Publications by authors named "Nathalie van der Velde"

111 Publications

Development and internal validation of a risk prediction model for falls among older people using primary care electronic health records.

J Gerontol A Biol Sci Med Sci 2021 Oct 12. Epub 2021 Oct 12.

Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC - Location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Currently used prediction tools have limited ability to identify community-dwelling older people at high risk for falls. Prediction models utilizing Electronic Heath Records (EHR) provide opportunities but up to now showed limited clinical value as risk stratification tool; because of among others the underestimation of falls prevalence. The aim of this study was to develop a fall prediction model for community-dwelling older people using a combination of structured data and free text of primary care EHR and to internally validate its predictive performance.

Methods: EHR data of individuals aged 65 or over. Age, sex, history of falls, medications and medical conditions were included as potential predictors. Falls were ascertained from the free text. We employed the Bootstrap-enhanced penalized logistic regression with the least absolute shrinkage and selection operator to develop the prediction model. We used 10-fold cross-validation to internally validate the prediction strategy. Model performance was assessed in terms of discrimination and calibration.

Results: Data of 36,470 eligible participants were extracted from the dataset. The number of participants who fell at least once was 4,778 (13.1%). The final prediction model included age, sex, history of falls, two medications and five medical conditions. The model had a median area under the receiver operating curve of 0.705 (IQR 0.700-0.714) .

Conclusions: Our prediction model to identify older people at high risk for falls achieved fair discrimination, and had reasonable calibration. It can be applied in clinical practice as it relies on routinely collected variables and does not require mobility assessment tests.
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http://dx.doi.org/10.1093/gerona/glab311DOI Listing
October 2021

The association between hyperkyphosis and fall incidence among community-dwelling older adults.

Osteoporos Int 2021 Sep 8. Epub 2021 Sep 8.

Department of Internal Medicine, Division of Geriatrics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Centre Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Hyperkyphosis, an increased kyphosis angle of the thoracic spine, was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Hyperkyphosis could serve as an indicator of an increased fall risk as well as a treatable condition.

Introduction: Hyperkyphosis is frequently found in adults aged 65 years and older and may be associated with falls. We aimed to investigate prospectively in community-dwelling older adults whether hyperkyphosis or change in the kyphosis angle is associated with fall incidence.

Methods: Community-dwelling older adults (n = 1220, mean age 72.9 ± 5.7 years) reported falls weekly over 2 years. We measured thoracic kyphosis through the Cobb angle between the fourth and 12th thoracic vertebra on DXA-based vertebral fracture assessments and defined hyperkyphosis as a Cobb angle ≥ 50°. The change in the Cobb angle during follow-up was dichotomized (< 5 or ≥ 5°). Through multifactorial regression analysis, we investigated the association between the kyphosis angle and falls.

Results: Hyperkyphosis was present in 15% of the participants. During follow-up, 48% of the participants fell at least once. In the total study population, hyperkyphosis was not associated with the number of falls (adjusted IRR 1.12, 95% CI 0.91-1.39). We observed effect modification by age (p = 0.002). In the oldest quartile, aged 77 years and older, hyperkyphosis was prospectively associated with a higher number of falls (adjusted IRR 1.67, 95% CI 1.14-2.45). Change in the kyphosis angle was not associated with fall incidence.

Conclusions: Hyperkyphosis was associated with a higher fall incidence in the oldest quartile of a large prospective cohort of community-dwelling older adults. Because hyperkyphosis is a partially reversible condition, we recommend investigating whether hyperkyphosis is one of the causes of falls and whether a decrease in the kyphosis angle may contribute to fall prevention.
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http://dx.doi.org/10.1007/s00198-021-06136-6DOI Listing
September 2021

Effect of Interventions With a Clinical Decision Support System for Hospitalized Older Patients: Systematic Review Mapping Implementation and Design Factors.

JMIR Med Inform 2021 Jul 16;9(7):e28023. Epub 2021 Jul 16.

Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: Clinical decision support systems (CDSSs) form an implementation strategy that can facilitate and support health care professionals in the care of older hospitalized patients.

Objective: Our study aims to systematically review the effects of CDSS interventions in older hospitalized patients. As a secondary aim, we aim to summarize the implementation and design factors described in effective and ineffective interventions and identify gaps in the current literature.

