Migraine or any headaches and white matter hyperintensities and their progression in women and men.

BACKGROUND: Cross-sectional and longitudinal studies have been conducted to investigate the association between migraine and any headache and white matter hyperintensities (WMH). However, studies are inconsistent regarding the strength of the association and its clinical significance. The aim of our study was to investigate the association between headache and its subtypes (migraine with aura (MigA+), migraine without aura (MigA-), non-migraine headache (nonMigHA)) and WMH and its course in the population-based 1000BRAINS study using state-of-the-art imaging techniques and migraine classification according to modified international classification of headache disorders. METHODS: Data from 1062 participants (45% women, 60.9 ± 13.0 years) with ever or never headache (neverHA) and complete quantitative (WMH volume) and qualitative (Fazekas classification) WMH data at first imaging and after 3.7 ± 0.7 years (393 participants) were analyzed. The sex-specific association between headache and its subtypes and WMH volume and its change was evaluated by linear regression, between headache and its subtypes and Fazekas score high vs. low (2-3 vs. 0-1) by log-binomial regression, adjusted for confounders. RESULTS: The lifetime prevalence of headache was 77.5% (10.5% MigA+, 26.9% MigA-, 40.1% nonMigHA). The median WMH volume was 4005 (IQR: 2454-6880) mm3 in women and 4812 (2842-8445) mm3 in men. Women with any headaches (all headache types combined) had a 1.23 [1.04; 1.45]-fold higher WMH volume than women who reported never having had a headache. There was no indication of higher Fazekas grading or more WMH progression in women with migraine or any headaches. Men with migraine or any headaches did not have more WMH or WMH progression compared to men without migraine or men who never had headache. CONCLUSIONS: Our study demonstrated no increased occurrence or progression of WMH in participants with mgiraine. But, our results provide some evidence of greater WMH volume in women with headache of any type including migraine. The underlying pathomechanisms and the reasons why this was not shown in men are unclear and require further research.

Current use of percutaneous image-guided tumor ablation for the therapy of liver tumors: lessons learned from the registry of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) 2018-2022.

OBJECTIVES: Percutaneous image-guided tumor ablation of liver malignancies has become an indispensable therapeutic procedure. The aim of this evaluation of the prospectively managed multinational registry of the voluntary German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) was to analyze its use, technical success, and complications in clinical practice. MATERIALS AND METHODS: All liver tumor ablations from 2018 to 2022 were included. Technical success was defined as complete ablation of the tumor with an ablative margin. RESULTS: A total of 7228 liver tumor ablations from 136 centers in Germany and Austria were analyzed. In total, 31.4% (2268/7228) of patients were female. Median age was 67 years (IQR 58-74 years). Microwave ablation (MWA) was performed in 65.1% (4703/7228), and radiofrequency ablation (RFA) in 32.7% (2361/7228). Of 5229 cases with reported tumor etiology, 60.3% (3152/5229) of ablations were performed for liver metastases and 37.3% (1950/5229) for hepatocellular carcinoma. The median lesion diameter was 19 mm (IQR 12-27 mm). In total, 91.8% (6636/7228) of ablations were technically successful. The rate of technically successful ablations was significantly higher in MWA (93.9%, 4417/4703) than in RFA (87.3%, 2061/2361) (p < 0.0001). The total complication rate was 3.0% (214/7228) and was significantly higher in MWA (4.0%, 189/4703) than in RFA (0.9%, 21/2361, p < 0.0001). Additional needle track ablation did not increase the rate of major complications significantly (24.8% (33/133) vs. 28.4% (23/81), p = 0.56)). CONCLUSION: MWA is the most frequent ablation method. Percutaneous image-guided liver tumor ablations have a high technical success rate, which is higher for MWA than RFA. The complication rate is generally low but is higher for MWA than RFA. CLINICAL RELEVANCE STATEMENT: Percutaneous image-guided liver ablation using microwave ablation and radiofrequency ablation are effective therapeutic procedures with low complication rates for the treatment of primary and secondary liver malignancies. KEY POINTS: • Percutaneous image-guided liver tumor ablations have a high technical success rate, which is higher for microwave ablation than radiofrequency ablation. • Microwave ablation is the most frequent ablation method ahead of radiofrequency ablation. • The complication rate is generally low but is higher for microwave ablation than radiofrequency ablation.

