Publications by authors named "Tobias Kurth"

326 Publications

Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions.

Neurology 2021 Oct 11. Epub 2021 Oct 11.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA

Background And Objective: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.

Methods: We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women's Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (N=54,552, N=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).

Results: There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci ( harboring , harboring , harboring , and harboring ) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (<0.05) in a smaller sample from the UK Biobank. The shared signal at colocalized with expression of and in multiple tissues.

Conclusions: The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.

Classification Of Evidence: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.
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http://dx.doi.org/10.1212/WNL.0000000000012919DOI Listing
October 2021

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

JAMA 2021 Sep 29. Epub 2021 Sep 29.

Research Center for Emergency Medicine, Department of Clinical Medicine and Emergency Department, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.

Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.

Design, Setting, And Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.

Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.

Main Outcomes And Measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).

Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.

Conclusions And Relevance: Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT03640949.
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http://dx.doi.org/10.1001/jama.2021.16628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482303PMC
September 2021

Prevalence of SARS-CoV-2 Infections Among Students, Teachers, and Household Members During Lockdown and Split Classes in Berlin, Germany.

JAMA Netw Open 2021 09 1;4(9):e2127168. Epub 2021 Sep 1.

Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.27168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479578PMC
September 2021

SARS-CoV-2 infection and transmission in school settings during the second COVID-19 wave: a cross-sectional study, Berlin, Germany, November 2020.

Euro Surveill 2021 08;26(34)

The members of the BECOSS study group are listed under Investigators.

BackgroundSchool attendance during the COVID-19 pandemic is intensely debated.AimIn November 2020, we assessed SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.MethodsWe collected oro-nasopharyngeal swabs and blood samples, examining SARS-CoV-2 infection and IgG antibodies by RT-PCR and ELISA. Household members self-swabbed. We assessed individual and institutional prevention measures. Classes with SARS-CoV-2 infection and connected households were retested after 1 week.ResultsWe examined 1,119 participants, including 177 primary and 175 secondary school students, 142 staff and 625 household members. SARS-CoV-2 infection occurred in eight classes, affecting each 1-2 individuals. Infection prevalence was 2.7% (95% confidence interval (CI): 1.2-5.0; 9/338), 1.4% (95% CI: 0.2-5.1; 2/140), and 2.3% (95% CI: 1.3-3.8; 14/611) among students, staff and household members. Six of nine infected students were asymptomatic at testing. We detected IgG antibodies in 2.0% (95%CI: 0.8-4.1; 7/347), 1.4% (95% CI: 0.2-5.0; 2/141) and 1.4% (95% CI: 0.6-2.7; 8/576). Prevalence increased with inconsistent facemask-use in school, walking to school, and case-contacts outside school. For three of nine households with infection(s), origin in school seemed possible. After 1 week, no school-related secondary infections appeared in affected classes; the attack rate in connected households was 1.1%.ConclusionSchool attendance under rigorously implemented preventive measures seems reasonable. Balancing risks and benefits of school closures need to consider possible spill-over infection into households. Deeper insight is required into the infection risks due to being a schoolchild vs attending school.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.34.2100184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393892PMC
August 2021

Development and external validation of a prognostic model for ischaemic stroke after surgery.

Br J Anaesth 2021 Nov 22;127(5):713-721. Epub 2021 Jul 22.

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Department of Anesthesiology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA; Klinik für Anästhesiologie, Universitätsklinikum Essen, Essen, Germany. Electronic address:

Background: There is an under-recognised patient cohort at elevated risk of postoperative ischaemic stroke. We aimed to develop and validate a prognostic model for the identification of such patients at high risk of ischaemic stroke within 1 yr after noncardiac surgery.

Methods: This was a hospital registry study of adult patients undergoing noncardiac surgery between 2005 and 2017 at two independent healthcare networks in Massachusetts, USA without a preoperative indication for therapeutic anticoagulation. Logistic regression was used to fit a model from a priori defined candidate predictors for the outcome 1 yr postoperative ischaemic stroke. To enhance clinical applicability, the model was simplified to a scoring system and externally validated.

Results: In the development (n=107 756) and validation (n=141 724) cohorts, 1.4% and 0.5% of patients had an ischaemic stroke up to 1 yr postoperatively. The final model included 13 variables (patient characteristics, comorbidities, procedural factors), considering sub-models conditional on a previous history of ischaemic stroke. Areas under the curve were 0.89 (95% confidence interval 0.89-0.90) and 0.88 (95% confidence interval 0.86-0.89) in the development and validation cohorts. Decision curve analysis indicated positive net benefits superior to other prediction instruments.