Methods: We conducted a systematic review with a search strategy combining the categories older patients, geriatric topic, hospital, CDSS, and intervention in the databases MEDLINE, Embase, and SCOPUS. We included controlled studies, extracted data of all reported outcomes, and potentially beneficial design and implementation factors. We structured these factors using the Grol and Wensing Implementation of Change model, the GUIDES (Guideline Implementation with Decision Support) checklist, and the two-stream model. The risk of bias of the included studies was assessed using the Cochrane Collaboration's Effective Practice and Organisation of Care risk of bias approach.

Results: Our systematic review included 18 interventions, of which 13 (72%) were effective in improving care. Among these interventions, 8 (6 effective) focused on medication review, 8 (6 effective) on delirium, 7 (4 effective) on falls, 5 (4 effective) on functional decline, 4 (3 effective) on discharge or aftercare, and 2 (0 effective) on pressure ulcers. In 77% (10/13) effective interventions, the effect was based on process-related outcomes, in 15% (2/13) interventions on both process- and patient-related outcomes, and in 8% (1/13) interventions on patient-related outcomes. The following implementation and design factors were potentially associated with effectiveness: a priori problem or performance analyses (described in 9/13, 69% effective vs 0/5, 0% ineffective interventions), multifaceted interventions (8/13, 62% vs 1/5, 20%), and consideration of the workflow (9/13, 69% vs 1/5, 20%).

Conclusions: CDSS interventions can improve the hospital care of older patients, mostly on process-related outcomes. We identified 2 implementation factors and 1 design factor that were reported more frequently in articles on effective interventions. More studies with strong designs are needed to measure the effect of CDSS on relevant patient-related outcomes, investigate personalized (data-driven) interventions, and quantify the impact of implementation and design factors on CDSS effectiveness.

Trial Registration: PROSPERO (International Prospective Register of Systematic Reviews): CRD42019124470; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=124470.
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http://dx.doi.org/10.2196/28023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325084PMC
July 2021

Appropriate deprescribing in older people: a challenging necessityCommentary to accompany themed collection on deprescribing.

Age Ageing 2021 09;50(5):1516-1519

Cerebral Haemodynamics in Ageing and Stroke Medicine (CHiASM) Research Group, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Older people are often taking several medications for a number of different medical conditions. Although physicians prescribe medications to treat diseases and symptoms, there may be also harmful side effects, especially so in older people taking several medications. Unfortunately, regular review of the benefits or risks of prescribed medications is as of yet not part of standard care. Also, data on how and in whom to stop medications in older people are scarce. The reason this is an important area of work is that medication related issues in older people are a common cause of harm, including both expected and unexpected effects of medications. Research to date tells us that to ensure successful implementation of structured and appropriate deprescribing, careful planning within hospital systems is needed. This includes involving different members of the team to ensure the patients truly benefit. The themed collection published on the Age and Ageing journal website offers key articles providing tools to assist decision-making, implementation strategies and multidisciplinary interventions-all with the aim of improving patient outcome and sustainability of deprescribing approaches.
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http://dx.doi.org/10.1093/ageing/afab142DOI Listing
September 2021

A Propensity Score Matched Approach to Assess the Associations of Commonly Prescribed Medications with Fall Risk in a Large Harmonized Cohort of Older Ambulatory Persons.

Drugs Aging 2021 09 5;38(9):797-805. Epub 2021 Jul 5.

Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

Introduction: Several medication classes are considered to present risk factors for falls. However, the evidence is mainly based on observational studies that often lack adequate adjustment for confounders. Therefore, we aimed to assess the associations of medication classes with fall risk by carefully selecting confounders and by applying propensity score matching (PSM).

Methods: Data from several European cohorts, harmonized into the ADFICE_IT cohort, was used. Our primary outcome was time until the first fall within 1-year follow-up. The secondary outcome was a fall in the past year. Our exposure variables were commonly prescribed medications. We used 1:1 PSM to match the participants with reported intake of specific medication classes with participants without. We constructed Cox regression models stratified by the pairs matched on the propensity score for our primary outcome and conditional logistic regression models for our secondary outcome.

Results: In total, 32.6% of participants fell in the 1-year follow-up and 24.4% reported falling in the past year. ACE inhibitor users (prevalence of use 15.3%) had a lower fall risk during follow-up when matched to non-users, with a hazard ratio (HR) of 0.82 (95% CI 0.68-0.98). Also, statin users (prevalence of use 20.1%) had a lower risk, with an HR of 0.76 (95% CI 0.65-0.90). Other medication classes showed no association with risk of first fall. Also, in our secondary outcome analyses, statin users had a significantly lower risk. Furthermore, β-blocker users had a lower fall risk and proton pump inhibitor use was associated with a higher risk in our secondary outcome analysis.