Association of regional white matter hyperintensities with hypertension and cognition in the population-based 1000BRAINS study.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are frequent in cerebral magnetic resonance imaging of older people. They are promoted by vascular risk factors, especially hypertension, and are associated with cognitive deficits at the group level. It has been suggested that not only the severity, but also the location, of lesions might critically influence cognitive deficits and represent different pathologies. METHODS: In 560 participants (65.2 ± 7.5 years, 51.4% males) of the population-based 1000BRAINS study, we analyzed the association of regional WMH using Fazekas scoring separately for cerebral lobes, with hypertension and cognition. RESULTS: WMH most often affected the frontal lobe (83.7% score >0), followed by the parietal (75.8%), temporal (32.7%), and occipital lobe (7.3%). Higher Fazekas scores in the frontal, parietal, and temporal lobe were associated with higher blood pressure and antihypertensive treatment in unadjusted ordinal regression models and in models adjusted for age, sex, and vascular risk factors (e.g., age- and sex-adjusted odds ratio = 1.14, 95% confidence interval = 1.03-1.25 for the association of frontal lobe WMH Fazekas score with systolic blood pressure [SBP] [per 10 mm Hg]; 1.13 [1.02-1.23] for the association of parietal lobe score with SBP; 1.72 [1.19-2.48] for the association of temporal lobe score with antihypertensive medications). In linear regressions, higher frontal lobe scores were associated with lower performance in executive function and non-verbal memory, and higher parietal lobe scores were associated with lower performance in executive function, verbal-, and non-verbal memory. CONCLUSIONS: Hypertension promotes WMH in the frontal, parietal, and temporal lobe. WMH in the frontal and parietal lobe are associated with reduced executive function and memory.

Identification of radiomic biomarkers in a set of four skeletal muscle groups on Dixon MRI of the NAKO MR study.

In this work, we propose a processing pipeline for the extraction and identification of meaningful radiomics biomarkers in skeletal muscle tissue as displayed using Dixon-weighted MRI. Diverse and robust radiomics features can be identified that may be of aid in the accurate quantification e.g. varying degrees of sarcopenia in respective muscles of large cohorts. As such, the approach comprises the texture feature extraction from raw data based on well established approaches, such as a nnU-Net neural network and the Pyradiomics toolbox, a subsequent selection according to adequate conditions for the muscle tissue of the general population, and an importance-based ranking to further narrow the amount of meaningful features with respect to auxiliary targets. The performance was investigated with respect to the included auxiliary targets, namely age, body mass index (BMI), and fat fraction (FF). Four skeletal muscles with different fiber architecture were included: the mm. glutaei, m. psoas, as well as the extensors and adductors of the thigh. The selection allowed for a reduction from 1015 available texture features to 65 for age, 53 for BMI, and 36 for FF from the available fat/water contrast images considering all muscles jointly. Further, the dependence of the importance rankings calculated for the auxiliary targets on validation sets (in a cross-validation scheme) was investigated by boxplots. In addition, significant differences between subgroups of respective auxiliary targets as well as between both sexes were shown to be present within the ten lowest ranked features by means of Kruskal-Wallis H-tests and Mann-Whitney U-tests. The prediction performance for the selected features and the ranking scheme were verified on validation sets by a random forest based multi-class classification, with strong area under the curve (AUC) values of the receiver operator characteristic (ROC) of 73.03 ± 0.70 % and 73.63 ± 0.70 % for the water and fat images in age, 80.68 ± 0.30 % and 88.03 ± 0.89 % in BMI, as well as 98.36 ± 0.03 % and 98.52 ± 0.09 % in FF.

Long-term Air Pollution Exposure and Pneumonia-related Mortality in a Large Pooled European Cohort.

