease physical health-related quality of life in young adulthood.

BackgroundMigraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.MethodsWe conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.ResultsNo significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.ConclusionThe evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.

Abstract Background A significant and growing portion of the global burden of diseases is caused by neurological disorders. Tele-neurology has the potential to improve access to health care services and the quality of care, particularly in rural and underserved areas. The economic evaluation of the stepped wedge randomised controlled trial NeTKoH aims to ascertain the cost-effectiveness and cost-utility regarding the effects of a tele-neurologic intervention in primary care in a rural area in Germany. Methods This protocol outlines the methods used when conducting the trial-based economic evaluation of NeTKoH. The outcomes used in our economic analysis are all prespecified endpoints of the NeTKoH trial. Outcomes considered for the cost-utility and cost-effectiveness analyses will be quality-adjusted life years (QALYs) derived from the EQ-5D-5L, proportion of neurologic problems being solved at the GP’s office (primary outcome), hospital length-of-stay and number of hospital stays. Costs will be prospectively collected during the trial by the participating statutory health insurances, and will be analysed from a statutory health insurance perspective within the German health care system. This economic evaluation will be reported complying with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Discussion This within-trial economic evaluation relaying the costs and outcomes of an interdisciplinary tele-consulting intervention will provide high-quality evidence for cost-effectiveness and policy implications of a tele-neurological programme, including the potential for application in other rural areas in Germany or other jurisdictions with a comparable health system. Trial registration German Clinical Trials Register (DRKS00024492), date registered: September 28, 2021.

Abstract Background Machine learning models promise to support diagnostic predictions, but may not perform well in new settings. Selecting the best model for a new setting without available data is challenging. We aimed to investigate the transportability by calibration and discrimination of prediction models for cognitive impairment in simulated external settings with different distributions of demographic and clinical characteristics. Methods We mapped and quantified relationships between variables associated with cognitive impairment using causal graphs, structural equation models, and data from the ADNI study. These estimates were then used to generate datasets and evaluate prediction models with different sets of predictors. We measured transportability to external settings under guided interventions on age, APOE ε4, and tau-protein, using performance differences between internal and external settings measured by calibration metrics and area under the receiver operating curve (AUC). Results Calibration differences indicated that models predicting with causes of the outcome were more transportable than those predicting with consequences. AUC differences indicated inconsistent trends of transportability between the different external settings. Models predicting with consequences tended to show higher AUC in the external settings compared to internal settings, while models predicting with parents or all variables showed similar AUC. Conclusions We demonstrated with a practical prediction task example that predicting with causes of the outcome results in better transportability compared to anti-causal predictions when considering calibration differences. We conclude that calibration performance is crucial when assessing model transportability to external settings.

Abstract Background Neurological disorders account for a large and increasing proportion of the global burden of disease. Therefore, it is important to strengthen the management of neurologic care, particularly in rural areas. The use of tele-neurology in primary care in rural areas is internationally considered to have the potential to increase access to health care services and improve the quality of care in these underserved areas. NeTKoH aims to address the existing knowledge gap regarding the effects of a tele-neurologic intervention in primary care under real-world conditions in a rural area in Germany. Methods NeTKoH is a cluster-randomized controlled trial with a stepped-wedge design involving 33 outpatient general practitioner’s (GP) offices (clusters) in a rural area in Northeast Germany. During 11 predetermined steps, all clusters are randomized before they cross over into groups from the control to the intervention arm. The targeted sample size is 1,089 patients with neurologic symptoms that are continuously being recruited. In the intervention arm, tele-neurologic consultations will be provided via a face-to-face video conferencing system with a neurologic expert at a university hospital. The control arm will receive usual care. The primary outcome is the proportion of neurologic problems being solved at the GP’s office. Secondary outcomes will comprise hospital stays and days, time until neurologic specialist appointments and diagnostics, patients’ health status and quality of life, outpatient and inpatient referrals. A concurrent observational study, together with a process, implementation, and health economic evaluation, will also be conducted. Discussion Using a stepped-wedge cluster design in a real-life situation can help with logistic challenges and enhance the motivation of the participating GPs, as all, at some point, will be in the intervention phase. With the additional implementation evaluation pertaining to external validity, an observational study, and a health economic evaluation, NeTKoH will be able to provide an extensive evaluation for health policy decision-makers regarding the uptake into standard care. Trial registration German Clinical Trials Register (DRKS00024492). Date registered: September 28, 2021. Date and protocol version: June 2023, version 1.

