Publications by authors named "Wolfgang Maier"

692 Publications

Non-random relations in drug use expressed as patterns comprising prescription and over-the-counter drugs in multimorbid elderly patients in primary care: Data of the exploratory analysis of the multicentre, observational cohort study MultiCare.

Eur J Gen Pract 2021 Dec;27(1):119-129

Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: The elderly population deals with multimorbidity (three chronic conditions) and increasinged drug use with age. A comprehensive characterisation of the medication - including prescription and over-the-counter (OTC) drugs - of elderly patients in primary care is still insufficient.

Objectives: This study aims to characterise the medication (prescription and OTC) of multimorbid elderly patients in primary care and living at home by identifying drug patterns to evaluate the relationship between drugs and drug groups and reveal associations with recently published multimorbidity clusters of the same cohort.

Methods: MultiCare was a multicentre, prospective, observational cohort study of 3189 multimorbid patients aged 65 to 85 years in primary care in Germany. Patients and general practitioners were interviewed between 2008 and 2009. Drug patterns were identified using exploratory factor analysis. The relations between the drug patterns with the three multimorbidity clusters were analysed with Spearman-Rank-Correlation.

Results: Patients (59.3% female) used in mean 7.7 drugs; in total 24,535 drugs (23.7% OTC) were detected. Five drug patterns for men (drugs for obstructive pulmonary diseases (D-OPD), drugs for coronary heart diseases and hypertension (D-CHD), drugs for osteoporosis (D-Osteo), drugs for heart failure and drugs for pain) and four drug patterns for women (D-Osteo, D-CHD, D-OPD and drugs for diuretics and gout) were detected. Significant associations between multimorbidity clusters and drug patterns were detectable (D-CHD and CMD: male:  = 0.376, CI 0.322-0.430; female:  = 0.301, CI 0.624-0.340).

Conclusion: The drug patterns demonstrate non-random relations in drug use in multimorbid elderly patients and systematic associations between drug patterns and multimorbidity clusters were found in primary care.
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http://dx.doi.org/10.1080/13814788.2021.1933425DOI Listing
December 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Development of a loop-mediated isothermal amplification assay for the detection of Tilletia controversa based on genome comparison.

Sci Rep 2021 Jun 2;11(1):11611. Epub 2021 Jun 2.

Institute for Epidemiology and Pathogen Diagnostics, Julius Kühn Institute (JKI) - Federal Research Centre for Cultivated Plants, Messeweg 11-12, 38104, Braunschweig, Germany.

Tilletia controversa causing dwarf bunt of wheat is a quarantine pathogen in several countries. Therefore, its specific detection is of great phytosanitary importance. Genomic regions routinely used for phylogenetic inferences lack suitable polymorphisms for the development of species-specific markers. We therefore compared 21 genomes of six Tilletia species to identify DNA regions that were unique and conserved in all T. controversa isolates and had no or limited homology to other Tilletia species. A loop-mediated isothermal amplification (LAMP) assay for T. controversa was developed based on one of these DNA regions. The specificity of the assay was verified using 223 fungal samples comprising 43 fungal species including 11 Tilletia species, in particular 39 specimens of T. controversa, 92 of T. caries and 40 of T. laevis, respectively. The assay specifically amplified genomic DNA of T. controversa from pure cultures and teliospores. Only Tilletia trabutii generated false positive signals. The detection limit of the LAMP assay was 5 pg of genomic DNA per reaction. A test performance study that included five laboratories in Germany resulted in 100% sensitivity and 97.7% specificity of the assay. Genomic regions, specific to common bunt (Tilletia caries and Tilletia laevis together) are also provided.
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http://dx.doi.org/10.1038/s41598-021-91098-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172862PMC
June 2021

Author Correction: The secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans.

Nat Commun 2021 May 28;12(1):3315. Epub 2021 May 28.

Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1038/s41467-021-23820-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163770PMC
May 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 Jun 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Social Support and Functional Decline in the Oldest Old.

Gerontology 2021 May 12:1-9. Epub 2021 May 12.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: Longitudinal studies investigating the link between social support and functional decline are limited among the oldest old. Thus, the aim of this study was to examine whether changes in social support are associated with functional decline among the oldest old longitudinally using panel regression models.

Methods: Longitudinal data from 3 waves (waves 7, 8, and 9) of a multicenter prospective cohort study covering primary care patients aged ≥85 years were used. In the analytical sample, n equaled 624 individuals. The validated Lawton and Brody Instrumental Activities of Daily Living (IADL) scale and the well-established Barthel Index (ADL) were used to quantify functional status. The psychometrically sound Lubben Social Network Scale was used to measure social support. Several potential confounders such as age, marital status, cognitive decline, or depressive symptoms were included in the fixed effects (FE) regression models.

Results: Linear FE regressions showed that a decrease in social support is associated with functional decline (IADL: β = 0.03, p < 0.05; ADL: β = 0.27, p < 0.05) in men but not in women. With IADL as outcome measure, the interaction term (sex × social support) achieved statistical significance (p < 0.01). With regard to covariates, functional decline (IADL and ADL) was consistently associated with increasing age, an increase in the number of chronic conditions (except for women [ADL]), and cognitive decline (except for men [ADL]). Furthermore, functional decline (ADL) was associated with an increase in depressive symptoms.