Rationale: Ambient air pollution exposure has been linked to mortality from chronic cardiorespiratory diseases, while evidence on respiratory infections remains more limited. Objectives: We examined the association between long-term exposure to air pollution and pneumonia-related mortality in adults in a pool of eight European cohorts. Methods: Within the multicenter project ELAPSE (Effects of Low-Level Air Pollution: A Study in Europe), we pooled data from eight cohorts among six European countries. Annual mean residential concentrations in 2010 for fine particulate matter, nitrogen dioxide (NO2), black carbon (BC), and ozone were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and pneumonia, influenza, and acute lower respiratory infections (ALRI) mortality. Measurements and Main Results: Of 325,367 participants, 712 died from pneumonia and influenza combined, 682 from pneumonia, and 695 from ALRI during a mean follow-up of 19.5 years. NO2 and BC were associated with 10-12% increases in pneumonia and influenza combined mortality, but 95% confidence intervals included unity (hazard ratios, 1.12 [0.99-1.26] per 10 µg/m3 for NO2; 1.10 [0.97-1.24] per 0.5 10-5m-1 for BC). Associations with pneumonia and ALRI mortality were almost identical. We detected effect modification suggesting stronger associations with NO2 or BC in overweight, employed, or currently smoking participants compared with normal weight, unemployed, or nonsmoking participants. Conclusions: Long-term exposure to combustion-related air pollutants NO2 and BC may be associated with mortality from lower respiratory infections, but larger studies are needed to estimate these associations more precisely.

Long-Term Exposure to Source-Specific Fine Particles and Mortality─A Pooled Analysis of 14 European Cohorts within the ELAPSE Project.

We assessed mortality risks associated with source-specific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5 identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5 components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 µg/m3 increase) across five identified sources. On a 1 µg/m3 basis, the residual oil-related PM2.5 had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5 mass, suggesting that past estimates using the generic PM2.5 exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.

Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.

AIMS: Previous work in our lab has identified the protease kallikrein-8 (KLK8) as a potential upstream mover in the pathogenesis of Alzheimer's disease (AD). We showed pathologically elevated levels of KLK8 in the cerebrospinal fluid and blood of patients with mild cognitive impairment or dementia due to AD, and in brains of patients and transgenic CRND8 (TgCRND8) mice in incipient stages of the disease. Furthermore, short-term antibody-mediated KLK8 inhibition in moderate stage disease alleviated AD pathology in female mice. However, it remains to be shown whether long-term reversal of KLK8 overexpression can also counteract AD. Therefore, the effects of genetic Klk8-knockdown were determined in TgCRND8 mice. METHODS: The effects of heterozygous ablation of murine Klk8 (mKlk8) gene on AD pathology of both sexes were examined by crossbreeding TgCRND8 [hAPP+/-] with mKlk8-knockdown [mKlk8+/-] mice resulting in animals with or without AD pathology which revealed pathologically elevated or normal KLK8 levels. RESULTS: mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aß) and tau pathology as well as an improvement of structural neuroplasticity in a sex-specific manner in transgenics. These changes were mediated by a shift to non-amyloidogenic cleavage of the human amyloid precursor protein (APP), recovery of the neurovascular unit and maintaining microglial metabolic fitness. Mechanistically, Klk8-knockdown improved Aß phagocytosis in primary glia and Aß resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance. CONCLUSIONS: These results reinforce the potential of KLK8 as a therapeutic target in AD.

Prevalence and risk factors of migraine and non-migraine headache in older people - results of the Heinz Nixdorf Recall study.

BACKGROUND: The prevalence of migraine and non-migraine headache declines with age. METHODS: Data from the third visit (2011-2015) of the population-based Heinz Nixdorf Recall study were analysed (n = 2038, 51% women, 65-86 years). Possible risk factors for headache activity (obesity, education, smoking, sports, alcohol, partnership status, living alone, having children, sleep quality, depression, hypertension, diabetes mellitus, stroke, coronary heart disease, medication), and headache symptoms were assessed. We estimated the lifetime prevalence and the prevalence of current active headache of migraine with and without aura, and non-migraine headache. The associations between possible risk factors and headache activity (active vs. inactive) were estimated by age and sex-adjusted odds ratios and 95% confidence intervals (OR [95% CI]) using multiple logistic regression. RESULTS: The lifetime prevalence of migraine was 28.6% (n = 584). One hundred and ninety-two (9.4%) had still-active migraine, 168 (3.5%) had migraine with aura, and 416 (5.9%) had migraine without aura. One hundred and sixty-eight (8.2%) had "episodic infrequent migraine, 0-8 headache days/month", 10 (0.5%) had "episodic frequent migraine, 9-14 headache days/month", and five (0.2%) had "chronic migraine, ≥15 headache days/month". Overall, 10 (0.5%) had "chronic headache, any headache on ≥15 days/month". Female gender and younger age were the most important associated migraine risk factors. Depression (1.62 [1.06; 2.47]) and poor sleep (1.06 [1.00; 1.12]) were associated with migraine and headache activity in general. Antihypertensives were associated with headache remission (0.80 [0.64; 1.00]). Additionally, undertaking less sports (0.72 [0.51; 1.03]) was associated with higher migraine activity. CONCLUSIONS: Headaches and migraines are not rare in the older population. They are related to mood and sleep disturbance, and migraine even to less physical activity. Antihypertensives are related to headache remission.

