Publications by authors named "Klaus Berger"

277 Publications

Quality of Care for Patients With Multiple Sclerosis-A Review of Existing Quality Indicators.

Front Neurol 2021 5;12:708723. Epub 2021 Aug 5.

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

The care of patients with multiple sclerosis (MS) calls for a lifelong guidance and treatment and results in a high resource utilization. Therefore, strategies for the assessment and improvement of the care process are crucial. Quality indicators have become a widely used instrument to determine quality in many areas of the healthcare system. The currently available sets of indicators for the quality of MS care are summarized in this review. A literature search was conducted for reports that include statements on quality indicators for the care of people with MS. For the determination of the strength of the underlying evidence of the identified publications appropriate criteria of the PRISMA and AGREE-Statements were used. A further prioritization of the eligible indicators was based on the internal grading by the initial authors. Of the 465 included records in the search, 6 sources were finally identified, 3 demonstrating a high and the others a medium strength of evidence. In total, these six reports described 226 quality indicators for the treatment of MS. Of them, 147 were further included in the assessment due to the scope of this article. Among the 101 indicators that originated from reports with a high strength of evidence, 6 also had a high initial internal grading. These six identified quality indicators describe five important characteristics of a high-quality care of MS. The search led to a scientifically evident set of six quality indicators for the assessment of care for patients with MS. These should be seen as starting points in the development of comprehensive sets of quality indicators in MS that addresses the individual objective of their use.
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http://dx.doi.org/10.3389/fneur.2021.708723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374044PMC
August 2021

[Loneliness during the first wave of the SARS-CoV-2 pandemic-results of the German National Cohort (NAKO)].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2021 Sep 29;64(9):1157-1164. Epub 2021 Jul 29.

Zentrum Psychiatrische Rehabilitation, Universitäre Psychiatrische Dienste Bern, Bern, Schweiz.

Background: Early during the pandemic and the following protective countermeasures, an interest in the consequences of the enacted restriction of social contacts for the mental health of the population arose. Loneliness describes the perceived quality of one's own contacts and relationships with other individuals. Several prior studies reported associations of loneliness with different somatic and psychiatric disorders.

Aim: To analyse the frequency of loneliness and its association with depression and anxiety symptoms in the first wave of the pandemic in Germany in May 2020.

Methods: The German National Cohort (NAKO) had recruited and examined 205,000 individuals aged 20 to 69 years in 18 study centres across Germany between 2014 and 2019. The follow-up examination was temporarily stopped due to the pandemic between March and July 2020. In this period a COVID-related questionnaire was developed and sent to all participants. We analysed the first 113,928 questionnaires that were sent back within four weeks in May 2020. Loneliness was assessed with the three-item UCLA Loneliness Scale and anxiety and depression symptoms were collected using the PHQ‑9 and GAD‑7 scales from the Patient Health Questionnaire.

Results: Among the NAKO participants, 31.7% reported to be lonely in May 2020. Women and young adults reported more loneliness than men and older adults. With increasing scores of loneliness, the severity of depression and anxiety symptoms also steadily increased. Individuals who were lonely during the pandemic had already reported higher PHQ‑9 and GAD‑7 scores during the baseline examination on average 2.5 years earlier, compared to those who did not feel lonely.

Conclusions: Among participants of the German National Cohort, we observed an increase in loneliness during the first wave of the SARS-CoV‑2 pandemic in spring 2020 and a strong relationship of increasing loneliness with decreasing mental health.
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http://dx.doi.org/10.1007/s00103-021-03393-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320420PMC
September 2021

A method to define the relevant ego-centred spatial scale for the assessment of neighbourhood effects: the example of cardiovascular risk factors.

BMC Public Health 2021 07 7;21(1):1346. Epub 2021 Jul 7.

Department of Epidemiology and International Public Health, School of Public Health, Bielefeld University, Bielefeld, Germany.

Introduction: The neighbourhood in which one lives affects health through complex pathways not yet fully understood. A way to move forward in assessing these pathways direction is to explore the spatial structure of health phenomena to generate hypotheses and examine whether the neighbourhood characteristics are able to explain this spatial structure. We compare the spatial structure of two cardiovascular disease risk factors in three European urban areas, thus assessing if a non-measured neighbourhood effect or spatial processes is present by either modelling the correlation structure at individual level or by estimating the intra-class correlation within administrative units.

Methods: Data from three independent studies (RECORD, DHS and BaBi), covering each a European urban area, are used. The characteristics of the spatial correlation structure of cardiovascular risk factors (BMI and systolic blood pressure) adjusted for age, sex, educational attainment and income are estimated by fitting an exponential model to the semi-variogram based on the geo-coordinates of places of residence. For comparison purposes, a random effect model is also fitted to estimate the intra-class correlation within administrative units. We then discuss the benefits of modelling the correlation structure to evaluate the presence of unmeasured spatial effects on health.