Discussion: Our findings highlight the meaning of social support for functional status among the oldest old. Finding ways to sustain social support in highest age may be a promising approach in order to postpone functional decline.
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http://dx.doi.org/10.1159/000516077DOI Listing
May 2021

The moderating effects of social support and depressive symptoms on pain among elderly multimorbid patients-data from the multicentre, prospective, observational cohort study MultiCare.

Aging Ment Health 2021 May 5:1-7. Epub 2021 May 5.

Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Depressive symptoms and chronic pain are common among patients with multimorbidity creating a complex medical condition for both the patient and the general practitioner. Perceived social support may function as a protective measure.

To examine the impact of perceived social support as a potential moderator between depressive symptoms and pain intensity and pain disability in daily activities in multimorbid patients aged 75+.

Method: Data from 3,189 patients of the German longitudinal cohort study MultiCare were obtained at baseline and follow-ups during 5 years. Multilevel linear mixed-effects analyses were conducted for pain intensity (model 1) and pain disability in daily activities (model 2). The interaction term social support by depression score was included to test for moderation.

Results: The interaction between social support and depressive symptoms was significantly associated with the pain intensity score 0.41 (SE=.17; 95-CI[.08;.74]) but not with the pain disability score 0.35 (SE=.19; 95-CI[-.01;.72]). Additionally, men and individuals with medium or higher educational level showed reduced pain intensity and disability scores. Pain disability scores increased with age and depressive symptoms. Increased pain scores were also found for body mass index and burden of multimorbidity.

Conclusion: Perceived social support amplified the association of depressive symptoms on pain intensity and did not show a protective function. The high scores of perceived social support among the participants may point to the practice of secondary gain due to the patients immense health burden.
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http://dx.doi.org/10.1080/13607863.2021.1916882DOI Listing
May 2021

Health-related quality of life and ego integrity among the oldest old - Evidence from the multicenter AgeCoDe-AgeQualiDe study.

Arch Gerontol Geriatr 2021 Jul-Aug;95:104408. Epub 2021 Mar 31.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address:

Purpose: To investigate the association between health-related quality of life and ego integrity among the oldest old.

Materials And Methods: Cross-sectional data were taken from follow-up wave 9 of the multicenter prospective cohort study "Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe). Our analytical sample comprised n = 495 observations. Mean age was 90.2 years (SD: 2.7 years). Health-related quality of life was quantified using the EQ-5D-3L questionnaire (including the visual analogue scale EQ-VAS). Ego integrity was measured using the Ego Integrity Scale.

Results: Regressions showed an association between decreased ego integrity and problems with 'usual activities', 'pain/discomfort' and 'anxiety/depression'. Furthermore, regressions showed a marginally significant association between decreased ego integrity and problems with 'mobility' and a decreased EQ-VAS score. Ego integrity was not significantly associated with problems with 'self-care'.

Conclusions: Findings stress the importance of health-related quality of life for ego integrity among the oldest old. Future studies are required to clarify the underlying mechanisms.
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http://dx.doi.org/10.1016/j.archger.2021.104408DOI Listing
March 2021

Freely accessible ready to use global infrastructure for SARS-CoV-2 monitoring.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

The COVID-19 pandemic is the first global health crisis to occur in the age of big genomic data.Although data generation capacity is well established and sufficiently standardized, analytical capacity is not. To establish analytical capacity it is necessary to pull together global computational resources and deliver the best open source tools and analysis workflows within a ready to use, universally accessible resource. Such a resource should not be controlled by a single research group, institution, or country. Instead it should be maintained by a community of users and developers who ensure that the system remains operational and populated with current tools. A community is also essential for facilitating the types of discourse needed to establish best analytical practices. Bringing together public computational research infrastructure from the USA, Europe, and Australia, we developed a distributed data analysis platform that accomplishes these goals. It is immediately accessible to anyone in the world and is designed for the analysis of rapidly growing collections of deep sequencing datasets. We demonstrate its utility by detecting allelic variants in high-quality existing SARS-CoV-2 sequencing datasets and by continuous reanalysis of COG-UK data. All workflows, data, and documentation is available at https://covid19.galaxyproject.org .
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http://dx.doi.org/10.1101/2021.03.25.437046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010728PMC
March 2021

Correlates of institutionalization among the oldest old-Evidence from the multicenter AgeCoDe-AgeQualiDe study.

Int J Geriatr Psychiatry 2021 Jul 2;36(7):1095-1102. Epub 2021 Apr 2.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: There is a lack of studies identifying the correlates of institutionalization specifically among the oldest old. Therefore, our aim was to fill this gap in knowledge.

Methods: Cross-sectional data (Follow up wave 9; n = 633 observations in the analytical sample) were used from the multicenter prospective cohort study "Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" Correlates of institutionalization among the oldest old-Evidence from a multicenter cohort study. The sample consists of primary care patients aged 86 years and over (mean 90.5 years, SD: 2.9 years). Sociodemographic and health-related independent variables were included in our regression model. Institutionalization was defined as living in a nursing home or an old-age home (not including assisted living facilities).