Conclusions: Stroke after surgery (STRAS) screening can reliably identify patients with a high risk for ischaemic stroke during the first year after surgery. A STRAS-guided risk stratification may inform the recruitment to future randomised trials testing the efficacy of treatments for the prevention of postoperative ischaemic stroke.
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http://dx.doi.org/10.1016/j.bja.2021.05.035DOI Listing
November 2021

COVID-19 Vaccine-Associated Cerebral Venous Thrombosis in Germany.

Ann Neurol 2021 10 23;90(4):627-639. Epub 2021 Aug 23.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Objective: We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.

Methods: A web-based questionnaire was e-mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states.

Results: A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38-0.78) per 100,000 person-months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00-2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (95% CI = 1.22-10.65) for females compared to non-females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable.

Interpretation: Given an incidence of 0.02 to 0.15 per 100,000 person-months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women. ANN NEUROL 2021;90:627-639.
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http://dx.doi.org/10.1002/ana.26172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427115PMC
October 2021

Determining the Evolution of Headache Among Regular Users of a Daily Electronic Diary via a Smartphone App: Observational Study.

JMIR Mhealth Uhealth 2021 07 7;9(7):e26401. Epub 2021 Jul 7.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Smartphone-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.

Objective: In 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.

Methods: The 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.

Results: We 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<.001; 95% CI 2.80-3.25). MMD, AMD, and migraine intensity were also significantly reduced. Similar results were found in 985 users with episodic migraine and in 126 users with chronic migraine.

Conclusions: Among regular users of an electronic headache diary, headache and migraine frequency, in addition to other headache characteristics, improved over time. The use of an electronic headache diary may support standard headache care.
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http://dx.doi.org/10.2196/26401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295831PMC
July 2021

HIT-6 and EQ-5D-5L in patients with migraine: assessment of common latent constructs and development of a mapping algorithm.

Eur J Health Econ 2021 Jul 10. Epub 2021 Jul 10.

Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Objective: The aims of this study were to assess whether there is a conceptual overlap between the questionnaires HIT-6 and EQ-5D and to develop a mapping algorithm allowing the conversion of HIT-6 to EQ-5D utility scores for Germany.

Methods: This study used data from an ongoing randomised controlled trial for patients suffering from migraine. We assessed the conceptual overlap between the two instruments with correlation matrices and exploratory factor analysis. Linear regression, tobit, mixture, and two-part models were used for mapping, accounting for repeated measurements, tenfold cross-validation was conducted to validate the models.

Results: We included 1010 observations from 410 patients. The EQ-5D showed a substantial ceiling effect (47.3% had the highest score) but no floor effect, while the HIT-6 showed a very small ceiling effect (0.5%). The correlation between the instruments' total scores was moderate (- 0.30), and low to moderate among each domain (0.021-0.227). The exploratory factor analysis showed insufficient conceptual overlap between the instruments, as they load on different factors. Thus, there is reason to believe that the instruments' domains do not capture the same latent constructs. To facilitate future mapping, we provide coefficients and a variance-covariance matrix for the preferred model, a two-part model with the total HIT-6 score as the explanatory variable.

Conclusion: This study showed that the German EQ-5D and the HIT-6 lack the conceptual overlap needed for appropriate mapping. Thus, the estimated mapping algorithms should only be used as a last resort for estimating utilities to be employed in economic evaluations.
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http://dx.doi.org/10.1007/s10198-021-01342-9DOI Listing
July 2021

Vasopressin and methylprednisolone for in-hospital cardiac arrest - Protocol for a randomized, double-blind, placebo-controlled trial.

Resusc Plus 2021 Mar 30;5:100081. Epub 2021 Jan 30.

Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Denmark.

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.
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http://dx.doi.org/10.1016/j.resplu.2021.100081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244400PMC
March 2021

Emergence of SARS-CoV-2 B.1.1.7 Lineage at Outpatient Testing Site, Berlin, Germany, January-March 2021.

Emerg Infect Dis 2021 07;27(7)

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.
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http://dx.doi.org/10.3201/eid2707.210845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237906PMC
July 2021

SARS-CoV-2 infections in kindergartens and associated households at the start of the second wave in Berlin, Germany - a cross sectional study.