Vitamin D and white matter hyperintensities: results of the population-based Heinz Nixdorf Recall Study and 1000BRAINS.

BACKGROUND AND PURPOSE: Cross-sectional studies showed an inverse association between serum 25-hydroxyvitamin D (25OHD) and white matter hyperintensities (WMHs) whereas the few longitudinal studies did not. The association between baseline 25OHD and WMHs at 10-year follow-up in the Heinz Nixdorf Recall Study plus 1000BRAINS was investigated. METHODS: Data of 505 participants (49% women, 56.2 ± 6.6 years) with 25OHD at baseline (2000-2003) and WMH volume and grade of WMHs using the Fazekas classification at 10-year follow-up were analysed. The association between deseasonalized 25OHD and the base-10 logarithm of WMH volume was evaluated by multiple linear regression, adjusted for age, sex, education, smoking, alcohol consumption, sports, diabetes mellitus, systolic blood pressure and total cholesterol. ß-estimators were transformed back (10ß ). Using multiple logistic regression, odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated to evaluate the association between deseasonalized 25OHD and Fazekas grades (0, absence and 1, punctate foci vs. 2, beginning and 3, large confluence). RESULTS: Mean 25OHD was 17.0 ± 8.2 ng/ml, and mean deseasonalized 25OHD was 16.9 ± 7.5 ng/ml. Mean WMH volume was 16.6 ± 17.4 ml, range 1-132 ml. Most grade 2-3 WMHs were found to be periventricular (39% of the participants), parietal (32%) and frontal (31%) (temporal 6%, occipital 3%). The linear regression showed an inverse association between 25OHD and WMH volume. On average, a 25OHD increase of 1 ng/ml was associated with a reduced WMH volume by a factor of 0.99 (95% CI 0.98; 1.00) (fully adjusted). There was also some indication for an inverse association between 25OHD and extent of periventricular (OR 0.98 [95% CI 0.96; 1.01]), frontal (0.99 [0.97; 1.02]) and parietal (0.98 [0.95; 1.00]) WMHs according to the Fazekas classification. CONCLUSIONS: Lower 25OHD may be a risk factor for the occurrence of WMHs.

Social Impact of Prophylactic Migraine Treatments in Germany: A State-Transition and Open Cohort Approach.

OBJECTIVES: Migraine is a highly prevalent neurological disorder. The most characteristic symptom of migraine is moderate to severe recurrent headache along with other neurological symptoms. In this study, we modeled the potential reduction in migraine days and corresponding avoided productivity losses if erenumab was prescribed to the patient population indicated for prophylactic migraine treatment (≥ 4 monthly migraine days [MMDs]) in Germany from 2020 to the end of 2027. METHODS: We simulated the incremental benefits of erenumab against the standard of care. Response rates, transition probabilities, discontinuation rates, and productivity estimates were derived from the erenumab clinical trial program. Patients had a probability of residing in 1 of 7 states, given the MMDs in addition to the probability of death. Based on accrued MMDs in every cycle, days of absenteeism and presenteeism for paid and unpaid work were derived. Paid work was monetized according to gross value added using the human capital approach, whereas unpaid work was valuated according to the proxy good method. In addition, downstream macroeconomic effects were captured using value-added multipliers. Direct medical costs were concomitantly calculated. RESULTS: Our results show that prescribing erenumab for the indicated population in Germany could lead to a reduction of 166 million migraine days annually and reduce productivity losses in the range of €27 billion. This includes €13.1 billion from direct productivity and €13.5 billion from economic value chain effects. CONCLUSIONS: This study highlights the macroeconomic effects of a systematic introduction of novel inhibitors of the calcitonin gene-related peptide pathway for migraine in Germany.

The socioeconomic burden of migraine: An evaluation of productivity losses due to migraine headaches based on a population study in Germany.