Results: BMI and blood pressure are consistently found to be spatially structured across the studies, the spatial correlation structures being stronger for BMI. Eight to 22% of the variability in BMI were spatially structured with radii ranging from 100 to 240 m (range). Only a small part of the correlation of residuals was explained by adjusting for the correlation within administrative units (from 0 to 4 percentage points).

Discussion: The individual spatial correlation approach provides much stronger evidence of spatial effects than the multilevel approach even for small administrative units. Spatial correlation structure offers new possibilities to assess the relevant spatial scale for health. Stronger correlation structure seen for BMI may be due to neighbourhood socioeconomic conditions and processes like social norms at work in the immediate neighbourhood.
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http://dx.doi.org/10.1186/s12889-021-11356-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265054PMC
July 2021

A method to define the relevant ego-centred spatial scale for the assessment of neighbourhood effects: the example of cardiovascular risk factors.

BMC Public Health 2021 07 7;21(1):1346. Epub 2021 Jul 7.

Department of Epidemiology and International Public Health, School of Public Health, Bielefeld University, Bielefeld, Germany.

Introduction: The neighbourhood in which one lives affects health through complex pathways not yet fully understood. A way to move forward in assessing these pathways direction is to explore the spatial structure of health phenomena to generate hypotheses and examine whether the neighbourhood characteristics are able to explain this spatial structure. We compare the spatial structure of two cardiovascular disease risk factors in three European urban areas, thus assessing if a non-measured neighbourhood effect or spatial processes is present by either modelling the correlation structure at individual level or by estimating the intra-class correlation within administrative units.

Methods: Data from three independent studies (RECORD, DHS and BaBi), covering each a European urban area, are used. The characteristics of the spatial correlation structure of cardiovascular risk factors (BMI and systolic blood pressure) adjusted for age, sex, educational attainment and income are estimated by fitting an exponential model to the semi-variogram based on the geo-coordinates of places of residence. For comparison purposes, a random effect model is also fitted to estimate the intra-class correlation within administrative units. We then discuss the benefits of modelling the correlation structure to evaluate the presence of unmeasured spatial effects on health.

Results: BMI and blood pressure are consistently found to be spatially structured across the studies, the spatial correlation structures being stronger for BMI. Eight to 22% of the variability in BMI were spatially structured with radii ranging from 100 to 240 m (range). Only a small part of the correlation of residuals was explained by adjusting for the correlation within administrative units (from 0 to 4 percentage points).

Discussion: The individual spatial correlation approach provides much stronger evidence of spatial effects than the multilevel approach even for small administrative units. Spatial correlation structure offers new possibilities to assess the relevant spatial scale for health. Stronger correlation structure seen for BMI may be due to neighbourhood socioeconomic conditions and processes like social norms at work in the immediate neighbourhood.
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http://dx.doi.org/10.1186/s12889-021-11356-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265054PMC
July 2021

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

Ann Neurol 2021 Sep 22;90(3):477-489. Epub 2021 Jun 22.

Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening.

Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG and IgM ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models.

Results: By categorical analysis, in patients with IgM the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG . Furthermore, quantitative analyses revealed that in patients with IgM  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM  < median. Dose-dependent associations were also found for IgM but not for IgG with magnetic resonance imaging-defined disease activity and sNfL.

Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.
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http://dx.doi.org/10.1002/ana.26137DOI Listing
September 2021

Childhood trauma and personality explain more variance in depression scores than sociodemographic and lifestyle factors - Results from the BiDirect Study.

J Psychosom Res 2021 Aug 15;147:110513. Epub 2021 May 15.

Institute of Epidemiology and Social Medicine, University of Münster, Germany. Electronic address:

Objective: Sociodemographic and lifestyle factors, childhood adversities, and personality aspects have been identified as contributing to the onset and course of depression. However, only few studies examined all aspects concomitantly in different populations. This was the objective of the study presented here.

Methods: The BiDirect Study includes three distinct cohorts: Cross-sectional data for 670 patients with depression (DEP), 283 patients with cardiovascular disease (CVD), and 787 population controls (POP) were available for the present analysis. Participants answered interviews and filled in questionnaires assessing depression details, childhood trauma, the Big Five personality traits, trait resilience as well as socioeconomic and lifestyle factors. Descriptive statistics and hierarchical linear regression analyses were employed to identify those factors, which contributed significantly to the explanation of depression severity scores (assessed by the Center for Epidemiologic Studies Depression Scale, CESD).

Results: In all three cohorts, the psychological variables explained most variance in depression scores (35-44%), while sociodemographic and lifestyle factors explained only very little variance (1-2%). When all postulated predictors were entered in the same regression model, higher neuroticism and lower resilience scores were associated with higher depression severity levels in all three cohorts, while higher childhood trauma proved significant in the cardiovascular and population cohort.