Results: Out of the 633 participants, 502 individuals (79.3%) did not live in an institutionalized setting, whereas 73 individuals (20.7%) lived in an institutionalized setting. Multiple logistic regressions showed that the likelihood of institutionalization increased with being divorced/widowed/single (compared to being married; OR: 5.35 [95% CI: 1.75-16.36]), the presence of social isolation (OR: 2.07 [1.20-3.59]), more depressive symptoms (OR: 1.11 [1.01-1.23]), increased cognitive impairment (OR: 1.67 [1.31-2.15]) and higher levels of frailty (OR: 1.48 [1.07-2.06]).

Conclusion: The study findings identified various sociodemographic and health-related factors associated with institutionalization among the oldest old. Longitudinal studies are required to gain further insights into these associations.
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http://dx.doi.org/10.1002/gps.5548DOI Listing
July 2021

Anticholinergic drug burden according to the anticholinergic drug scale and the German anticholinergic burden and their impact on cognitive function in multimorbid elderly German people: a multicentre observational study.

BMJ Open 2021 03 23;11(3):e044230. Epub 2021 Mar 23.

Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: The aims of our study were to examine the anticholinergic drug use and to assess the association between anticholinergic burden and cognitive function in the multimorbid elderly patients of the MultiCare cohort.

Setting: MultiCare was conducted as a longitudinal cohort study in primary care, located in eight different study centres in Germany.

Participants: 3189 patients (59.3% female).

Primary And Secondary Outcome Measures: Baseline data were used for the following analyses. Drugs were classified according to the well-established anticholinergic drug scale (ADS) and the recently published German anticholinergic burden (German ACB). Cognitive function was measured using a letter digit substitution test (LDST) and a mixed-effect multivariate linear regression was performed to calculate the influence of anticholinergic burden on the cognitive function.

Results: Patients used 1764 anticholinergic drugs according to ADS and 2750 anticholinergics according to the German ACB score (prevalence 38.4% and 53.7%, respectively). The mean ADS score was 0.8 (±1.3), and the mean German ACB score was 1.2 (±1.6) per patient. The most common ADS anticholinergic was furosemide (5.8%) and the most common ACB anticholinergic was metformin (13.7%). The majority of the identified anticholinergics were drugs with low anticholinergic potential: 80.2% (ADS) and 73.4% (ACB), respectively. An increasing ADS and German ACB score was associated with reduced cognitive function according to the LDST (-0.26; p=0.008 and -0.24; p=0.003, respectively).

Conclusion: Multimorbid elderly patients are in a high risk for using anticholinergic drugs according to ADS and German ACB score. We especially need to gain greater awareness for the contribution of drugs with low anticholinergic potential from the cardiovascular system. As anticholinergic drug use is associated with reduced cognitive function in multimorbid elderly patients, the importance of rational prescribing and also deprescribing needs to be further evaluated.

Trial Registration Number: ISRCTN89818205.
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http://dx.doi.org/10.1136/bmjopen-2020-044230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993236PMC
March 2021

Do self-reported hearing and visual impairments predict longitudinal dementia in older adults?

J Am Geriatr Soc 2021 Jun 18;69(6):1519-1528. Epub 2021 Mar 18.

Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.

Background: Sensory impairments have been associated with dementia in older adults. However, the contribution of different impairments and how they interact in the development of dementia is not clear. We examined the independent and interaction effects of hearing impairment (HI) and visual impairment (VI) on incident dementia.

Design: Multi-centric population-based prospective cohort study.

Setting: Data were taken from the AgeDifferent.de platform, pooling participants aged 75 and older from the German LEILA75+ and AgeCoDe/AgeQualiDe cohorts.

Participants: Older adults (N = 3497) with mean age 79.8 years, 67.2% female.

Measurements: Standardized interviews and questionnaires were used to assess self-reported HI and VI at baseline and all-cause dementia in 9 follow-ups, spanning over 20 years.

Methods: Competing risk regression models were conducted to test the main and interaction effects of HI and VI on dementia incidence, adjusting for established risk factors of dementia and accumulated mortality.

Results: HI and VI at baseline were reported by 30.3% and 16.6% of individuals, respectively. Adjusting for baseline information on sociodemographics, substance use, cognitive functioning and morbidity, and controlling for accumulated mortality risk, HI (sHR 1.16, 95% CI 1.04-1.30, p = 0.011) but not VI (sHR 1.07, 95% CI 0.90-1.28, p = 0.462) was significantly associated with incident dementia. There was no interaction between HI and VI (sHR 1.09, 95% CI 0.81-1.46, p = 0.567).

Conclusions: Hearing impairment is associated with an increased incidence of all-cause dementia in older adults. There is no excess risk or risk compensation through the additional presence or absence of visual impairment. Early prevention measures for hearing impairment might help to reduce the long-term risk of dementia.
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http://dx.doi.org/10.1111/jgs.17074DOI Listing
June 2021

The secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans.