BACKGROUND: This study estimates the socioeconomic impact of migraine headaches on paid and unpaid work productivity in the adult German population in 1 year. METHODS: We used data on headache frequency (days per month) from a longitudinal population-based study. Prevalence estimates of migraine were derived from the Global Burden of Disease Collaborative Network. Demography data were derived from official statistics in 2017. Aggregate headache days in 1 year were translated to losses in paid and unpaid productive hours based on estimates of presenteeism and absenteeism along with other socioeconomic parameters. Paid hours lost were distributed across the industry sectors. In this way, an age-, gender- and industry sector-specific monetary value was calculated for paid hours lost. Unpaid hours lost were valued by assigning the unpaid activities to their nearest market substitute. In a last step, value-added multipliers derived from input-output tables were used to calculate the economic value chain effects. RESULTS: A total of 15.5 million persons (20 years or older) suffer from migraine in Germany. Our analysis shows that 60% of those have three or fewer headache days per month, while patients suffering chronic migraine (15+ headache days per month) account for 5.4% of the adult migraine population. Females bear 65% of the total 836 million headache days per year. The socioeconomic losses due to migraine amount to €100.4 billion (€6493 on average per patient) in one year. CONCLUSION: In addition to time losses in paid work, migraine causes substantial socioeconomic losses to unpaid work activities due to its disproportionate prevalence among females. Economic value chain effects provide a novel perspective on losses beyond a patient's time loss. Overall, the elements of socioeconomic burden provide a strong rationale that innovative migraine therapies could be of high value to society.

[Persons with migration background in the German National Cohort (NAKO)-sociodemographic characteristics and comparisons with the German autochthonous population]. / Personen mit Migrationshintergrund in der NAKO Gesundheitsstudie ­ soziodemografische Merkmale und Vergleiche mit der autochthonen deutschen Bevölkerung.

BACKGROUND: Persons with a migration background (PmM) as a population group usually differ from the autochthonous population in terms of morbidity, mortality, and use of the health care system, but they participate less frequently in health studies. The PmM group is very heterogeneous, which has hardly been taken into account in studies so far. OBJECTIVES: Sociodemographic characteristics of PmM in the NAKO health study (age, sex, time since migration, education) are presented. In addition, it is examined through an example whether migration background is related to the use of cancer screening for colorectal cancer (hemoccult test). METHODS: Data of the first 101,816 persons of the NAKO were analyzed descriptively and cartographically. The migration background was assigned on the basis of the definition of the Federal Statistical Office, based on nationality, country of birth, year of entry, and country of birth of the parents. RESULTS: Overall, the PmM proportion is 16.0%. The distribution across the 18 study centers varies considerably between 6% (Neubrandenburg) and 33% (Düsseldorf). With 153 countries of origin, most countries are represented in the NAKO. All variables show clear differences between the different regions of origin. In the hemoccult test, persons of Turkish origin (OR = 0.67) and resettlers (OR = 0.60) have a lower participation rate. PmM born in Germany do not differ in this respect from the autochthonous population (OR = 0.99). CONCLUSION: PmM in the NAKO are a very heterogeneous group. However, due to the sample size, individual subgroups of migrants can be studied separately with respect to region of origin.

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.

Remission of chronic headache: Rates, potential predictors and the role of medication, follow-up results of the German Headache Consortium (GHC) Study.

Objectives To estimate remission rates of chronic headache (CH), focusing on potential predictors of headache remission and medication. Methods We used data from the longitudinal population-based German Headache Consortium (GHC) Study (n = 9,944, 18-65 years). Validated questionnaires were used at baseline (t0, 2003-2007, response rate: 55.2%), first follow-up after 1.87 ± 0.39 years (t1, 37.2%) and second follow-up after 3.26 ± 0.60 years (t2, 38.8%) to assess headache type and frequency, use of analgesics and anti-migraine drugs, medication overuse, education, BMI, smoking and alcohol consumption. CH was defined as ≥ 15 headache days/month at t0 over three months. Outcomes were: CH remission (<15 headache days/month at both follow-ups), CH persistence (≥ 15 headache days/month at both follow-ups); all others were considered as partially remitted. To estimate predictors of remission, univariate and multiple logistic regression were calculated. Results At baseline, 255 (2.6%) participants were identified with CH. Of these, 158 (62.0%) participants responded at both follow-ups. Remission was observed in 58.2% of participants, partial remission in 17.7% and persistence in 24.1%. Remission was associated with female sex (adjusted odds ratio: 3.10, 95% confidence interval: 1.06-9.08) and no medication overuse (4.16, 1.45-11.94) compared to participants with persistent CH; participants with higher headache frequency at t0 were less likely to remit (0.90, 0.84-0.97). Medication, age, education, BMI, smoking and drinking showed no effects on remission. Similar results were observed for partial remission. Conclusion The majority of CH participants remitted from CH. Female sex, no overuse of pain medication and lower headache frequency were associated with remission.