Conclusion: Childhood trauma, neuroticism, and low resilience are significantly associated with depression in different populations. Although a considerable part of the variance in depression severity levels was explained by the variables studied here, more research on the impact of lifestyle and social factors on depression is needed.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110513DOI Listing
August 2021

Genetic factors influencing a neurobiological substrate for psychiatric disorders.

Transl Psychiatry 2021 03 29;11(1):192. Epub 2021 Mar 29.

Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Jülich, Germany.

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.
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http://dx.doi.org/10.1038/s41398-021-01317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007575PMC
March 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 05 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
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http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity.

Nat Commun 2021 02 19;12(1):1152. Epub 2021 Feb 19.

Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.

The humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.
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http://dx.doi.org/10.1038/s41467-021-20973-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896075PMC
February 2021

Interrater sleep stage scoring reliability between manual scoring from two European sleep centers and automatic scoring performed by the artificial intelligence-based Stanford-STAGES algorithm.

J Clin Sleep Med 2021 06;17(6):1237-1247

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Study Objectives: The objective of this study was to evaluate interrater reliability between manual sleep stage scoring performed in 2 European sleep centers and automatic sleep stage scoring performed by the previously validated artificial intelligence-based Stanford-STAGES algorithm.

Methods: Full night polysomnographies of 1,066 participants were included. Sleep stages were manually scored in Berlin and Innsbruck sleep centers and automatically scored with the Stanford-STAGES algorithm. For each participant, we compared (1) Innsbruck to Berlin scorings (INN vs BER); (2) Innsbruck to automatic scorings (INN vs AUTO); (3) Berlin to automatic scorings (BER vs AUTO); (4) epochs where scorers from Innsbruck and Berlin had consensus to automatic scoring (CONS vs AUTO); and (5) both Innsbruck and Berlin manual scorings (MAN) to the automatic ones (MAN vs AUTO). Interrater reliability was evaluated with several measures, including overall and sleep stage-specific Cohen's κ.

Results: Overall agreement across participants was substantial for INN vs BER (κ = 0.66 ± 0.13), INN vs AUTO (κ = 0.68 ± 0.14), CONS vs AUTO (κ = 0.73 ± 0.14), and MAN vs AUTO (κ = 0.61 ± 0.14), and moderate for BER vs AUTO (κ = 0.55 ± 0.15). Human scorers had the highest disagreement for N1 sleep (κ = 0.40 ± 0.16 for INN vs BER). Automatic scoring had lowest agreement with manual scorings for N1 and N3 sleep (κ = 0.25 ± 0.14 and κ = 0.42 ± 0.32 for MAN vs AUTO).

Conclusions: Interrater reliability for sleep stage scoring between human scorers was in line with previous findings, and the algorithm achieved an overall substantial agreement with manual scoring. In this cohort, the Stanford-STAGES algorithm showed similar performances to the ones achieved in the original study, suggesting that it is generalizable to new cohorts. Before its integration in clinical practice, future independent studies should further evaluate it in other cohorts.
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http://dx.doi.org/10.5664/jcsm.9174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314654PMC
June 2021

Serum neurofilament light and tau as prognostic markers for all-cause mortality in the elderly general population-an analysis from the MEMO study.

BMC Med 2021 02 15;19(1):38. Epub 2021 Feb 15.

Institute of Epidemiology and Social Medicine, University of Münster, Domagkstraße 3, 48149, Münster, Germany.

Background: Neurofilament light chain (NfL) is a cytoskeletal protein component whose release into blood is indicative of neuronal damage. Tau is a microtubule-associated protein in neurons and strongly associated with overall brain degeneration. NfL and tau levels are associated with mortality in different neurological diseases, but studies in the general population are missing. We investigated whether NfL and tau serum levels could serve as prognostic markers for overall mortality in elderly individuals without pre-defined neurological conditions. Further, we investigated the cross-sectional associations between NfL, tau, neuropsychological functioning, and brain structures.

Methods: In 1997, 385 inhabitants of Augsburg who were aged 65 years and older were included in the Memory and Morbidity in Augsburg Elderly (MEMO) study. They participated in a face-to-face medical interview including neuropsychological tests and magnetic resonance imaging (MRI) of the brain. NfL and tau were measured from non-fasting blood samples using highly sensitive single molecule array assays. To assess the prognostic accuracy of the biomarkers, concordance statistics based on the predicted 5-year survival probabilities were calculated for different Cox regression models. Associations between the biomarkers and the neuropsychological test scores or brain structures were investigated using linear or logistic regression.