Nat Commun 2021 02 24;12(1):1262. Epub 2021 Feb 24.

Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, Freiburg, Germany.

Multicellular organisms coordinate tissue specific responses to environmental information via both cell-autonomous and non-autonomous mechanisms. In addition to secreted ligands, recent reports implicated release of small RNAs in regulating gene expression across tissue boundaries. Here, we show that the conserved poly-U specific endoribonuclease ENDU-2 in C. elegans is secreted from the soma and taken-up by the germline to ensure germline immortality at elevated temperature. ENDU-2 binds to mature mRNAs and negatively regulates mRNA abundance both in the soma and the germline. While ENDU-2 promotes RNA decay in the soma directly via its endoribonuclease activity, ENDU-2 prevents misexpression of soma-specific genes in the germline and preserves germline immortality independent of its RNA-cleavage activity. In summary, our results suggest that the secreted RNase ENDU-2 regulates gene expression across tissue boundaries in response to temperature alterations and contributes to maintenance of stem cell immortality, probably via retaining a stem cell specific program of gene expression.
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http://dx.doi.org/10.1038/s41467-021-21516-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904951PMC
February 2021

Frailty and Autonomy among the Oldest Old: Evidence from the Multicenter Prospective AgeCoDe-AgeQualiDe Study.

Gerontology 2021 Feb 17:1-8. Epub 2021 Feb 17.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: There is a lack of studies examining the link between perceived autonomy and frailty among the oldest old. Therefore, our objective was to fill this gap.

Methods: Data were used from the multicenter prospective cohort study "Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe; follow-up [FU] wave 9; n = 510 observations in the analytical sample). The average age was 90.3 years (SD: 2.7 years). The Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale (CFS) was used to assess frailty. Socioeconomic and health-related covariates were included in our regression model. The autonomy scale developed by Schwarzer was used to assess perceived autonomy in old age.

Results: Adjusting for various confounders, multiple linear regressions showed that lower perceived autonomy was associated with increased levels of frailty (total sample: β = -0.13, p < 0.001; women: β = -0.14, p < 0.001; and men: β = -0.12, p < 0.001). Furthermore, lower perceived autonomy was associated with more depressive symptoms, higher cognitive impairment, and being institutionalized (except for men) in the total sample and in both sexes, but it was not significantly associated with age, sex, marital status, educational level, and social support.

Conclusion: Findings indicate that frailty is associated with lower autonomy among the oldest old. More generally, while health-related factors were consistently associated with autonomy, sociodemographic factors (except for being institutionalized) were not associated with autonomy among the oldest old. We should be aware of the strong association between autonomy and physical as well as mental health in very old age.
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http://dx.doi.org/10.1159/000514170DOI Listing
February 2021

Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer's Dementia in the Oldest Old.

Nutrients 2021 Jan 30;13(2). Epub 2021 Jan 30.

German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.

Background: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties.

Methods: We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer's disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD.

Results: During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia.

Conclusions: Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.
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http://dx.doi.org/10.3390/nu13020461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912244PMC
January 2021

GPs' awareness of car driving among oldest patients: exploratory results from a primary care cohort.

BJGP Open 2021 Apr 26;5(2). Epub 2021 Apr 26.

Institute of Social Medicine, Occupational Medicine and Public Health (ISAP), Medical Faculty, University of Leipzig, Germany.

Background: Increasingly more very old people are active drivers. Sensory, motor and cognitive limitations, and medication can increase safety risks. Timely attention to driving safety in the patient-doctor relationship can promote patient-centred solutions.

Aim: To explore the following questions: do GPs know which patients drive a car? Is fitness to drive addressed with patients?

Design & Setting: Cross-sectional data from patient interviews and GP survey in the ninth follow-up phase of a prospective primary care cohort (the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe) and the Study on Needs, Health Service Use, Costs and Health-Related Quality of Life in a large sample of 'oldest-old' primary care patients (≥85 years; AgeQualiDe)) .

Method: The sample consisted of patients in the age group ≥85 years and their GPs. Independent reports were gathered on driving activity from the GP and the patient, and information was gained from GPs on whether driving ability was discussed with the patient. Statistical analyses included validity parameters and bivariate characterisation of subgroups (non-parametric significance tests, effect size).

Results: Self-reports of 553 patients were available (69.5% female; mean age 90.5 years; 15.9% drive a car). For 427 patients, GP data were also available: GPs recognised 67.1% correctly as drivers and 94.9% as non-drivers. GPs said that they had discussed fitness to drive with 32.1% of potentially driving patients. Among drivers who were not recognised and with whom driving had not been discussed, there were more patients with a low educational level.

Conclusion: The GP's assessment of driving activity among very old patients showed moderate sensitivity and good specificity. Driving ability was seldom discussed. Asking an appropriate question during assessment could increase GPs' awareness of older patients' automobility.
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http://dx.doi.org/10.3399/BJGPO.2020.0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170606PMC
April 2021

Disorientation in Time and Place in Old Age: Longitudinal Evidence from Three Old Age Cohorts in Germany (AgeDifferent.de Platform).