[Assessing incident cardiovascular and metabolic diseases in epidemiological cohort studies in Germany]. / Erfassung inzidenter kardiovaskulärer und metabolischer Erkrankungen in epidemiologischen Kohortenstudien in Deutschland.

BACKGROUND: Cardiovascular and metabolic diseases are a major cause of mortality and loss of quality of life in Germany. Research into risk factors of these diseases requires large population-based cohort studies. Complete and accurate assessment of the incidence of cardiovascular and metabolic diseases is a key element for valid interpretation of the results from such studies. OBJECTIVE: Our aim was to identify population-based cohort studies with incidence of cardiovascular and metabolic diseases in Germany and to summarize their methods for assessment and classification of disease endpoints, including myocardial infarction, type 2 diabetes, stroke, heart failure, and arterial hypertension. METHODS: Within the framework of a workshop, representatives of the ascertained population-based cohort studies in Germany with incidence of cardiovascular or metabolic diseases were invited to present and to systematically provide information on their methods of endpoint identification. RESULTS: We identified eight studies from different regions in Germany with a total of 100,571 participants, aged 18-83 years at baseline. Self-reporting by study participants is the major source for further inquiries to assess disease endpoints in these studies. Most studies use additional data sources to verify the incidence of diseases, such as documents provided by the treating physician or hospital. CONCLUSIONS: Our results highlight the central role of self-reporting and the efforts associated with identification and verification of disease endpoints in cohort studies. They also provide a basis for future population-based studies that aim for standardized assessment of the incidence of cardiovascular and metabolic diseases.

Headache service quality: evaluation of quality indicators in 14 specialist-care centres.

BACKGROUND: The study was a collaboration between Lifting The Burden (LTB) and the European Headache Federation (EHF). Its aim was to evaluate the implementation of quality indicators for headache care Europe-wide in specialist headache centres (level-3 according to the EHF/LTB standard). METHODS: Employing previously-developed instruments in 14 such centres, we made enquiries, in each, of health-care providers (doctors, nurses, psychologists, physiotherapists) and 50 patients, and analysed the medical records of 50 other patients. Enquiries were in 9 domains: diagnostic accuracy, individualized management, referral pathways, patient's education and reassurance, convenience and comfort, patient's satisfaction, equity and efficiency of the headache care, outcome assessment and safety. RESULTS: Our study showed that highly experienced headache centres treated their patients in general very well. The centres were content with their work and their patients were content with their treatment. Including disability and quality-of-life evaluations in clinical assessments, and protocols regarding safety, proved problematic: better standards for these are needed. Some centres had problems with follow-up: many specialised centres operated in one-touch systems, without possibility of controlling long-term management or the success of treatments dependent on this. CONCLUSIONS: This first Europe-wide quality study showed that the quality indicators were workable in specialist care. They demonstrated common trends, producing evidence of what is majority practice. They also uncovered deficits that might be remedied in order to improve quality. They offer the means of setting benchmarks against which service quality may be judged. The next step is to take the evaluation process into non-specialist care (EHF/LTB levels 1 and 2).

The association between stress and headache: A longitudinal population-based study.

INTRODUCTION: We studied the association between stress intensity and headache frequency for tension-type headache (TTH), migraine and migraine with coexisting TTH (MigTTH). METHOD: We studied a population-based sample of 5159 participants (21-71 years) who were asked quarterly between March 2010 and April 2012 about headache and stress. Log-linear regression in the framework of generalized estimating equations was used to estimate regression coefficients presented as percent changes to describe the association between stress intensity (modified visual analog scale (VAS) from 0 to 100) and headache frequency (days/month) stratified by headache subtypes and age groups and adjusted for sex, age, frequent intake of acute pain drugs, drinking, smoking, BMI and education. RESULTS: TTH was reported in 31% participants (48.1 ± 12.5years, 51.5% women, 2.2 ± 3.9 mean headache days/month, 52.3 ± 26.7 mean stress), migraine in 14% (44.8 ± 11.3years, 73.3%, 4.5 ± 5.2 days/month, 62.4 ± 23.3), MigTTH in 10.6% (43.5 ± 11.5 years, 61.0%, 3.6 ± 4.8 days/month, 58.6 ± 24.1), 23.6% were unclassifiable, and 20.8% had no headache. In participants with TTH an increase of 10 points on VAS was associated with an increase of headaches days/month of 6.0% (adjusted). Higher effects were observed in younger age groups (21-30/31-40/41-50/51-60/61-71 years: 9.8/10.2/7.0/6.5/3.5%). Slightly lower effects were observed for migraine (4.3%, 8.1/5.1/3.4/6.3/0.3%) and MigTTH (4.2%, 5.5/6.8/6.9/5.8/-0.7%). CONCLUSION: Our study provides evidence for an association between stress intensity and headache frequency.