Abstract Background Migraine is a very common headache disorder on the population level, characterized by symptomatic attacks (activity). For many people with migraine, the migraine symptoms intermittently or permanently cease during their lifetime (inactive migraine). The current diagnostic classification of migraine considers two states: active migraine (having migraine symptoms within the last year) and not having active migraine (including both individuals with inactive migraine and those who never had migraine). Defining a state of inactive migraine that has gone into remission may better capture the trajectories of migraine across the lifespan and contribute to a better understanding of its biological processes. We aimed to quantify the prevalence of never, active, and inactive migraine separately, using modern prevalence and incidence estimation methodology to better describe the complexity of migraine trajectories at the population level. Methods Using a multistate modeling approach, data from the Global Burden of Disease (GBD) study, and results from a population-based study, we estimated the transition rates by which individuals moved between migraine disease states and estimated prevalences of never, active and inactive migraine. We used data from the GBD project and a hypothetical cohort of 100,000 people with a starting age of 30 and 30 years of follow-up, both in Germany and globally, stratified by sex. Results In Germany, the estimated rate of transition from active to inactive migraine (remission rate) increased after the age of 22.5 in women and 27.5 in men. The pattern for men in Germany was similar to the one observed on the global level. The prevalence of inactive migraine among women reaches 25.7% in Germany and 16.5% globally at age 60. For men, the inactive migraine prevalence estimates at the same age were 10.4% in Germany and 7.1% globally. Conclusions Considering an inactive migraine state explicitly reflects a different epidemiological picture of migraine across the lifecourse. We have demonstrated that many women of older ages may be in an inactive migraine state. Many pressing research questions can only be answered if population-based cohort studies collect information not only on active migraine but also on inactive migraine states.

In the earlier phases of the COVID-19 pandemic, studies in Germany and elsewhere found an overall reduction in health-related quality of life (HRQoL) among students. However, there is little evidence on later pandemic stages as well as socioeconomic influencing factors. We aimed to (1) describe HRQoL in a Berlin student cohort at two time points in mid-2021, and to (2) analyze the effects of household income and education. We assessed HRQoL of students from 24 randomly selected primary and secondary schools in Berlin, Germany, with the KIDSCREEN-10 index in June and September 2021. To adjust for non-response bias, inverse probability weighting was applied. The potential effects of both household income and education (lower vs. higher) were estimated in generalized linear mixed models, based on prior assumptions presented in directed acyclic graphs. Our cohort comprised 660 students aged 7-19 years. In June 2021, 11.3% [95% CI = 9.0% - 14.0%] reported low HRQoL, whereas in September 2021, this increased to 13.7% [95% CI = 11.1% - 16.5%], with adolescent girls more frequently reporting low HRQoL at both time points (20% [95% CI = 17.1% - 23.3%] and 29% [95% CI = 25.5% - 32.5%]) compared to boys and younger children. While there was no statistically significant total effect of lower household income on HRQoL, a negative effect of lower household education was statistically significant (β = -2.15, SE 0.95, 95% CI = -4.01 to -0.29, p = 0.024). In summary, students' HRQoL in mid-2021 was better than that documented in other studies conducted at pandemic onset using KIDSCREEN-10. Female adolescents reported low HRQoL more often, and lower household education significantly reduced children's HRQoL. Support strategies for psychosocial wellbeing should consider socioeconomically disadvantaged children as important target groups.

Abstract Purpose The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs. Methods The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients’ disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process. Results Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients. Conclusion The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

SARS-CoV-2 serology may be helpful to retrospectively understand infection dynamics in specific settings including kindergartens. We assessed SARS-CoV-2 seroprevalence in individuals connected to kindergartens in Berlin, Germany in September 2021. Children, staff, and household members from 12 randomly selected kindergartens were interviewed on COVID-19 history and sociodemographic parameters. Blood samples were collected on filter paper. SARS-CoV-2 anti-S and anti-N antibodies were assessed using Roche Elecsys. We assessed seroprevalence and the proportion of so far unrecognized SARS-CoV-2 infections. We included 277 participants, comprising 48 (17.3%) kindergarten children, 37 (13.4%) staff, and 192 (69.3%) household members. SARS-CoV-2 antibodies were present in 65.0%, and 52.7% of all participants were vaccinated. Evidence of previous infection was observed in 16.7% of kindergarten children, 16.2% of staff, and 10.4% of household members. Undiagnosed infections were observed in 12.5%, 5.4%, and 3.6%, respectively. Preceding infections were associated with facemask neglect. In conclusion, two-thirds of our cohort were SARS-CoV-2 seroreactive in September 2021, largely as a result of vaccination in adults. Kindergarten children showed the highest proportion of non-vaccine-induced seropositivity and an increased proportion of previously unrecognized SARS-CoV-2 infection. Silent infections in pre-school children need to be considered when interpreting SARS-CoV-2 infections in the kindergarten context.

Abstract Background During the COVID-19 pandemic, children and adolescents worldwide have disproportionally been affected in their psychological health and wellbeing. We conducted a cohort study among German school children, aiming at assessing levels of general anxiety disorder (GAD) and identifying associated factors in the second pandemic year. Methods A cohort of 660 students from 24 Berlin schools was recruited to fill in questionnaires including the GAD-7 tool on anxiety symptoms at three time points between June and September 2021. To adjust for non-random attrition, we applied inverse probability weighting. We describe reported GAD levels stratified by time point, sex, and school type and report odds ratios from univariate logistic regression. Results In total, 551 participants (83%) filled in at least one questionnaire at any time point. At the first time point in June 2021, 25% of the children and adolescents reported anxiety symptoms with a GAD-7 score ≥ 5, decreasing to 16% in August 2021 directly after the summer holidays and rising again to 26% in September 2021. The majority of reported anxiety levels belonged to the least severe category. Being female, attending secondary school, coming from a household with lower education or with lower income level, and being vaccinated against COVID-19 were significantly linked with reporting anxiety symptoms. Preceding COVID-19 infection and anxiety were negatively associated. Conclusion Overall, anxiety in school children was lower in mid-2021 than in the first pandemic year, but still double compared to pre-pandemic data. Reporting of anxiety symptoms during the second pandemic year was especially high in females and in secondary school students. Policy makers should pay additional attention to the mental health status of school children, even as the pandemic situation might stabilize.