J Alzheimers Dis 2021 ;79(4):1589-1599

Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Germany.

Background: Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer's disease and related dementias.

Objectives: The aim of this study was to investigate the prevalence of disorientation in older age in association with the level of cognitive status, personal characteristics, and life events.

Methods: Three longitudinal population-based cohort studies on cognitive health of elderly adults were harmonized (LEILA 75 + , AgeCoDe/AgeQualiDe, AgeMooDe). Participants who completed a baseline and at least one follow-up assessment of cognitive functioning and who did not have stroke, Parkinson's disease, atherosclerosis, kidney disease, and/or alcoholism were included in the analysis (n = 2135, 72.6% female, mean age 80.2 years). Data was collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant's general practitioner.

Results: Making three errors in the MMSE other than in the questions on orientation (MMSEwo) came with a probability of 7.8% for disorientation, making ten errors with a probability of 88.9%. A lower MMSEwo score (HR 0.75, CI 95 0.71-0.79, p < 0.001), older age (HR 1.11, CI 95 1.08-1.14, p < 0.001), and living in a nursing home (HR 1.64, CI 95 1.02-2.64, p = 0.042) were associated with incident disorientation. Impairments in walking (OR 2.41, CI 95 1.16-4.99, p = 0.018) were associated with a greater probability for prevalent disorientation. None of the life events were significant.

Conclusion: Our findings suggest that disorientation is primarily associated with cognitive status. Regular walking activities might possibly reduce the risk for disorientation but further research is necessary.
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http://dx.doi.org/10.3233/JAD-201008DOI Listing
January 2021

Convective isolation of Hadean mantle reservoirs through Archean time.

Proc Natl Acad Sci U S A 2021 Jan;118(2)

Institut für Geowissenschaften, Universität zu Kiel, 24118 Kiel, Germany.

Although Earth has a convecting mantle, ancient mantle reservoirs that formed within the first 100 Ma of Earth's history (Hadean Eon) appear to have been preserved through geologic time. Evidence for this is based on small anomalies of isotopes such as W, Nd, and Xe that are decay products of short-lived nuclide systems. Studies of such short-lived isotopes have typically focused on geological units with a limited age range and therefore only provide snapshots of regional mantle heterogeneities. Here we present a dataset for short-lived Hf-W (half-life 9 Ma) in a comprehensive rock suite from the Pilbara Craton, Western Australia. The samples analyzed preserve a unique geological archive covering 800 Ma of Archean history. Pristine W signatures that directly reflect the W isotopic composition of parental sources are only preserved in unaltered mafic samples with near canonical W/Th (0.07 to 0.26). Early Paleoarchean, mafic igneous rocks from the East Pilbara Terrane display a uniform pristine µW excess of 12.6 ± 1.4 ppm. From 3.3Ga onward, the pristine W signatures progressively vanish and are only preserved in younger rocks of the craton that tap stabilized ancient lithosphere. Given that the anomalous W signature must have formed by 4.5 Ga, the mantle domain that was tapped by magmatism in the Pilbara Craton must have been convectively isolated for nearly 1.2 Ga. This finding puts lower bounds on timescale estimates for localized convective homogenization in early Earth's interior and on the widespread emergence of plate tectonics that are both important input parameters in many physical models.
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http://dx.doi.org/10.1073/pnas.2012626118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812741PMC
January 2021

Depressive Symptoms and Frailty Among the Oldest Old: Evidence from a Multicenter Prospective Study.

J Am Med Dir Assoc 2021 Mar 19;22(3):577-582.e2. Epub 2020 Nov 19.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center, Hamburg-Eppendorf, Germany.

Objective: There is a lack of studies disentangling whether changes in frailty are associated with subsequent changes in depressive symptoms or vice versa among the oldest old. Consequently, we aimed to disentangle this link.

Design: Three waves [follow-up (FU) wave 7 to FU wave 9; n = 423 individuals in the analytical sample] were used from the multicenter prospective cohort study "Needs, Health Service Use, Costs and Health-Related Quality of Life in a Large Sample of Oldest-Old Primary Care Patients (85+)" (AgeQualiDe).

Setting And Participants: Primary care patients aged 85 years and older.

Methods: The Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale (CFS) was used to quantify frailty, and the Geriatric Depression Scale was used to measure depressive symptoms. It was adjusted for several covariates (sociodemographic and health-related factors) in regression analysis.

Results: Multiple linear regressions with first differences showed that initial increases in depressive symptoms (from FU wave 7 to FU wave 8) were associated with subsequent increases in frailty (from FU wave 8 to FU wave 9; β = 0.06, P < .05), whereas initial increases in frailty (from FU wave 7 to FU wave 8) were not associated with subsequent increases in depressive symptoms (from FU wave 8 to FU wave 9).

Conclusions And Implications: The study findings suggest the relevance of increases in depressive symptoms for subsequent increases in frailty. Treatment of depressive symptoms may also be beneficial to postpone frailty.
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http://dx.doi.org/10.1016/j.jamda.2020.10.008DOI Listing
March 2021

Prediction of dementia of Alzheimer type by different types of subjective cognitive decline.