Results: NfL (HR 1.27, 95% CI [1.14-1.42]) and tau (1.20 [1.07-1.35]) serum levels were independently associated with all-cause mortality. NfL, but not tau, increased the prognostic accuracy when added to a model containing sociodemographic characteristics (concordance statistic 0.684 [0.612-0.755] vs. 0.663 [0.593-0.733]), but not when added to a model containing sociodemographic characteristics and brain atrophy or neuropsychological test scores. NfL serum levels were cross-sectionally associated with neuropsychological test scores and brain structures.

Conclusions: The association between NfL serum levels and brain atrophy and neuropsychological performance in individuals without overt neurological disease is similar to that seen in patients with neurodegenerative diseases. These findings support the concept of a continuum of physiological aging and incipient, subclinical pathology, and manifest disease. NfL, but not tau, serum levels might serve as a prognostic marker for all-cause mortality if no other clinical information is available.
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http://dx.doi.org/10.1186/s12916-021-01915-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883435PMC
February 2021

Female Stroke: Sex Differences in Acute Treatment and Early Outcomes of Acute Ischemic Stroke.

Stroke 2021 Jan 25;52(2):406-415. Epub 2021 Jan 25.

Institute of Epidemiology and Social Medicine, University of Muenster, Germany (A.K.B., A.K., J.W., K.B.).

Background And Purpose: Men and women are differently affected by acute ischemic stroke (AIS) in many aspects. Prior studies on sex disparities were limited by moderate sample sizes, varying years of data acquisition, and inconsistent inclusions of covariates leading to controversial findings. We aimed to analyze sex differences in AIS severity, treatments, and early outcome and to systematically evaluate the effect of important covariates in a large German stroke registry.

Methods: Analyses were based on the Stroke Registry of Northwestern Germany from 2000 to 2018. We focused on admission-stroke severity and disability, acute recanalization treatment, and early stroke outcomes. Potential sex divergences were investigated via odds ratio (OR) using logistic regression models. Covariates were introduced in 3 steps: (1) base models (age and admission year), (2) partially adjusted models (additionally corrected for acute stroke severity and recanalization treatment), (3) fully adjusted models (additionally adjusted for onset-to-admission time interval, prestroke functional status, comorbidities, and stroke cause). Models were separately fitted for the periods 2000 to 2009 and 2010 to 2018.

Results: Data from 761 106 patients with AIS were included. In fully adjusted models, there were no sex differences with respect to treatment with intravenous thrombolysis (2000-2009: OR, 0.99 [95% CI, 0.94-1.03]; 2010-2018: OR, 1.0 [0.98-1.02]), but women were more likely to receive intraarterial therapy (2010-2018: OR, 1.12 [1.08-1.15]). Despite higher disability on admission (2000-2009: OR, 1.10 [1.07-1.13]; 2010-2018: OR, 1.09 [1.07-1.10]), female patients were more likely to be discharged with a favorable functional outcome (2003-2009: OR, 1.05 [1.02-1.09]; 2010-2018: OR, 1.05 [1.04-1.07]) and experienced lower in-hospital mortality (2000-2009: OR, 0.92 [0.86-0.97]; 2010-2018: OR, 0.91 [0.88-0.93]).

Conclusions: Female patients with AIS have a higher chance of receiving intraarterial treatment that cannot be explained by clinical characteristics, such as age, premorbid disability, stroke severity, or cause. Women have a more favorable in-hospital recovery than men because their higher disability upon admission was followed by a lower in-hospital mortality and a higher likelihood of favorable functional outcome at discharge after adjustment for covariates.
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http://dx.doi.org/10.1161/STROKEAHA.120.032850DOI Listing
January 2021

Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care.

Mult Scler 2021 Jan 20:1352458520985118. Epub 2021 Jan 20.

Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany.

Background: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy.

Objectives: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug.

Methods: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing-remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not.

Results: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%).

Conclusion: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials.
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http://dx.doi.org/10.1177/1352458520985118DOI Listing
January 2021

Associations of major depressive disorder and related clinical characteristics with 25-hydroxyvitamin D levels in middle-aged adults.

Nutr Neurosci 2020 Dec 9:1-10. Epub 2020 Dec 9.