Background During the COVID-19 pandemic, telephone hotlines of local health authorities in Germany were overloaded due to information requests by the public. Objective Evaluating the use of a COVID-19-specific voicebot (CovBot) in local health authorities in Germany during the COVID-19 pandemic. This study investigates the performance of the CovBot by assessing a perceptible relief of staff in the hotline service. Methods This prospective mixed-methods study enrolled local health authorities in Germany from 01 February 2021 to 11 February 2022 to deploy the CovBot, which was mainly designed to answer frequently asked questions. To capture the user perspective and acceptance, we performed semistructured interviews and online surveys with their staff, conducted an online survey among callers, and analyzed the performance metrics of the CovBot. Results The CovBot was implemented in 20 local health authorities serving 6.1 million German citizens and processed almost 1.2 million calls during the study period. The overall assessment was that the CovBot contributed to a perceived relief of the hotline service. In a survey among callers, 79% indicated that a voicebot could not replace a human. The analyzed anonymous metadata revealed that 15% of calls hung up immediately, 32% after hearing an FAQ answer, and 51% of calls were forwarded to the local health authority offices. Conclusions A voicebot primarily answering FAQs can provide additional support to relieve the hotline service of local health authorities in Germany during the COVID-19 pandemic. For complex concerns, a forwarding option to a human proved to be an essential functionality.

Abstract Background Living conditions in homeless shelters facilitate the transmission of COVID-19. Social determinants and pre-existing health conditions place homeless people at increased risk of severe disease. Described outbreaks in homeless shelters resulted in high proportions of infected residents and staff members. In addition to other infection prevention strategies, regular shelter-wide (universal) testing for COVID-19 may be valuable, depending on the level of community transmission and when resources permit. Methods This was a prospective feasibility cohort study to evaluate universal testing for COVID-19 at a homeless shelter with 106 beds in Berlin, Germany. Co-researchers were recruited from the shelter staff. A PCR analysis of saliva or self-collected nasal/oral swab was performed weekly over a period of 3 weeks in July 2020. Acceptability and implementation barriers were analyzed by process evaluation using mixed methods including evaluation sheets, focus group discussion and a structured questionnaire. Results Ninety-three out of 124 (75%) residents were approached to participate in the study. Fifty-one out of the 93 residents (54.8%) gave written informed consent; thus 41.1% (51 out of 124) of all residents were included in the study. Among these, high retention rates (88.9–93.6%) of a weekly respiratory specimen were reached, but repeated collection attempts, as well as assistance were required. Around 48 person-hours were necessary for the sample collection including the preparation of materials. A self-collected nasal/oral swab was considered easier and more hygienic to collect than a saliva specimen. No resident was tested positive by RT-PCR. Language barriers were the main reason for non-participation. Flexibility of sample collection schedules, the use of video and audio materials, and concise written information were the main recommendations of the co-researchers for future implementation. Conclusions Voluntary universal testing for COVID-19 is feasible in homeless shelters. Universal testing of high-risk facilities will require flexible approaches, considering the level of the community transmission, the available resources, and the local recommendations. Lack of human resources and laboratory capacity may be a major barrier for implementation of universal testing, requiring adapted approaches compared to standard individual testing. Assisted self-collection of specimens and barrier free communication may facilitate implementation in homeless shelters. Program planning must consider homeless people’s needs and life situation, and guarantee confidentiality and autonomy.

Within 5 weeks in 2021, B.1.1.7 became the dominant severe acute respiratory syndrome coronavirus 2 lineage at an outpatient testing site in Berlin, Germany. Compared with outpatients with wild-type virus infection, patients with B.1.1.7 had similar cycle threshold values, more frequent sore throat and travel history, and less frequent anosmia/ageusia.

BackgroundDigitalization and electronic health (eHealth) offer new treatment approaches for patients with migraine. Current smartphone applications (apps) for migraine patients include a wide spectrum of functions ranging from digital headache diaries to app-based headache treatment by, among others, analysis of the possible triggers, behavioral therapy approaches and prophylactic non-drug treatment methods with relaxation therapy or endurance sport. Additional possibilities arise through the use of modern, location-independent communication methods, such as online consultations. However, there is currently insufficient evidence regarding the benefits and/or risks of these electronic tools for patients. To date, only few randomized controlled trials have assessed eHealth applications.MethodsSMARTGEM is a randomized controlled trial assessing whether the provision of a new digital integrated form of care consisting of the migraine app M-sense in combination with a communication platform (with online consultations and medically moderated patient forum) leads to a reduction in headache frequency in migraine patients, improving quality of life, reducing medical costs and work absenteeism (DRKS-ID: DRKS00016328).DiscussionSMARTGEM constitutes a new integrated approach for migraine treatment, which aims to offer an effective, location-independent, time-saving and cost-saving treatment. The design of the study is an example of how to gather high quality evidence in eHealth. Results are expected to provide insightful information on the efficacy of the use of electronic health technology in improving the quality of life in patients suffering from migraine and reducing resource consumption.