Alzheimers Dement 2020 12 2;16(12):1745-1749. Epub 2020 Nov 2.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Introduction: Subjective cognitive decline (SCD) is a risk condition for dementia, including dementia of Alzheimer type (DAT).

Methods: We report sensitivity, specificity, positive and negative predictive values (PPV, NPV) for conversion to all-cause dementia, and DAT in different SCD types (decline in memory, assocated worries, longitudinal consitency, of the AgeCoDe study (n = 2.402, 12 years follow-up).

Results: 82.7% of those converting to any dementia and 84.4% of those converting with DAT at follow-up, reported memory decline and fulfilled criteria of SCD at least at one time point before. SCD with worries at two consecutive time points showed a specificity of 92.2% for any dementia and also for DAT as well as a PPV of 44.3% for any dementia and of 36.9% for DAT at follow-up at the expense of low sensitivity.

Discussion: Different SCD subtypes were either sensitive or specific for future all-cause dementia and DAT in cognitively unimpaired individuals. Modest PPV of the most specific SCD subtypes were achieved in this low prevalence population.
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http://dx.doi.org/10.1002/alz.12163DOI Listing
December 2020

EQ-5D-3L health status and health state utilities of the oldest-old (85 +) in Germany: results from the AgeCoDe-AgeQualiDe study.

Qual Life Res 2020 Dec 26;29(12):3223-3232. Epub 2020 Aug 26.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: To describe health status and health state utilities measured by the EQ-5D-3L in a population-based sample of individuals aged 85 + in Germany, and to analyze associations with basic socio-demographic variables.

Methods: Cross-sectional data from follow-up wave 7 (n = 761) of the German AgeCoDe Study were used. The EQ-5D-3L questionnaire was used to record problems in five health dimensions, its visual analogue scale (EQ VAS) was used to record self-rated health status, and the German EQ-5D-3L index was used to derive health state utilities.

Results: Mean age of respondents was 88.9 years (SD 2.9; range 85 to 100), 67.4% were female. 81.9% reported problems in at least one of the EQ-5D dimensions, with 15.3% reporting extreme problems. Most frequent were problems with pain/discomfort (64.8%), followed by mobility (62.5%), usual activities (42.6%), self-care (28.2%), and anxiety/depression (20.5%). Mean EQ VAS score was 62.4 (SD 18.8), and mean EQ-5D index was 0.77 (SD 0.24). Multiple regression analysis showed associations of problem frequency in various EQ-5D dimensions with age, gender, living situation, marital status, and education. The EQ VAS score was negatively associated with age (β =  - 0.56; p < 0.05) and female gender (β =  - 3.49; p < 0.05). The EQ-5D index was negatively associated with not living in the community (β =  - 0.10; p < 0.001) and being single (β =  - 0.09; p < 0.05).

Conclusions: The results show a substantially impaired health status of the oldest-old population. The data can be used for comparing health status of population groups as well as for health economic models.
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http://dx.doi.org/10.1007/s11136-020-02597-0DOI Listing
December 2020

Effects of APOE e4-allele and mental work demands on cognitive decline in old age: Results from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe).

Int J Geriatr Psychiatry 2021 01 1;36(1):152-162. Epub 2020 Oct 1.

Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.

Objectives: Previous studies have observed protective effects of high mental demands at work on cognitive functioning and dementia risk. However, it is unclear what types of demands drive this effect and whether this effect is subject to a person's genetic risk. We investigated to what extent eight different types of mental demands at work together with the APOE e4 allele, a major risk gene for late-onset Alzheimer's disease, affect cognitive functioning in late life.

Methods/design: The population-based German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe, n = 2 154) followed cognitively healthy individuals aged 75 years and older in seven assessment waves. Cognitive functioning was assessed via the mini-mental status examination.

Results: Mixed-effects modeling (adjusted for education, gender, marital status, stroke, depression, and diabetes) indicated that participants who had an occupational history of working in jobs with high compared to low demands in "Language & Knowledge", "Pattern detection", "Information processing", and "Service" had a slower cognitive decline. APOE e4-allele carriers had an accelerated cognitive decline, but this decline was significantly smaller if they had a medium compared to a low level of demands in contrast to non-carriers.

Conclusions: Our longitudinal observations suggest that cognitive decline could be slowed by an intellectually enriched lifestyle even in risk gene carriers. Fostering intellectual engagement throughout the life-course could be a key prevention initiative to promote better cognitive health in old age.
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http://dx.doi.org/10.1002/gps.5409DOI Listing
January 2021

No more business as usual: Agile and effective responses to emerging pathogen threats require open data and open analytics.

PLoS Pathog 2020 08 13;16(8):e1008643. Epub 2020 Aug 13.

Temple University, Philadelphia, Pennsylvania, United States of America.