Eur J Public Health 2021 May 6. Epub 2021 May 6.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Institute of Tropical Medicine and International Health, Berlin, Germany.

Actual surveys in kindergartens on SARS-CoV-2 infections are rare. At the beginning of the second pandemic wave, we screened twelve randomly selected kindergartens in Berlin, Germany. A total of 720 participants (pre-school children, staff, and connected household members) were briefly examined and interviewed, and SARS-CoV-2 infections and anti-SARS-Cov-2 IgG antibodies were assessed. About a quarter of the participants showed common cold-resembling symptoms. However, no SARS-CoV-2 infection was detected, and only one childcare worker showed IgG seroreactivity. Against a backdrop of increased pandemic activity in the community, this cross-sectional study does not suggest that kindergartens are silent transmission reservoirs.
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http://dx.doi.org/10.1093/eurpub/ckab079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135989PMC
May 2021

Re: Prognosis of Neurological Improvement in Inpatient Acute Ischemic Stroke Survivors: A Propensity Score Matching Analysis.

J Stroke Cerebrovasc Dis 2021 07 22;30(7):105813. Epub 2021 Apr 22.

Harvard T.H. Chan School of Public Health, Boston, MA, 02115 USA; Institute of Public Health, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105813DOI Listing
July 2021

Association of Migraine With Incident Hypertension After Menopause: A Longitudinal Cohort Study.

Neurology 2021 07 21;97(1):e34-e41. Epub 2021 Apr 21.

From Center for Research in Epidemiology and Population Health (CESP) (C.J.M., D.E.F., A.-L.M., G.S., M.-C.B.-R.), Institut Gustave Roussy, INSERM (Institut National de la Santé et de la Recherche Médicale) U1018; Université Paris-Saclay (C.J.M., D.E.F., A.-L.M., G.S., M.-C.B.-R.), Université Paris-Sud, Villejuif; EA 2694-Santé Publique: Épidémiologie et Qualité des Soins (A.-L.M.), Université de Lille, CHU Lille, France; Deep Digital Phenotyping Research Unit, Department of Population Health (G.F.), Luxembourg Institute of Health, Strassen; Institute of Public Health Charité-Universitätsmedizin Berlin (T.K.), Germany; and Department of Statistics, Computer Science and Applications (DISIA) (G.S.), University of Florence, Italy.

Objective: Migraine has been identified as a potential risk factor for hypertension in prospective studies. In women, migraine prevalence decreases after menopause, but no studies have determined whether migraine is associated with hypertension after menopause. This study sought to determine whether history of migraine was associated with an increased risk of hypertension among menopausal women.

Methods: We assessed associations between migraine and hypertension in a longitudinal cohort study of 56,202 menopausal women participating in the French E3N cohort, with follow-up beginning in 1993. We included women who did not have hypertension or cardiovascular disease at the time of menopause. Migraine was classified as ever or never at each questionnaire cycle. Cox proportional hazards models were used to investigate relations between migraine and hypertension, controlling for potential confounding. A secondary analysis with baseline in 2011 considered aura status, grouping participants reporting migraine as migraine with aura, migraine without aura, or unknown migraine type.

Results: During 826,419 person-years, 12,501 cases of incident hypertension were identified, including 3,100 among women with migraine and 9,401 among women without migraine. Migraine was associated with an increased risk of hypertension in menopausal women (hazard ratio [HR] 1.29 [95% confidence interval 1.24, 1.35]) and was consistent in post hoc sensitivity analyses, such as when controlling for common migraine medications. Associations between migraine and hypertension were similar whether or not women reported aura (HR 1.54 [1.04, 2.30], HR 1.32 [0.87, 2.02], heterogeneity 0.60). Associations were slightly stronger among ever users of menopausal hormone therapy (HR 1.34 [1.27, 1.41]) than among never users (HR 1.19 [1.11, 1.28]).

Conclusions: Migraine was associated with an increased risk of hypertension among menopausal women. In secondary analysis, we did not observe a significant difference between migraine with aura and migraine without aura.
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http://dx.doi.org/10.1212/WNL.0000000000011986DOI Listing
July 2021

SARS-CoV-2 Infection, Risk Perception, Behaviour and Preventive Measures at Schools in Berlin, Germany, during the Early Post-Lockdown Phase: A Cross-Sectional Study.