Abstract Background Significant inequalities in caries distribution among children in Germany have been reported, but small‐scale areas remain understudied. Aim To examine spatio‐temporal trends in children's dental caries at the small‐area level in Berlin‐Mitte. Design Routinely collected data from Berlin's annual Health Examination Surveys were used, which also include information on age, sex, country of origin, and residential area. The study population consists of 14,866 children aged 5 to 7 between 2006 and 2014 in the district of Berlin‐Mitte. Outcome variables are the dmft (decayed, missing, and filled teeth), the presence of any caries experience, untreated caries, and caries risk. The outcomes are summarized descriptively and graphically presented for 10 quarters and 41 communities within Berlin‐Mitte. Results Relevant gaps in children's dental caries were discovered between the quarters of Mitte. Three quarters in the northeast part of Mitte have consistently indicated the lowest oral health status in all four outcomes, and children having high caries risk have been increasingly concentrating in this area over time. Despite the continuous improvements in the southern part, the averages in total of Mitte for all outcomes have risen. Conclusion Our findings confirm the spatiotemporally mounting disparities in children's oral health between the quarters in Berlin‐Mitte and that particular quarters need urgent attention. The small‐area approach made it easier and more effective to reveal the spatial distribution of children's dental caries at the local level. The small‐area analysis should be strongly encouraged in future caries research to narrow the inequalities in children's oral health.

Abstract Background The aim of this study was to develop a standardized method to reconstruct persons’ individual viral load (VL) courses to determine viral suppression and duration of viremia for the HIV care continuum in Germany using longitudinal cohort data. Methods We analyzed data from two large, multi-center German cohort studies under the direction of the Robert Koch Institute. We included data from 1999 to 2018 of all diagnosed people and of people who initiated antiretroviral treatment (ART). We developed a model generating virtual VL values and an individual VL course corresponding to real VL measurements with a maximum distance of 180 days, considering ART status and VL dynamics. If the distance between VL measurements was > 180 days, the time between was defined as gap time. Additionally, we considered blips, which we defined as a single detectable VL 1000 copies/ml decreased from 37% in 1999 to 3% in 2018. The proportion of people with gap time fluctuated and ranged between 18 and 28%. An analysis of the first VL after gap time showed that 90% showed viral suppression, 5% VL between 50- 1000 copies/ml. Conclusion We provide a method for estimating viral suppression and duration of viremia using longitudinal VL data. We observed a continuous and remarkable increase of viral suppression. Furthermore, a notable proportion of those with viremia showed low-level viremia and were therefore unlikely to transmit HIV. Individual health risks and HIV drug resistance among those with low-level viremia are problematic, and viral suppression remains the goal. In 2018, 93 and 96% of people after ART initiation showed VL

The association between blood pressure (BP) and migraine is poorly understood. Here, the authors explore this relationship using summary-level GWAS data for BP and migraine. Cross-trait meta-analysis reveals shared loci between BP and migraine, while Mendelian randomization suggests that diastolic BP specifically plays a key role in migraine susceptibility.

Abstract Background In epidemiology, causal inference and prediction modeling methodologies have been historically distinct. Directed Acyclic Graphs (DAGs) are used to model a priori causal assumptions and inform variable selection strategies for causal questions. Although tools originally designed for prediction are finding applications in causal inference, the counterpart has remained largely unexplored. The aim of this theoretical and simulation-based study is to assess the potential benefit of using DAGs in clinical risk prediction modeling. Methods We explore how incorporating knowledge about the underlying causal structure can provide insights about the transportability of diagnostic clinical risk prediction models to different settings. We further probe whether causal knowledge can be used to improve predictor selection in clinical risk prediction models. Results A single-predictor model in the causal direction is likely to have better transportability than one in the anticausal direction in some scenarios. We empirically show that the Markov Blanket, the set of variables including the parents, children, and parents of the children of the outcome node in a DAG, is the optimal set of predictors for that outcome. Conclusions Our findings provide a theoretical basis for the intuition that a diagnostic clinical risk prediction model including causes as predictors is likely to be more transportable. Furthermore, using DAGs to identify Markov Blanket variables may be a useful, efficient strategy to select predictors in clinical risk prediction models if strong knowledge of the underlying causal structure exists or can be learned.