The current state of much of the Wuhan pneumonia virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) research shows a regrettable lack of data sharing and considerable analytical obfuscation. This impedes global research cooperation, which is essential for tackling public health emergencies and requires unimpeded access to data, analysis tools, and computational infrastructure. Here, we show that community efforts in developing open analytical software tools over the past 10 years, combined with national investments into scientific computational infrastructure, can overcome these deficiencies and provide an accessible platform for tackling global health emergencies in an open and transparent manner. Specifically, we use all SARS-CoV-2 genomic data available in the public domain so far to (1) underscore the importance of access to raw data and (2) demonstrate that existing community efforts in curation and deployment of biomedical software can reliably support rapid, reproducible research during global health crises. All our analyses are fully documented at https://github.com/galaxyproject/SARS-CoV-2.
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http://dx.doi.org/10.1371/journal.ppat.1008643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425854PMC
August 2020

Mutual antagonism between Hippo signaling and cyclin E drives intracellular pattern formation.

J Cell Biol 2020 09;219(9)

Department of Cellular Biology, University of Georgia, Athens, GA.

Not much is known about how organelles organize into patterns. In ciliates, the cortical pattern is propagated during "tandem duplication," a cell division that remodels the parental cell into two daughter cells. A key step is the formation of the division boundary along the cell's equator. In Tetrahymena thermophila, the cdaA alleles prevent the formation of the division boundary. We find that the CDAA gene encodes a cyclin E that accumulates in the posterior cell half, concurrently with accumulation of CdaI, a Hippo/Mst kinase, in the anterior cell half. The division boundary forms between the margins of expression of CdaI and CdaA, which exclude each other from their own cortical domains. The activities of CdaA and CdaI must be balanced to initiate the division boundary and to position it along the cell's equator. CdaA and CdaI cooperate to position organelles near the new cell ends. Our data point to an intracellular positioning mechanism involving antagonistic Hippo signaling and cyclin E.
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http://dx.doi.org/10.1083/jcb.202002077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480119PMC
September 2020

Which Factors Contribute to Frailty among the Oldest Old? Results of the Multicentre Prospective AgeCoDe and AgeQualiDe Study.

Gerontology 2020 7;66(5):460-466. Epub 2020 Jul 7.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: There is a lack of studies investigating the link between time-varying factors associated with changes in frailty scores in very old age longitudinally. This is important because the level of frailty is associated with subsequent morbidity and mortality.

Objective: To examine time-dependent predictors of frailty among the oldest old using a longitudinal approach.

Methods: Longitudinal data were drawn from the multicentre prospective cohort study "Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe), covering primary care patients aged 85 years and over. Three waves were used (from follow-up, FU, wave 7 to FU wave 9 [with 10 months between each wave]; 1,301 observations in the analytical sample). Frailty was assessed using the Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale (CFS). As explanatory variables, we included sociodemographic factors (marital status and age), social isolation as well as health-related variables (depression, dementia, and chronic diseases) in a regression analysis.

Results: In total, 18.9% of the individuals were mildly frail, 12.4% of the individuals were moderately frail, and 0.4% of the individuals were severely frail at FU wave 7. Fixed effects regressions revealed that increases in frailty were associated with increases in age (β = 0.23, p < 0.001), and dementia (β = 0.84, p < 0.01), as well as increases in chronic conditions (β = 0.03, p = 0.058).

Conclusion: The study findings particularly emphasize the importance of changes in age, probably chronic conditions as well as dementia for frailty. Future research is required to elucidate the underlying mechanisms. Furthermore, future longitudinal studies based on panel regression models are required to confirm our findings.
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http://dx.doi.org/10.1159/000508723DOI Listing
July 2020

Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer's Disease Dementia via Lead-Lag Analysis.

J Alzheimers Dis 2020 ;76(3):1005-1015

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Psychiatry, Berlin, Germany.

Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer's disease. However, the temporal dynamics of this decline are inconsistent.

Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage.

Methods: Patients with mild Alzheimer's dementia (AD; MMSE = 23.9±2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD + test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale.

Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (ΔMMSE 5.8±8.64; ΔCDR-SOB 4.32±4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses.

Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures.
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http://dx.doi.org/10.3233/JAD-200230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504993PMC
June 2021

Changes in Social Network Size Are Associated With Cognitive Changes in the Oldest-Old.

Front Psychiatry 2020 4;11:330. Epub 2020 May 4.

Institute of Social Medicine, Occupational Health and Public Health (ISAP), Medical Faculty, University of Leipzig, Leipzig, Germany.

Objectives: Social isolation is increasing in aging societies and several studies have shown a relation with worse cognition in old age. However, less is known about the association in the oldest-old (85+); the group that is at highest risk for both social isolation dementia.

Methods: Analyses were based on follow-up 5 to 9 of the longitudinal German study on aging, cognition, and dementia in primary care patients (AgeCoDe) and the study on needs, health service use, costs, and health-related quality of life in a large sample of oldest-old primary care patients (AgeQualiDe), a multi-center population-based prospective cohort study. Measurements included the Lubben Social Network Scale (LSNS-6), with a score below 12 indicating social isolation, as well as the Mini-Mental Status Examination (MMSE) as an indicator of cognitive function.