Int J Environ Res Public Health 2021 03 8;18(5). Epub 2021 Mar 8.

Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020. Following re-opening, schools resumed operation at a reduced level for nine weeks. During this phase, we aimed at assessing, among students and teachers, infection status, symptoms, individual behaviour, and institutional infection prevention measures. Twenty-four primary and secondary school classes, randomly selected across Berlin, were examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to determine SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household characteristics, leisure activities, fear of infection, risk perception, hand hygiene, facemask wearing, and institutional preventive measures were assessed. Descriptive analysis was performed. Among 535 participants (385 students, 150 staff), one teenager was found to be infected with SARS-CoV-2 (0.2%), and seven individuals exhibited specific IgG (1.3%). Compared to pre-pandemic times, screen time (e.g., TV, gaming, social media) increased, and the majority of primary school students reported reduced physical activity (42.2%). Fear of infection and risk perception were relatively low, acceptance of adapted health behaviors was high. In this post-lockdown period of low SARS-CoV-2 incidence in Berlin, individual and school-level infection prevention measures were largely adhered to. Nevertheless, vigilance and continued preventive measures are essential to cope with future pandemic activity.
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http://dx.doi.org/10.3390/ijerph18052739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967466PMC
March 2021

Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis.

Neurology 2021 05 1;96(20):e2481-e2487. Epub 2021 Apr 1.

From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.

Objective: To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.

Methods: Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.

Results: There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, = 6.08 × 10), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, = 2.25 × 10), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, = 5.44 × 10) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, = 2.32 × 10) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.

Conclusions: The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.
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http://dx.doi.org/10.1212/WNL.0000000000011931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205479PMC
May 2021

Renewed absence of SARS-CoV-2 infections in the day care context in Berlin, January 2021.

Clin Infect Dis 2021 Mar 2. Epub 2021 Mar 2.

Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1093/cid/ciab199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989586PMC
March 2021

Association of Genetic Variants With Migraine Subclassified by Clinical Symptoms in Adult Females.

Front Neurol 2020 12;11:617472. Epub 2021 Feb 12.

Harvard Medical School, Boston, MA, United States.

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.
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http://dx.doi.org/10.3389/fneur.2020.617472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907521PMC
February 2021

Everything counts - a method to determine viral suppression among people living with HIV using longitudinal data for the HIV care continuum - results of two large, German, multi-center real-life cohort studies over 20 years (1999-2018).

BMC Public Health 2021 01 22;21(1):200. Epub 2021 Jan 22.

Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany.

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 within 180 days.

Results: A total of 22,120 people (164,691 person-years, PY) after ART initiation were included in the analyses. The proportion of people with viral suppression (VL < 50 copies/ml) increased from 34% in 1999 to 93% in 2018. The proportion of people with VL < 200 copies/ml increased from 47% in 1999 to 96% in 2018. The proportion of people with viremia > 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 and 5% VL > 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 < 50 copies/ml and VL < 200 copies/ml, respectively. Therefore, using the threshold of VL < 200 copies/ml, Germany reached the UNAIDS 95 target of viral suppression since 2017.
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http://dx.doi.org/10.1186/s12889-020-10088-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825204PMC
January 2021

Health technology assessment for the acute and preventive treatment of migraine: A position statement of the International Headache Society.

Cephalalgia 2021 03 20;41(3):279-293. Epub 2021 Jan 20.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments.
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http://dx.doi.org/10.1177/0333102421989247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961634PMC
March 2021

Effect of Vitamin D and/or Marine n-3 Fatty Acid Supplementation on Changes in Migraine Frequency and Severity.

Am J Med 2021 06 12;134(6):756-762.e5. Epub 2021 Jan 12.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Background: There is interest in whether supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective migraine prophylaxis. However, few studies have evaluated whether vitamin D or n-3 fatty acid supplementation may reduce migraine frequency or severity.

Methods: Participants in the VITamin D and OmegA-3 TriaL (VITAL) were assigned to vitamin D (2000 IU/d) or marine n-3 fatty acid (1 g/d) supplementation in a 2-by-2 factorial design. Lifetime history of migraine was assessed a median of 4.6 years after the start of the trial. Individuals were asked to self-report changes in migraine frequency (no change, more frequent, or less frequent) and severity (no change, more severe, less severe) in the past 5 years. We used χ tests to compare proportions of individuals reporting changes in migraine frequency and severity between active and placebo groups.