Conclusion: Many commonly prescribed medication classes showed no associations with fall risk in a relatively healthy population of community-dwelling older persons. However, the treatment effects and risks can be heterogeneous between individuals. Therefore, focusing on identification of individuals at risk is warranted to optimize personalized falls prevention.
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http://dx.doi.org/10.1007/s40266-021-00876-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419131PMC
September 2021

Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density.

J Endocr Soc 2021 Aug 15;5(8):bvab092. Epub 2021 May 15.

Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME 04101, USA.

Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects.

Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study.

Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD.

Results: One variation (rs11124190 in ) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings.

Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.
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http://dx.doi.org/10.1210/jendso/bvab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237849PMC
August 2021

Patterns of discordance of physical functioning in older persons; different associations for apathy and depression? Results from the NESDO-study.

Aging Ment Health 2021 Jun 14:1-9. Epub 2021 Jun 14.

Department of Epidemiology & Biostatistics, Medical Faculty Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Objectives: Discordance between self-reported functional limitations and performance-based physical functioning may have a negative impact in functional independence in older adults. We longitudinally examined baseline apathy- and depressive symptomatology as associates of discordance.

Method: 469 participants from the multi-site cohort study NESDO were included. Self-reported functional limitations were assessed by two items derived from the WHO-Disability Assessment Schedule. Performance-based physical functioning included walking speed and handgrip-strength. Both measures were rescaled, with final sum-scores ranging from 0 to 6. Discordance-scores were computed by subtracting sum-scores on performance-based measures from self-reported functional limitations. Using latent growth curve analysis, we estimated individual trajectories of discordance at baseline, 2-and 6-years follow-up, consisting of the baseline discordance-score (intercept) and the yearly change of discordance-score (slope). We then estimated associations with apathy and depression indicators.

Results: At baseline, persons (mean age 70.48 years, 65% female, 73% depressed) on average overestimated their daily functioning compared to performance tests ( = 0.77,  < 0.001). The average discordance-scores yearly increased by 0.15 ( < 0.001). Only in models adjusted for several demographic and clinical characteristics, depression severity was negatively associated with discordance-scores at baseline (-0.01,  = 0.02), while apathy was not (-0.02,  = 0.21). No associations with change over time were found.

Conclusion: In older persons, not indifference and diminished goal-directed activity, but negative emotions appear to underlie underestimation of one's physical capacity. Further research is needed to determine (1) to what extent targeting discordance results in actual preservation of physical functioning and (2) whether older persons with apathy and/or depression need different approaches for this purpose.
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http://dx.doi.org/10.1080/13607863.2021.1932738DOI Listing
June 2021

Barriers and facilitators influencing medication-related CDSS acceptance according to clinicians: A systematic review.

Int J Med Inform 2021 08 21;152:104506. Epub 2021 May 21.

Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: A medication-related Clinical Decision Support System (CDSS) is an application that analyzes patient data to provide assistance in medication-related care processes. Despite its potential to improve the clinical decision-making process, evidence shows that clinicians do not always use CDSSs in such a way that their potential can be fully realized. This systematic literature review provides an overview of frequently-reported barriers and facilitators for acceptance of medication-related CDSS.

Materials And Methods: Search terms and MeSH headings were developed in collaboration with a librarian, and database searches were conducted in Medline, Scopus, Embase and Web of Science Conference Proceedings. After screening 5404 records and 140 full papers, 63 articles were included in this review. Quality assessment was performed for all 63 included articles. The identified barriers and facilitators are categorized within the Human, Organization, Technology fit (HOT-fit) model.

Results: A total of 327 barriers and 291 facilitators were identified. Results show that factors most often reported were related to (a lack of) usefulness and relevance of information, and ease of use and efficiency of the system.

Discussion: This review provides a valuable insight into a broad range of barriers and facilitators for using a medication-related CDSS as perceived by clinicians. The results can be used as a stepping stone in future studies developing medication-related CDSSs.
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http://dx.doi.org/10.1016/j.ijmedinf.2021.104506DOI Listing
August 2021

New horizons in falls prevention and management for older adults: a global initiative.

Age Ageing 2021 09;50(5):1499-1507

Centre for Innovation in Medical Engineering (CIME), Faculty of Engineering, University of Malaya, Kuala Lumpur, Malaysia.