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

Vitamin D deficiency has been suggested to contribute to the onset of depression, but published results are inconsistent. The aims of this study were 1) to compare serum 25-hydroxyvitamin D (25(OH)D) levels in patients with depression and non-depressed controls and 2) to examine whether distinct subtypes and symptom severity of depression may vary in their association with 25(OH)D. The study involved cross-sectional data of n=1169 participants from the BiDirect Study (n=639 patients with clinically diagnosed major depressive disorder (MDD), n=530 controls). Serum 25(OH)D was measured via LS-MS/MS. We performed analysis of covariance to evaluate adjusted means of 25(OH)D levels and multinomial logistic regression to assess the association of depression and its clinical characteristics, namely distinct subtypes and symptom severity, with 25(OH)D status (adjusted for age, sex, education, season of blood sample collection, and lifestyle factors). In total, 45.0% of the participants had adequate 25(OH)D levels (≥20 ng/ml), whereas 24.9% had a deficiency (<12 ng/ml). Patients with MDD had lower 25(OH)D levels than controls (16.7 vs. 19.6 ng/ml, <0.001). Patients with atypical depression had the lowest levels (14.6 ng/ml). Symptom severity was inversely related to 25(OH)D. Moreover, patients with MDD had a more than 2-times higher odds of 25(OH)D deficiency than controls. Atypical depression showed the highest odds of deficiency. The results support that patients with depression have lower 25(OH)D concentrations than non-depressed individuals. Distinct subtypes, particularly the atypical subtype, may play a special role in this context. Therefore, depression heterogeneity should be considered in future research.
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http://dx.doi.org/10.1080/1028415X.2020.1843892DOI Listing
December 2020

The Impact of the COVID-19 Pandemic on Self-Reported Health.

Dtsch Arztebl Int 2020 12;117(50):861-867

Institute of Epidemiology and Social Medicine, University of Münster, Germany

Background: The pandemic caused by the coronavirus SARS-CoV-2 and the countermeasures taken to protect the public are having a substantial effect on the health of the population. In Germany, nationwide protective measures to halt the spread of the virus were implemented in mid-March for 6 weeks.

Methods: In May, the impact of the pandemic was assessed in the German National Cohort (NAKO). A total of 113 928 men and women aged 20 to 74 years at the time of the baseline examination conducted 1 to 5 years earlier (53%) answered, within a 30-day period, a follow-up questionnaire on SARS-CoV-2 test status, COVID-19- associated symptoms, and self-perceived health status.

Results: The self-reported SARS-CoV-2 test frequency among the probands was 4.6%, and 344 participants (0.3%) reported a positive test result. Depressive and anxiety-related symptoms increased relative to baseline only in participants under 60 years of age, particularly in young women. The rate of moderate to severe depressive symptoms increased from 6.4% to 8.8%. Perceived stress increased in all age groups and both sexes, especially in the young. The scores for mental state and self-rated health worsened in participants tested for SARS-CoV-2 compared with those who were not tested. In 32% of the participants, however, self-rated health improved.

Conclusion: The COVID-19 pandemic and the protective measures during the first wave had effects on mental health and on self-rated general health.
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http://dx.doi.org/10.3238/arztebl.2020.0861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025933PMC
December 2020

Investigating the roles of age, sex, depression, and anxiety for valence and arousal ratings of words: a population-based study.

BMC Psychol 2020 Nov 7;8(1):118. Epub 2020 Nov 7.

Institute of Epidemiology and Social Medicine, University of Münster, Albert-Schweitzer-Campus 1 (Building D3), 48149, Münster, Germany.

Background: The perception of the affective quality of stimuli with regard to valence and arousal has mostly been studied in laboratory experiments. Population-based research may complement such studies by accessing larger, older, better balanced, and more heterogeneous samples. Several characteristics, among them age, sex, depression, or anxiety, were found to be associated with affective quality perception. Here, we intended to transfer valence and arousal rating methods from experimental to population-based research. Our aim was to assess the feasibility of obtaining and determining the structure of valence and arousal ratings in the setting of the large observational BiDirect Study. Moreover, we explored the roles of age, sex, depression, and anxiety for valence and arousal ratings of words.

Methods: 704 participants provided valence and arousal ratings for 12 written nouns pre-categorized as unpleasant, neutral, or pleasant. Predictors of valence and arousal ratings (i.e. age, sex, depression, and anxiety) were analyzed for six outcomes that emerge by combining two affective dimensions with three words categories. Data were modeled with multiple linear regression. Relative predictor importance was quantified by model-explained variance decomposition.

Results: Overall, average population-based ratings replicated those found in laboratory settings. The model did not reach statistical significance in the valence dimension. In the arousal dimension, the model explained 5.4% (unpleasant), 4.6% (neutral), and 3.5% (pleasant) of the variance. (Trend) effects of sex on arousal ratings were found in all word categories (unpleasant: increased arousal in women; neutral, pleasant: decreased arousal in women). Effects of age and anxiety (increased arousal) were restricted to the neutral words.

Conclusions: We report results of valence and arousal ratings of words in the setting of a large, observational, population-based study. Method transfer yielded acceptable data quality. The analyses demonstrated small effects of the selected predictors in the arousal dimension.
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http://dx.doi.org/10.1186/s40359-020-00485-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648958PMC
November 2020

Chances and Challenges of Registry-Based Pharmacovigilance in Multiple Sclerosis: Lessons Learnt from the Implementation of the Multicenter REGIMS Registry.