Abstract Background This study evaluates the accuracy of an automated classification tool of single attacks of the two major primary headache disorders migraine and tension-type headache used in an electronic headache diary. Methods One hundred two randomly selected reported headache attacks from an electronic headache-diary of patients using the medical app M-sense were classified by both a neurologist with specialisation in headache medicine and an algorithm, constructed based on the ICHD-3 criteria for migraine and tension-type headache. The level of agreement between the headache specialist and the algorithm was compared by using a kappa statistic. Cases of disagreement were analysed in a disagreement validity assessment. Result The neurologist and the algorithm classified migraines with aura (MA), migraines without aura (MO), tension-type headaches (TTH) and non-migraine or non-TTH events. Of the 102 headache reports, 86 cases were fully agreed on, and 16 cases not, making the level of agreement unweighted kappa 0.74 and representing a substantial level of agreement. Most cases of disagreement (12 out of 16) were due to inadvertent mistakes of the neurologist identified in the disagreement validity assessment. The second most common reason (3 out of 16) was insufficient information for classification by the neurologist. Conclusions The substantial level of agreement indicates that the classification tool is a valuable instrument for automated evaluation of electronic headache diaries, which can thereby support the diagnostic and therapeutic clinical processes. Based on this study’s results, additional diagnostic functionalities of primary headache management apps can be implemented. Finally, future research can use this classification algorithm for large scale database analysis for epidemiological studies.

Abstract Background Migraine carries a high global burden, disproportionately affects women, and has been implicated as a risk factor for cardiovascular disease. Migraine with aura has been consistently associated with increased risk of cardiovascular mortality. However, published evidence on relationships between migraine or non-migraine headache and all-cause mortality is inconclusive. Therefore, we aimed to estimate the effect of non-migraine headache and migraine as well as migraine subtypes on all-cause and cause-specific mortality in women. Methods In total, 27,844 Women’s Health Study participants, aged 45 years or older at baseline, were followed up for a median of 22.7 years. We included participants who provided information on migraine (past history, migraine without aura, or migraine with aura) or headache status and a blood sample at study start. An endpoints committee of physicians evaluated reports of incident deaths and used medical records to confirm deaths due to cardiovascular, cancer, or female-specific cancer causes. We used multivariable Cox proportional hazards models to estimate the effect of migraine or headache status on both all-cause and cause-specific mortality. Results Compared to individuals without any headache, no differences in all-cause mortality for individuals suffering from non-migraine headache or any migraine were observed after adjustment for confounding (HR = 1.01, 95%CI, 0.93–1.10 and HR = 0.96, 95% CI: 0.89–1.04). No differences were observed for the migraine subtypes and all-cause death. Women having the migraine with aura subtype had a higher mortality due to cardiovascular disease (adjusted HR = 1.64, 95%CI: 1.06–2.54). As an explanation for the lack of overall association with all-cause mortality, we observed slightly protective signals for any cancer and female-specific cancers in this group. Conclusions In this large prospective study of women, we found no association between non-migraine headache or migraine and all-cause mortality. Women suffering from migraine with aura had an increased risk of cardiovascular death. Future studies should investigate the reasons for the increased risk of cardiovascular mortality and evaluate whether changes in migraine patterns across the life course have differential effects on mortality.

During the SARS-CoV-2 outbreak, several epidemiological measures, such as cumulative case-counts (CCC), incidence rates, effective reproduction numbers (Reff) and doubling times, have been used to inform the general public and to justify interventions such as lockdown. It has been very likely that not all infectious people have been identified during the course of the epidemic, which lead to incomplete case-detection. We compare CCC, incidence rates, Reff and doubling times in the presence of incomplete case-detection. For this, an infection-age-structured SIR model is used to simulate a SARS-CoV-2 outbreak followed by a lockdown in a hypothetical population. Different scenarios about temporal variations in case-detection are applied to the four measures during outbreak and lockdown. The biases resulting from incomplete case-detection on the four measures are compared in terms of relative errors. CCC is most prone to bias by incomplete case-detection in all of our settings. Reff is the least biased measure. The possibly biased CCC may lead to erroneous conclusions in cross-country comparisons. With a view to future reporting about this or other epidemics, we recommend including and placing an emphasis on Reff in those epidemiological measures used for informing the general public and policy makers.

BackgroundSmartphone-based apps represent a major development in health care management. Specifically in headache care, the use of electronic headache diaries via apps has become increasingly popular. In contrast to the soaring volume of available data, scientific use of these data resources is sparse. ObjectiveIn this analysis, we aimed to assess changes in headache and migraine frequency, headache and migraine intensity, and use of acute medication among people who showed daily use of the headache diary as implemented in the freely available basic version of the German commercial app, M-sense. MethodsThe basic version of M-sense comprises an electronic headache diary, documentation of lifestyle factors with a possible impact on headaches, and evaluation of headache patterns. This analysis included all M-sense users who had entered data into the app on a daily basis for at least 7 months. ResultsWe analyzed data from 1545 users. Mean MHD decreased from 9.42 (SD 5.81) at baseline to 6.39 (SD 5.09) after 6 months (P