Evaluation of headache service quality indicators: pilot implementation in two specialist-care centres.

BACKGROUND: Evaluating quality of health care is increasingly recognized as an important contributor to the advancement of health-care delivery. We recently developed a set of quality indicators for headache care, intended to be applicable across countries, cultures and settings so that deficiencies in headache care worldwide might be recognized and rectified. These indicators themselves require evaluation and proof of fitness for purpose. This pilot study begins this process. METHODS: We tested the quality indicators in the tertiary headache centres of the University of Duisburg-Essen in Essen, Germany, and the Hospital da Luz in Lisbon, Portugal. Using seven previously-developed enquiry instruments, we interrogated health-care providers (HCPs), including doctors, nurses, psychologists and physiotherapists, as well as consecutive patients and their medical records. RESULTS: The questionnaires were easily understood by both HCPs and patients and were not unduly time-consuming. The results from the two headache centres were comparable despite their differences in structure, staffing and language. These findings met the purpose of the study. Diagnoses were made according to ICHD criteria and critically evaluated during follow-up. However, diagnostic diaries and instruments assessing burden and response to treatment were not always in place or routinely utilised. Triage systems adjusted waiting times to urgency of need. Treatment plans included pathways to other specialities. Patients felt welcomed, reassured and educated, and were mostly satisfied. Discussion points arose over inclusion of psychological therapies in treatment plans; over recording of outcomes; over indicators of efficiency and equitability (protocols to limit wastage of resources, systems to measure input costs and means of ensuring equal access to the services); and over protocols for reporting serious adverse events. CONCLUSION: This pilot study to assess feasibility of the methods and acceptability of the instruments of headache service quality evaluation was successful. The project is ready to be taken into its next stages.

Sex-Specific Differences in Serum Kallikrein-8 (KLK8): An Exploratory Study.

Background: There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer's disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed. Objective: The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones. Methods: In 290 participants (45% women, 69.7±7.4 years (mean±SD)) we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression. Results: The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: -95.3 [-324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); -261 [-493.1; -29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [-0.4;24.3] pg/ml) and DHEAS (1.4 [-0.5;3.3] pg/ml) with KLK8, while testosterone had no impact. Conclusions: The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer's disease pathology.

Aggregation of type-2 diabetes, prediabetes, and metabolic syndrome in German couples.

We aimed to examine the concordance of type-2 diabetes, prediabetes and the metabolic syndrome in couples. In cross-sectional analyses, we used data from 1173 couples with index persons from the Heinz Nixdorf Recall Study (2011-2015), a population-based cohort study in Western Germany, and partners from the associated Heinz Nixdorf Multigeneration Study (2013-2016). Mean age (standard deviation) was 67.2 (6.6) years in index persons, and 67.8 (7.7) years in partners. The exposure was the presence of diabetes, prediabetes or metabolic syndrome in index persons, the outcome was the presence of the same health status in partners. Diabetes was defined by either self-reported diagnosis, intake of antidiabetic drugs or insulin, or HbA1c ≥ 6.5%. If the index person had prediabetes or diabetes, the partner was 1.46 (95% CI 1.07-2.00) times more likely to have diabetes than partners of index persons without the condition in the crude model (adjusted model: 1.33 (0.97-1.83)). For self-reported diabetes and for the metabolic syndrome, the corresponding prevalence ratios were 1.33 (0.90-1.97) and 1.17 (1.03-1.32), respectively (adjusted models: 1.23 (0.77-1.94), 1.04 (0.91-1.18)). In German couples, there was weak to moderate concordance of type-2 diabetes, prediabetes and the metabolic syndrome in crude, but poor concordance in adjusted models.