Drug Saf 2021 Jan 23;44(1):7-15. Epub 2020 Oct 23.

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

The long-term and potential rare side effects of new immunomodulating drugs for the treatment of multiple sclerosis (MS) are often not well known. Spontaneous case report systems of adverse drug effects are a valuable source in pharmacovigilance, but have several limitations. Primary data collections within registries allow a comprehensive analysis of potential side effects, but face several challenges. This article will outline the chances and challenges of registry-based adverse event reporting, using the example of the German immunotherapeutic registry REGIMS. REGIMS is an observational, clinical multicenter registry that aims to assess the incidence, type, and consequences of side effects of MS immunotherapies. Patients treated with an approved MS medication are recruited by their physicians during routine visits in hospitals, outpatient clinics, and MS-specialized practices. REGIMS incorporates an electronic physician-based documentation in each center and a paper-based patient documentation, both at baseline and regular follow-up visits. By the end of 2019, 43 REGIMS centers were actively recruiting patients and performing follow-up documentations. The majority of the first 1000 REGIMS patients were female (69.3%), had relapse-remitting MS (89.8%), and were treated with a second-line therapy. During the implementation of REGIMS, several logistic and procedural challenges had to be overcome, which are outlined in this paper. Pharmacovigilance registries such as REGIMS provide high-quality primary data from a specific patient population in a real-world care setting and enable pharmacovigilance research that cannot be carried out using secondary data. Despite the logistic and procedural challenges in establishing a multicenter pharmacovigilance registry in Germany, the advantages outweigh the drawbacks.
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http://dx.doi.org/10.1007/s40264-020-01007-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813707PMC
January 2021

A Self-administered Version of the Functioning Assessment Short Test for Use in Population-based Studies: A Pilot Study.

Clin Pract Epidemiol Ment Health 2020 25;16:192-203. Epub 2020 Sep 25.

Institute for Clinical Epidemiology und Biometry, University of Würzburg, Würzburg, Germany.

Background: The Functioning Assessment Short Test (FAST) is an interviewer-administered scale assessing functional impairment originally developed for psychiatric patients.

Objectives: To adapt the FAST for the general population, we developed a self-administered version of the scale and assessed its properties in a pilot study.

Methods: The original FAST scale was translated into German forward and backward translation. Afterwards, we adjusted the scale for self-administered application and inquired participants from two ongoing studies in Germany, 'STAAB' (Würzburg) and 'BiDirect' (Münster), both recruiting subjects from the general population across a wide age range (STAAB: 30-79 years, BiDirect: 35-65 years). To assess reliability, agreement of self-assessment with proxy-assessment by partners was measured intraclass correlation coefficient (ICC) over the FAST score. Construct validity was estimated by conducting correlations with validated scales of depression (PHQ-9), anxiety (GAD-7), and health-related quality of life (SF-12) and regression analyses using these scales besides potentially disabling comorbidities ( Chronic Back Pain (CBP)).

Results: Participants (n=54) had a median age of 57.0 years (quartiles: 49.8, 65.3), 46.3% were female. Reliability was moderate: ICC 0.50 (95% CI 0.46-0.54). The FAST score significantly correlated with PHQ-9, GAD-7, and the mental sub-scale of SF-12. In univariable linear regression, all three scales and chronic back pain explained variance of the FAST score. In multivariable analysis, only CBP and the SF-12 remained significant predictors.

Conclusion: The German self-administered version of the FAST yielded moderate psychometric properties in this pilot study, indicating its applicability to assess functional impairment in the general population.
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http://dx.doi.org/10.2174/1745017902016010192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539537PMC
September 2020

[Multiple sclerosis in Germany: updated analysis of the German MS Registry 2014-2018].

Fortschr Neurol Psychiatr 2020 Jul 16;88(7):e1. Epub 2020 Oct 16.

Klinik und Poliklinik für Neurologie, Sektion Neuroimmunologie, Universitätsmedizin Rostock.

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http://dx.doi.org/10.1055/a-1248-5258DOI Listing
July 2020

Association Between Adherence to Quality Indicators and 7-Day In-Hospital Mortality After Acute Ischemic Stroke.

Stroke 2020 12 12;51(12):3664-3672. Epub 2020 Oct 12.

Institute of Clinical Epidemiology and Biometry, University of Würzburg (K.H., V.R., P.U.H.).

Background And Purpose: Quality indicators (QI) are an accepted tool to measure performance of hospitals in routine care. We investigated the association between quality of acute stroke care defined by overall adherence to evidence-based QI and early outcome in German acute care hospitals.