Abstract Background Although an “epidemic” of depression is frequently claimed, empirical evidence is inconsistent, depending on country, study design and depression assessment. Little is known about changes in depression over time in Germany, although health insurance companies report frequency increases. Here we examined time trends in depression prevalence, severity and health-related correlates in the general population. Methods Data were obtained from the mental health module of the “German Health Interview and Examination Survey for Adults” (2009–2012, n = 3265) and the mental health supplement of the “German National Health Interview and Examination Survey 1998” (1997–1999, n = 4176), excluding respondents older than 65. 12-month major depressive disorder (MDD), severity and symptoms were assessed based on the WHO Composite International Diagnostic Interview. Health-related quality of life (SF-36), self-reported sick days or days with limitations in normal daily life activities were examined, too. Calculations were carried out population-weighted. Additional age-standardized analyses were conducted to account for demographic changes. Results Overall, MDD 12-month prevalence remained stable at 7.4%. Women showed a shifted age distribution with increased prevalence at younger ages, and increasing MDD severity. Time trends in health-related correlates occurred both in participants with and without MDD. Mental health disability increased over time, particularly among men with MDD, reflected by the mental component score of the SF-36 and days with activity limitation due to mental health problems. Demographic changes had a marginal impact on the time trends. Conclusions In contrast to the ongoing international debate regarding increased depression rates in western countries, we found no increase in overall MDD prevalence in Germany over a long period. In conclusion, increased depression frequencies in national health insurance data and growing health care costs associated with depression are not attributable to overall prevalence changes at a population level. However, shifted age distribution and increased severity among women may reflect a rising depression risk within this specific subgroup, and changes in health-related correlates indicate a growing mental health care need for depression, particularly among men.

Objective: To describe the clinical trial “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest” (VAM-IHCA). Methods: The VAM-IHCA trial is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. The study drugs consist of 40 mg methylprednisolone and 20 IU of vasopressin given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU).The primary outcome is return of spontaneous circulation and key secondary outcomes include survival and survival with a favorable neurological outcome at 30 days. 492 patients will be enrolled. The trial was registered at the EU Clinical Trials Register (EudraCT Number: 2017-004773-13) on Jan. 25, 2018 and ClinicalTrials.gov (Identifier: NCT03640949) on Aug. 21, 2018. Results: The trial started in October 2018 and the last patient is anticipated to be included in January 2021. The primary results will be reported after 3-months follow-up and are, therefore, anticipated in mid-2021. Conclusion: The current article describes the design of the VAM-IHCA trial. The results from this trial will help clarify whether the combination of vasopressin and methylprednisolone when administered during in-hospital cardiac arrest improves outcomes.

Migraine is heritable and formally diagnosed by structured criteria that require presence of some but not all possible migraine symptoms which include aura, several distinct manifestations of pain, nausea/vomiting, and sensitivity to light or sound. The most recent genome-wide genetic association study (GWAS) for migraine identified 38 loci. We investigated whether 46 single-nucleotide polymorphisms (SNPs), i.e., genetic variants, at these loci may have especially pronounced, i.e., selective, association with migraine presenting with individual symptoms compared to absence of migraine. Selective genetic associations of SNPs were evaluated through a likelihood framework in the Women's Genome Health Study (WGHS), a population-based cohort of middle-aged women including 3,003 experiencing migraine and 18,108 not experiencing migraine, all with genetic information. SNPs at 12 loci displayed significant selective association for migraine subclassified by specific symptoms, among which six selective associations are novel. Symptoms showing selective association include aura, nausea/vomiting, photophobia, and phonophobia. The selective associations were consistent whether the women met all formal criteria for diagnostic for migraine or lacked one of the diagnostic criteria, formally termed probable migraine. Subsequently, we performed latent class analysis of migraine diagnostic symptoms among 69,861 women experiencing migraine from the WGHS recruitment sample to assess whether there were clusters of specific symptoms that might also have a genetic basis. However, no globally robust latent migraine substructures of diagnostic symptoms were observed nor were there selective genetic associations with specific combinations of symptoms revealed among weakly supported latent classes. The findings extend previously reported selective genetic associations with migraine diagnostic symptoms while supporting models for shared genetic susceptibility across all qualifying migraine at many loci.

Migraine is a common neurovascular disorder affecting ~15% of the general population. Ranking second in the list of years lived with disability (YLD), people living with migraine are greatly impacted by this especially burdensome primary headache disorder. In ~30% of individuals with migraine, transient neurological symptoms occur (migraine aura) that further increase migraine burden. However, migraine burden is differential with respect to sex. Though one-year prevalences in childhood are similar, starting with puberty, migraine incidence increases at a much higher rate in females than males. Thus, migraine over the life course occurs in women three to four times more often than in men. Attacks are also more severe in women, leading to greater disability and a longer recovery period. The sex disparity in migraine is believed to be partly mediated through fluctuations in ovarian steroid hormones, especially estrogen and progesterone, although the exact mechanisms are not yet completely understood. The release of the neuropeptide calcitonin gene-related peptide (CGRP), followed by activation of the trigeminovascular system, is thought to play a key role in the migraine pathophysiology. Given the burden of migraine and its disproportionate distribution, the underlying cause(s) for the observed differences between sexes in the incidence, frequency, and intensity of migraine attacks must be better understood. Relevant biological as well as behavioral differences must be taken into account. To evaluate the scope of the existing knowledge on the issue of biological sex as well as gender differences in migraine, we conducted a systematized review of the currently available research. The review seeks to harmonize existing knowledge on the topic across the domains of biological/preclinical, clinical, and population-level research, which are traditionally synthesized and interpreted in isolation. Ultimately, we identify knowledge gaps and set priorities for further interdisciplinary and informed research on sex and gender differences as well as gender-specific therapies in migraine.