Results: Dementia-free study participants (n = 942) were = 86.4 ( = 3.0) years old at observation onset, 68.2% were women. One third (32.3%) of them were socially isolated. Adjusted linear hybrid mixed effects models revealed significantly lower cognitive function in individuals with smaller social networks ( = 0.5, 95% CI = 0.3-0.7, < .001). Moreover, changes in an individual's social network size were significantly associated with cognitive changes over time ( = 0.2, 95% CI = 0.1-0.4, = .003), indicating worse cognitive function with shrinking social networks.

Conclusion: Social isolation is highly prevalent among oldest-old individuals, being a risk factor for decreases in cognitive function. Consequently, it is important to maintain a socially active lifestyle into very old age. Likewise, this calls for effective ways to prevent social isolation.
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http://dx.doi.org/10.3389/fpsyt.2020.00330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212889PMC
May 2020

Association of a CAMK2A genetic variant with logical memory performance and hippocampal volume in the elderly.

Brain Res Bull 2020 08 11;161:13-20. Epub 2020 May 11.

Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Calcium/Calmodulin-dependent kinase alpha (αCaMKII) has been shown to play an essential role in synaptic plasticity and in learning and memory in animal models. However, there is little evidence for an involvement in specific memories in humans. Here we tested the potential involvement of the αCaMKII coding gene CAMK2A in verbal logical memory in two Caucasian populations from Germany, in a sample of 209 elderly people with cognitive impairments and a sample of 142 healthy adults. The association of single nucleotide polymorphisms (SNPs) located within the genomic region of CAMK2A with verbal logical memory learning and retrieval from the Wechsler Memory Scale was measured and hippocampal volume was assessed by structural MRI. In the elderly people, we found the minor allele of CAMK2A intronic SNP rs919741 to predict a higher hippocampal volume and better logical memory retrieval. This association was not found in healthy adults. The present study may provide evidence for an association of a genetic variant of the CAMK2A gene specifically with retrieval of logical memory in elderly humans. This effect is possibly mediated by a higher hippocampal volume.
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http://dx.doi.org/10.1016/j.brainresbull.2020.05.001DOI Listing
August 2020

Prevalence and factors associated with obesity among the oldest old.

Arch Gerontol Geriatr 2020 Jul - Aug;89:104069. Epub 2020 Apr 10.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Germany.

Purpose: To determine the prevalence of overweight and obesity, and to identify factors associated with obesity, among the oldest old.

Methods: For this study, data from follow-up (FU) wave 7 and FU wave 8 of the "Study on Needs, Health Service Use, Costs and Health-Related Quality of Life in a Large Sample of Oldest-Old Primary Care Patients (85+)" (AgeQualiDe) were used. At FU wave 7, the mean age was 88.9 years (SD: 2.9; 85-100 years). Body-mass-index (BMI) categories were defined according to the World Health Organization (WHO) thresholds: underweight (BMI < 18.5 kg/m²), normal weight (18.5 kg/m² ≤ BMI < 25 kg/m²), overweight (25 kg/m² ≤ BMI < 30 kg/m²), and obesity (BMI ≥ 30 kg/m²). Longitudinal regression analysis was used to determine factors associated with obesity.

Results: At FU wave 7, 3.0 % were underweight, 48.9 % were normal weight, 37.9 % were overweight, and 10.2 % were obese. Regressions showed that the probability of obesity decreased with age (OR: 0.77 [95 % CI: .593-.999]) and less chronic conditions (OR: 1.32 [95 % CI: 1.11-1.57]). The probability of obesity was not associated with sex, educational level, marital status, social isolation, visual impairment, hearing impairment, depression, and dementia.

Conclusion: Nearly half of the individuals in very late life had excess weight. Thus, excess weight remains a major challenge, even in very old age. Given the demographic ageing in upcoming decades, this is an issue which we should be aware of.
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http://dx.doi.org/10.1016/j.archger.2020.104069DOI Listing
November 2020

New Peptaibiotics and a Cyclodepsipeptide from : Isolation, Identification, Cytotoxic and Nematicidal Activities.

Antibiotics (Basel) 2020 Mar 22;9(3). Epub 2020 Mar 22.

Department of Microbial Drugs, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.

Fungal associations with nematodes have attracted scientific attention because of the need to develop new biocontrol agents. In this context, , an antagonistic fungus previously isolated from the plant parasitic cyst nematode , was selected to carry out an in-depth metabolomic study for its active metabolites. Herein, three new nonapeptide peptaibols with leucinostatin based sequences were isolated and identified by 1, 2D NMR, and HR-ESI-MS-MS. The absolute configuration was assigned based on Marfay's analysis and Mosher ester formation. The new leucinostatins manifested moderate nematicidal effect against the plant pathogenic nematode with LD values ranging from 5 to 7 µg/mL. Furthermore, a cyclodepsipeptide, named arthrichitin D, with five amino acid residues attached to a 3-hydroxy-2,4-dimethylhexadeca-4,6-dienoic fatty acid chain was discovered and showed weak nematicidal effect against . Chaetoglobosin B and its 19--acetyl derivative were also obtained as minor metabolites, and the activity of chaetoglobosin B on the actin cytoskeleton of mammalian cells was assessed.
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http://dx.doi.org/10.3390/antibiotics9030132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148537PMC
March 2020