Methods: Patients with ischemic stroke admitted to one of the hospitals cooperating within the ADSR (German Stroke Register Study Group) were analyzed. The ADSR is a voluntary network of 9 regional stroke registers monitoring quality of acute stroke care across 736 hospitals in Germany. Quality of stroke care was defined by adherence to 11 evidence-based indicators of early processes of stroke care. The correlation between overall adherence to QI with outcome was investigated by assessing the association between 7-day in-hospital mortality with the proportion of QI fulfilled from the total number of QI the individual patient was eligible for. Generalized linear mixed model analysis was performed adjusted for the variables age, sex, National Institutes of Health Stroke Scale and living will and as random effect for the variable hospital.

Results: Between 2015 and 2016, 388 012 patients with ischemic stroke were reported (median age 76 years, 52.4% male). Adherence to distinct QI ranged between 41.0% (thrombolysis in eligible patients) and 95.2% (early physiotherapy). Seven-day in-hospital mortality was 3.4%. The overall proportion of QI fulfilled was median 90% (interquartile range, 75%-100%). In multivariable analysis, a linear association between overall adherence to QI and 7-day in-hospital-mortality was observed (odds ratio adherence <50% versus 100%, 12.7 [95% CI, 11.8-13.7]; <0.001).

Conclusions: Higher quality of care measured by adherence to a set of evidence-based process QI for the early phase of stroke treatment was associated with lower in-hospital mortality.
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http://dx.doi.org/10.1161/STROKEAHA.120.029968DOI Listing
December 2020

Sleep characteristics, cognitive performance, and gray matter volume: findings from the BiDirect Study.

Sleep 2021 03;44(3)

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

Study Objectives: Sleep is essential for restorative metabolic changes and its physiological correlates can be examined using overnight polysomnography. However, the association between physiological sleep characteristics and brain structure is not well understood. We aimed to investigate gray matter volume and cognitive performance related to physiological sleep characteristics.

Methods: Polysomnographic recordings from 190 community-dwelling participants were analyzed with a principal component analysis in order to identify and aggregate shared variance into principal components. The relationship between aggregated sleep components and gray matter volume was then analyzed using voxel-based morphometry. In addition, we explored how cognitive flexibility, selective attention, and semantic fluency were related to aggregated sleep components and gray matter volume.

Results: Three principal components were identified from the polysomnographic recordings. The first component, primarily described by apnea events and cortical arousal, was significantly associated with lower gray matter volume in the left frontal pole. This apnea-related component was furthermore associated with lower cognitive flexibility and lower selective attention.

Conclusions: Sleep disrupted by cortical arousal and breathing disturbances is paralleled by lower gray matter volume in the frontal pole, a proposed hub for the integration of cognitive processes. The observed effects provide new insights on the interplay between disrupted sleep, particularly breathing disturbances and arousal, and the brain.
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http://dx.doi.org/10.1093/sleep/zsaa209DOI Listing
March 2021

Associations between sleep apnea and advanced brain aging in a large-scale population study.

Sleep 2021 03;44(3)

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer's dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea-hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.
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http://dx.doi.org/10.1093/sleep/zsaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953208PMC
March 2021

Management of MS Patients Treated With Daclizumab - a Case Series of 267 Patients.

Front Neurol 2020 8;11:996. Epub 2020 Sep 8.

Neuroimmunological Section, Department of Neurology, University of Rostock, Rostock, Germany.

Daclizumab was approved by the FDA and the EMA in 2016 for the treatment of relapsing forms of multiple sclerosis (MS). Cases of severe inflammatory brain disease with fatal outcome led to the withdrawal of approval in Europe and the US on March 2, 2018. Approximately 8,000 patients worldwide received daclizumab, but little is known about the further therapy management of these patients after the withdrawal of daclizumab. The aim of this study is to further analyze therapy management in MS patients after safety warnings and market withdrawal. Data from two registries in Germany, the German MS Registry (GMSR) and REGIMS, were used for this analysis. In total, 267 patients were included in this study. For almost 25% of patients (in the GMSR) daclizumab was the initial treatment. Most common pre-treatments were fingolimod, dimethyl fumarate, and natalizumab; various injectables summed up to 25.9%. The most common follow-up therapies were ocrelizumab and fingolimod. In most patients, follow-up therapies were administered shortly after discontinuation of daclizumab. The wash-out time for subsequent therapies varied between 1.2 and 4.0 months. Warnings and decisions by authorities led to a rapid decline and termination of therapies in both cohorts, indicating that such warnings have an immediate impact on the treatment landscape. Therapies that were started within a short time after the discontinuation of daclizumab were subsequently replaced by other therapies and may be considered as bridging therapies.
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http://dx.doi.org/10.3389/fneur.2020.00996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506133PMC
September 2020

[Multiple sclerosis in Germany: updated analysis of the German MS Registry 2014-2018].