Results: Among the 25,871 participants in VITAL, 1032 participants had a history of probable migraine and provided information on changes in migraine frequency and severity. The percentage of individuals reporting decreases in migraine frequency did not differ between active (69.0%) and placebo vitamin D (68.4%) (P value = 0.54) or between active (67.8%) and placebo n-3 fatty acid (69.6%) (P value = 0.82). Similarly, the percentage of individuals reporting decreases in migraine severity did not differ between active (64.1%) and placebo vitamin D (65.0%) (P value = 0.86) or between active (64.5%) and placebo n-3 fatty acid (64.5%) (P value = 0.96).

Conclusions: Neither vitamin D nor marine n-3 fatty acid supplementation, compared to placebo, affected migraine frequency or severity among middle-aged or older adults.
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http://dx.doi.org/10.1016/j.amjmed.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164960PMC
June 2021

Migraine Headache Day Response Rates and the Implications to Patient Functioning: An Evaluation of 3 Randomized Phase 3 Clinical Trials of Galcanezumab in Patients With Migraine.

Headache 2020 Nov;60(10):2304-2319

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.

Objective: This post hoc study investigated the relationship between patient response in terms of migraine headache day reduction and patient-reported outcomes of health-related quality of life (HRQoL) and disability categories.

Background: Migraine causes considerable disease-related disability and negatively impacts HRQoL of patients. Calcitonin gene-related peptide inhibitors improve these outcomes and may eliminate disability due to migraine in some patients.

Methods: Analyses used data from 3 double-blind, placebo (PBO)-controlled, phase 3 studies in adults with episodic migraine (EM) (EVOLVE-1: N = 858 and EVOLVE-2: N = 915) or chronic migraine (CM) (REGAIN: N = 1113). Patients were randomized 2:1:1 to subcutaneous injection of PBO, galcanezumab (GMB) 120 mg, or GMB 240 mg once monthly for 6 months in EVOLVE-1 and -2 and for 3 months in REGAIN. Primary endpoint was overall mean change from baseline in monthly migraine headache days. Patients were divided into 4 response-level groups based on percent change from baseline (<30%, ≥30% to <50%, ≥50% to <75%, ≥75%). Patient-reported outcomes included the 14-item Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ) and Migraine Disability Assessment (MIDAS) questionnaire.

Results: Among patients with migraine, mean improvements from baseline in MSQ domain scores increased with each successive level of migraine headache day response. On a 100-pt scale, increases in Role Function-Restrictive score in EM were 16.8 and 36.0 at the <30% and ≥75% response levels, respectively, and for CM were 10.7 and 46.5. Similar patterns in scores were observed for the Role Function-Preventive and Emotional Function domains. Examination of improvement in MSQ item score by treatment group showed that, in patients with EM, approximately 10 to 20% more GMB-treated patients (N = 796 for GMB 120 mg and GMB 240 mg) had improvements in all 14 MSQ items compared with PBO-treated patients (N = 773) (all P < .001). In patients with CM, 3 to 16% more GMB-treated patients (N = 507) had improvements in the 14 MSQ items compared with PBO (N = 494), though differences were statistically significant in only 19 of 28 comparisons. At baseline, mean MIDAS scores (EM, 33.1; CM, 67.2) indicated severe mean disability for patients with EM and very severe disability for patients with CM. Among patients with EM, 215 of 425 (50.6%) of those treated with GMB 120 mg and 212 of 413 (51.3%) treated with 240 mg had little/no disability due to migraine after 6 months (PBO: 277 of 832 (33.3%), P < .001 for both). Among patients with CM, 50 of 254 (19.7%) of those treated with GMB 120 mg and 54 of 258 (20.9%) treated with 240 mg reached the level of little/no disability after 3 months of treatment (PBO: 70 of 504 (13.9%), P = .045 for 120 mg, P = .017 for 240 mg).

Conclusions: Because migraine greatly impairs an individual's ability to participate in activities of daily living, measurements of HRQoL are essential in clinical research. This study showed that function in daily life, as measured by MSQ score, improved as migraine headache days were reduced and that GMB-treated patients were more likely to see improvement in MSQ item scores compared with PBO-treated patients. Elimination of migraine-related disability was also more frequent in GMB-treated patients compared with placebo-treated patients.
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http://dx.doi.org/10.1111/head.14013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756324PMC
November 2020

Sex Differences in Response to Triptans: A Systematic Review and Meta-analysis.