Objectives To investigate authors’ awareness and use of authorship guidelines, and to assess their perceptions of the fairness of authorship decisions.Design A cross-sectional online survey.Setting and participants Corresponding authors of research papers submitted in 2014 to 18 BMJ journals.Results 3859/12 646 (31%) researchers responded. They worked in 93 countries and varied in research experience. Of these, 1326 (34%) reported their institution had an authorship policy providing criteria for authorship; 2871 (74%) were ‘very familiar’ with the International Committee of Medical Journal Editors’ authorship criteria and 3358 (87%) reported that guidelines were beneficial when preparing manuscripts. Furthermore, 2609 (68%) reported that their use was ‘sometimes’ or ‘frequently’ encouraged in their research setting. However, 2859 respondents (74%) reported that they had been involved in a study at least once where someone was added as an author who had not contributed substantially (honorary authorship), and 1305 (34%) where someone was not listed as an author but had contributed substantially (ghost authorship). Only 740 (19%) reported that they had never experienced either honorary or ghost authorship; 1115 (29%) reported that they had experienced both at least once. There was no clear pattern in experience of authorship misappropriation by continent. For their last coauthored article, 2187 (57%) reported that explicit authorship criteria had been used to determine eligibility, and 3088 (80%) felt that the decision made was fair. When institutions frequently encouraged use of authorship guidelines, authorship eligibility was more likely to be discussed early (817 of 1410, 58%) and perceived as fairer (1273 of 1410, 90%) compared with infrequent encouragement (974 of 2449, 40%, and 1891 of 2449, 74%).Conclusions Despite a high level of awareness of authorship guidelines and criteria, these are not so widely used; more explicit encouragement of their use by institutions may result in more favourable use of guidelines by authors.

Rare diseases are difficult if not impossible to study outside of population-based registries. Particularly in the context of rare neurodegenerative diseases characterized by case heterogeneity, difficult differential diagnosis by specialists, and small numbers of patients, registries make otherwise unfeasible incidence studies cost-effective and manageable. Building up and maintaining such registries is challenging and requires strong, active, and collaborative networks. Centralization around a leading institution provides structure and consistency, but this single-site storage leads to inefficiency and bottlenecks and is prone to failures, attacks, and manipulation. Furthermore, a substantial amount of trust is required between parties sharing data in a traditional registry. Patients are increasingly reluctant to share data in light of regular news reports about healthcare data breaches. Underfunded rare disease specialized centers are also hesitant to exchange with the leading institution out of fear that the low numbers of patients may seek treatment elsewhere. A lack of electronic health records and information system interoperability in certain settings leads to information silos and only further exacerbate the other issues. Blockchain technology may provide unique, innovative solutions to many of these challenges. Specifically, through digital trust and the use of an immutable distributed ledger, automated data transaction processing, guaranteed integrity, and enhanced security, blockchain technology seems to be perfectly suitable to optimize current population-based rare neurodegenerative disease registry construction and maintenance.

BACKGROUND:European guidelines recommend the use of the Systematic COronary Risk Evaluation (SCORE) to assess 10-year risk of fatal cardiovascular events in people aged 40 to 65. The SCORE Older Persons (SCORE OP, 5-year and 10-year versions) was recently developed for people aged 65 or older. We assessed the performance of these risk scores in predicting fatal cardiovascular events in older persons in Berlin. METHODS AND FINDINGS:Data from the Berlin Initiative Study (BIS), a prospective, population-based study of older persons recruited from a German public health insurance company database were used. 1,657 participants aged 70 or older without reported previous myocardial infarction were included. We assessed calibration by comparing predicted risks to observed (for 5-year versions, 5y) or projected (for 10-year versions) probabilities. During follow-up (median: 4.8 years), 118 cardiovascular deaths occurred. The calibration assessment of the SCORE OP-H 5y and SCORE OP-L 5y equations revealed 2.1- and 1.5-fold overestimation. Comparing 10-year versions, the SCORE OP showed better discrimination ability compared to the SCORE (C-indices of around 0.80 compared to 0.72) and the SCORE for high-risk regions showed the best calibration (chi-square = 29.68). The SCORE OP overestimated the true risk; 519 and 677 events were predicted using the low-risk and high-risk region SCORE OP equations compared to 397 to 399 events projected based on BIS follow-up data (predicted/actual ratios of 1.3 and 1.7). CONCLUSIONS:Given the low transportability of the SCORE OP observed in our population, we caution against its use in routine clinical practice until further information is available to avoid possible overtreatment among older persons in Berlin.

[This corrects the article DOI: 10.1371/journal.pone.0231097.].