Fortschr Neurol Psychiatr 2020 Jul 27;88(7):436-450. Epub 2020 Jul 27.

Klinik und Poliklinik für Neurologie, Sektion Neuroimmunologie, Universitätsmedizin Rostock.

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http://dx.doi.org/10.1055/a-0985-4124DOI Listing
July 2020

Seropositivity for pathogens associated with chronic infections is a risk factor for all-cause mortality in the elderly: findings from the Memory and Morbidity in Augsburg Elderly (MEMO) Study.

Geroscience 2020 10 9;42(5):1365-1376. Epub 2020 Jul 9.

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.
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http://dx.doi.org/10.1007/s11357-020-00216-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525922PMC
October 2020

Cross-Disorder Analysis of Brain Structural Abnormalities in Six Major Psychiatric Disorders: A Secondary Analysis of Mega- and Meta-analytical Findings From the ENIGMA Consortium.

Biol Psychiatry 2020 11 11;88(9):678-686. Epub 2020 May 11.

Department of Psychiatry, University of Münster, Münster, Germany.

Background: Neuroimaging studies have consistently reported similar brain structural abnormalities across different psychiatric disorders. Yet, the extent and regional distribution of shared morphometric abnormalities between disorders remains unknown.

Methods: Here, we conducted a cross-disorder analysis of brain structural abnormalities in 6 psychiatric disorders based on effect size estimates for cortical thickness and subcortical volume differences between healthy control subjects and psychiatric patients from 11 mega- and meta-analyses from the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) consortium. Correlational and exploratory factor analyses were used to quantify the relative overlap in brain structural effect sizes between disorders and to identify brain regions with disorder-specific abnormalities.

Results: Brain structural abnormalities in major depressive disorder, bipolar disorder, schizophrenia, and obsessive-compulsive disorder were highly correlated (r = .443 to r = .782), and one shared latent underlying factor explained between 42.3% and 88.7% of the brain structural variance of each disorder. The observed shared morphometric signature of these disorders showed little similarity with brain structural patterns related to physiological aging. In contrast, patterns of brain structural abnormalities independent of all other disorders were observed in both attention-deficit/hyperactivity disorder and autism spectrum disorder. Brain regions showing high proportions of independent variance were identified for each disorder to locate disorder-specific morphometric abnormalities.

Conclusions: Taken together, these results offer novel insights into transdiagnostic as well as disorder-specific brain structural abnormalities across 6 major psychiatric disorders. Limitations comprise the uncertain contribution of risk factors, comorbidities, and medication effects to the observed pattern of results that should be clarified by future research.
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http://dx.doi.org/10.1016/j.biopsych.2020.04.027DOI Listing
November 2020

Effects of age on trait resilience in a population-based cohort and two patient cohorts.

J Psychosom Res 2020 09 12;136:110170. Epub 2020 Jun 12.

Institute of Epidemiology and Social Medicine, University of Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.

Objective: We examined (i) the mean-level stability and change of trait resilience with age in three cohorts from a single study (population-based controls, depression patients, cardiovascular disease (CVD) patients), (ii) associations of sociodemographic, personality, and other factors (sex, education, Big Five, childhood trauma, depressive symptoms) with trait resilience, and (iii) the intra-individual stability across repeated trait resilience self-assessments.

Methods: 1544 participants from the BiDirect Study completed the Resilienzskala-11 (RS-11; German short version of the resilience scale 25) up to three times over about four years. The repeated-measures data were analyzed using linear mixed models, stratified by cohort. Outcome was the RS-11 score, the underlying time variable was age. All factors mentioned above were considered as fixed main effects. Bland-Altman plots assessed intra-individual stability of RS-11 scores.

Results: (i) In the population-based control cohort, there was no association between age and trait resilience (est.: -0.01; 95%-CI: -0.06, 0.04). There were modest positive associations in the patient cohorts (depression: est.: 0.08; 95%-CI: -0.01, 0.16; CVD: est.: 0.15; 95%-CI: 0.03, 0.26). (ii) For all cohorts, female sex, high education, extraversion, openness, agreeableness, and conscientiousness (Big Five) were associated positively with trait resilience. Childhood trauma, depressive symptoms, and neuroticism were associated negatively with trait resilience. (iii) In all cohorts, the level of intra-individual stability was moderate.

Conclusion: We found that trait resilience was rather stable across decades of age in all cohorts, albeit intra-individual self-assessments agreed only moderately. We confirmed previous findings regarding negative and positive associations of personality and sociodemographic factors with trait resilience.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110170DOI Listing
September 2020

ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing.

Transl Psychiatry 2020 05 29;10(1):172. Epub 2020 May 29.

Illinois Institute of Technology, Chicago, IL, USA.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.
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http://dx.doi.org/10.1038/s41398-020-0842-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260219PMC
May 2020
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