Neurology 2021 01 18;96(4):162-170. Epub 2020 Nov 18.

From the Department of Internal Medicine (D.S.v.C.), Erasmus University Medical Center, Rotterdam and Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Institute of Public Health (T.K.), Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Internal Medicine (A.H.J.D., A.M.V.D.B.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Neurology (G.M.T.), Leiden University Medical Center, Leiden, The Netherlands.

Objective: To examine the effect of sex on clinical response to triptans in migraine and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis.

Methods: We searched clinical trials distinguishing clinical response to or pharmacokinetic parameters of triptans between sexes in PubMed, MEDLINE, Cochrane Library, Embase, and Web of Science up to Dec 12, 2019. Analysis was based on data extracted from published reports. Male-to-female pooled risk ratios (RR) were calculated for clinical outcomes and pooled ratio of means (RoM) for pharmacokinetic outcomes using random-effects models.

Results: Of 1,188 publications on clinical trials with triptans, 244 were identified with sex-related search terms. Only 19 publications presented sex-specific results, comprising n = 2,280 men and n = 13,899 women. No sex differences were revealed for 2-hour headache and pain-free responses, but men had a lower risk for headache recurrence (male-to-female RR 0.64, 95% confidence interval [CI]: 0.55-0.76, Q = 0.81) and adverse events (RR 0.82, 95% CI: 0.72-0.93, Q = 4.93). Men had lower drug exposure with lower area under the curve (RoM 0.69, 95% CI: 0.60-0.81, Q = 18.06) and peak drug concentration (RoM 0.72, 95% CI: 0.64-0.82, Q = 8.24) than women.

Conclusions: Remarkably few publications about sex differences in triptan response are available. The limited number of eligible studies show sex differences in adverse event frequency, which may be partly because of drug exposure differences. This higher drug exposure in women is not reflected in different response rates. Despite higher exposure, women have higher headache recurrence rates possibly because of longer attack duration related to sex hormonal changes.
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http://dx.doi.org/10.1212/WNL.0000000000011216DOI Listing
January 2021

Spatio-temporal trends in caries: A study on children in Berlin-Mitte.

Clin Exp Dent Res 2021 04 17;7(2):196-204. Epub 2020 Nov 17.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1002/cre2.354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019772PMC
April 2021

Giving Researchers a Headache - Sex and Gender Differences in Migraine.

Front Neurol 2020 22;11:549038. Epub 2020 Oct 22.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.3389/fneur.2020.549038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642465PMC
October 2020

Predicting the pandemic.

BMJ 2020 10 12;371:m3932. Epub 2020 Oct 12.

Department for Statistics, Ludwig-Maximilians-University Munich, Germany.

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http://dx.doi.org/10.1136/bmj.m3932DOI Listing
October 2020

Awareness, usage and perceptions of authorship guidelines: an international survey of biomedical authors.

BMJ Open 2020 09 21;10(9):e036899. Epub 2020 Sep 21.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-036899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507845PMC
September 2020

Public perspectives on protective measures during the COVID-19 pandemic in the Netherlands, Germany and Italy: A survey study.

PLoS One 2020 5;15(8):e0236917. Epub 2020 Aug 5.

Leiden University Medical School, Leiden University, Leiden, The Netherlands.

Background: The 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 Findings: An 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.

Conclusions: During 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236917PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406072PMC
August 2020

A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine.

Nat Commun 2020 07 6;11(1):3368. Epub 2020 Jul 6.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N/N = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r = 0.11, P = 3.56 × 10) and systolic BP (SBP, r = 0.06, P = 0.01), but not pulse pressure (PP, r = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.
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http://dx.doi.org/10.1038/s41467-020-17002-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338361PMC
July 2020

Directed acyclic graphs and causal thinking in clinical risk prediction modeling.

BMC Med Res Methodol 2020 07 2;20(1):179. Epub 2020 Jul 2.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1186/s12874-020-01058-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331263PMC
July 2020

Validation of an algorithm for automated classification of migraine and tension-type headache attacks in an electronic headache diary.

J Headache Pain 2020 Jun 12;21(1):75. Epub 2020 Jun 12.

Institute of Public Health, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

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.
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http://dx.doi.org/10.1186/s10194-020-01139-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291668PMC
June 2020
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