BackgroundThe extent to which people implement government-issued protective measures is critical in preventing further spread of coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2. Our study aimed to describe the public belief in the effectiveness of protective measures, the reported implementation of these measures, and to identify communication channels used to acquire information on COVID-19 in European countries during the early stage of the pandemic.Methods and findingsAn online survey available in multiple languages was disseminated starting on March 19th, 2020. After five days, we computed descriptive statistics for countries with more than 500 respondents. Each day, we assessed enacted community containment measures by stage of stringency (I-IV). In total, 9,796 adults responded, of whom 8,611 resided in the Netherlands (stage III), 604 in Germany (stage III), and 581 in Italy (stage IV). To explore possible dynamics as containment strategies intensified, we also included 1,365 responses submitted during the following week. Participants indicated support for governmental measures related to avoiding social gatherings, selective closure of public places, and hand hygiene and respiratory measures (range for all measures: 95.0%-99.7%). Respondents from the Netherlands less frequently considered a complete social lockdown effective (59.2%), compared to respondents in Germany (76.6%) or Italy (87.2%). Italian residents applied enforced social distancing measures more frequently (range: 90.2%-99.3%, German and Dutch residents: 67.5%-97.0%) and self-initiated hygienic and social distancing behaviors (range: 36.3%-96.6%, German and Dutch residents: 28.3%-95.7%). Respondents reported being sufficiently informed about the outbreak and behaviors to avoid infection (range: 90.2%-91.1%). Information channels most commonly reported included television newspapers, official health websites, and social media. One week later, we observed no major differences in submitted responses.ConclusionsDuring the early stage of the COVID-19 pandemic, belief in the effectiveness of protective measures among survey respondents from three European countries was high and participants reported feeling sufficiently informed. In March 2020, implementation of measures differed between countries and were highest among respondents from Italy, who were subjected to the most stringent lockdown measures and greatest COVID-19 burden in Europe during this period.

Abstract We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

Abstract Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migraineurs is magnified by the use of hormonal contraceptives. As migraine prevalence is high in women of reproductive age, it is common to face the issue of migraine and hormonal contraceptive use in clinical practice. In this document, we systematically reviewed data about the association between migraine, ischemic stroke and hormonal contraceptive use. Thereafter a consensus procedure among international experts was done to develop statements to support clinical decision making, in terms of cardiovascular safety, for prescription of hormonal contraceptives to women with migraine. Overall, quality of current evidence regarding the risk of ischemic stroke in migraineurs associated with the use of hormonal contraceptives is low. Available data suggest that combined hormonal contraceptive may further increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura. Thus, our current statements privilege safety and provide several suggestions to try to avoid possible risks. As the quality of available data is poor further research is needed on this topic to increase safe use of hormonal contraceptives in women with migraine.

Abstract Background Postoperative respiratory complications (PRCs) are associated with significant morbidity, mortality, and hospital costs. Obstructive sleep apnea (OSA), often undiagnosed in the surgical population, may be a contributing factor. Thus, we aimed to develop and validate a score for preoperative prediction of OSA (SPOSA) based on data available in electronic medical records preoperatively. Methods OSA was defined as the occurrence of an OSA diagnostic code preceded by a polysomnography procedure. A priori defined variables were analyzed by multivariable logistic regression analysis to develop our score. Score validity was assessed by investigating the score’s ability to predict non-invasive ventilation. We then assessed the effect of high OSA risk, as defined by SPOSA, on PRCs within seven postoperative days and in-hospital mortality. Results A total of 108,781 surgical patients at Partners HealthCare hospitals (2007–2014) were studied. Predictors of OSA included BMI >25 kg*m−2 and comorbidities, including pulmonary hypertension, hypertension, and diabetes. The score yielded an area under the curve of 0.82. Non-invasive ventilation was significantly associated with high OSA risk (OR 1.44, 95% CI 1.22–1.69). Using a dichotomized endpoint, 26,968 (24.8%) patients were identified as high risk for OSA and 7.9% of these patients experienced PRCs. OSA risk was significantly associated with PRCs (OR 1.30, 95% CI 1.19–1.43). Conclusion SPOSA identifies patients at high risk for OSA using electronic medical record-derived data. High risk of OSA is associated with the occurrence of PRCs.

Objectives To examine the longitudinal relationship between cardiovascular fitness in young adult men and future risk of migraine and to estimate eventual differential effects among categories of body mass index (BMI) and blood pressure.Design National, prospective, population-based cohort study.Setting Sweden 1968–2014.Participants 18-year-old Swedish men (n=1 819 828) who underwent mandatory military conscription examinations during the years 1968–2005.Primary and secondary outcomes The primary outcome was the first dispensation of prescribed migraine-specific medication, identified using the Swedish Prescribed Drug Register. The secondary outcome was documented migraine diagnosis from the Swedish National Hospital Register.Results During follow-up, 22 533 men filled a prescription for migraine-specific medication. After confounding adjustment, compared with high cardiovascular fitness, low and medium fitness increased the risk of migraine-specific medication (risk ratio (RR)low: 1.29, 95% CI 1.24 to 1.35; population attributable fraction: 3.6%, 95% CI 1.7% to 5.3% and RRmedium: 1.15, 95% CI 1.12 to 1.19; population attributable fraction: 8.0%, 95% CI 4.0% to 11.7%). To assess potential effect measure modification, stratified analyses of these association by levels of BMI and blood pressure showed that lower fitness levels increased risk of migraine across all groups except among underweight men or men with high diastolic blood pressure.Conclusions Young men with a lower cardiovascular fitness had a higher long-term risk of developing pharmacological prescription-requiring migraine. This study contributes with information regarding risk factors for migraine in men, an understudied population in migraine research.