Background: falls and fall-related injuries are common in older adults, have negative effects both on quality of life and functional independence and are associated with increased morbidity, mortality and health care costs. Current clinical approaches and advice from falls guidelines vary substantially between countries and settings, warranting a standardised approach. At the first World Congress on Falls and Postural Instability in Kuala Lumpur, Malaysia, in December 2019, a worldwide task force of experts in falls in older adults, committed to achieving a global consensus on updating clinical practice guidelines for falls prevention and management by incorporating current and emerging evidence in falls research. Moreover, the importance of taking a person-centred approach and including perspectives from patients, caregivers and other stakeholders was recognised as important components of this endeavour. Finally, the need to specifically include recent developments in e-health was acknowledged, as well as the importance of addressing differences between settings and including developing countries.

Methods: a steering committee was assembled and 10 working Groups were created to provide preliminary evidence-based recommendations. A cross-cutting theme on patient's perspective was also created. In addition, a worldwide multidisciplinary group of experts and stakeholders, to review the proposed recommendations and to participate in a Delphi process to achieve consensus for the final recommendations, was brought together.

Conclusion: in this New Horizons article, the global challenges in falls prevention are depicted, the goals of the worldwide task force are summarised and the conceptual framework for development of a global falls prevention and management guideline is presented.
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http://dx.doi.org/10.1093/ageing/afab076DOI Listing
September 2021

Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density.

Am J Clin Nutr 2021 08;114(2):578-587

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Background: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine β-synthase (CBS).

Objectives: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength.

Methods: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing.

Results: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified.

Conclusions: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength.  These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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http://dx.doi.org/10.1093/ajcn/nqab093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326042PMC
August 2021

International Validation of the Turkish Inappropriate Medication Use in the Elderly (TIME) Criteria Set: A Delphi Panel Study.

Drugs Aging 2021 06 13;38(6):513-521. Epub 2021 Apr 13.

Section of Geriatrics, Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.

Objective: Explicit screening tools and implicit evaluation methods have been developed to assist healthcare professionals in the management of pharmacotherapy in older adults. As prescribing habits and locally available medications vary considerably between countries, guides tailored to the needs of specific regions may be required. We aimed to report the results of the international Delphi validation study for the Turkish Inappropriate Medication use in the Elderly (TIME) criteria set, which aims to detect inappropriate prescribing in older adults in Eastern Europe.

Methods: The study was conducted between June 2019 and March 2020. Delphi rounds were conducted by the TIME international working group, which included 11 internationally recognized experts in geriatric pharmacotherapy as Delphi panelists. They were asked to indicate to what extent they agreed or disagreed with each TIME criterion, taking into account both the available evidence and their own experience. We used a five-point Likert scale from 1 (strongly agree) to 5 (strongly disagree) and an online software program (SurveyMonkey) to grade the level of agreement. Criteria with a median value of 1 or 2 and a 75th centile value of 1 or 2 were accepted, and criteria with a median value > 2 were rejected. Those with a median value of 1 or 2 but a 75th centile value > 2 were retained, to be assessed in the following round. The initial list of Delphi criteria comprised 153 TIME items.

Results: After three Delphi rounds, 134 criteria were accepted and seven criteria were rejected, while 12 criteria did not achieve consensus, and so were not included in the final validated set of TIME criteria.

Conclusion: We developed the internationally validated TIME criteria set based on a Delphi process involving international experts. The validation study suggests that the TIME criteria set can be applied in both central and Eastern European settings. Further studies are needed to assess the utility and benefit of the TIME criteria in reducing inappropriate drug use and improving clinical outcomes.
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http://dx.doi.org/10.1007/s40266-021-00855-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041618PMC
June 2021

Can Fall Risk Screening and Fall Prevention Advice in Hospital Settings Motivate Older Adult Patients to Take Action to Reduce Fall Risk?

J Appl Gerontol 2021 Apr 2:7334648211004037. Epub 2021 Apr 2.

Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Objective: We investigated whether an in-hospital intervention consisting of fall risk screening and tailored advice could prompt patients to take preventive action.

Method: Patients (≥70) attending the emergency department and nephrology outpatient clinic in a Dutch hospital were screened. Patients at high risk received tailored advice based on their individual risk factors. Three months after screening, preventive steps taken by patients were surveyed.

Results: Two hundred sixteen patients were screened. Of the 83 patients completing a 3-month follow-up, 51.8% took action; among patients who received tailored advice ( = 20), 70% took action. Patients most often adhered to advice on improving muscle strength and undergoing vision checkups (20%). Tailored advice and a reported low quality of life were associated with consulting a health care provider.

Discussion: Patients at risk in these settings are inclined to take action after screening. However, they do not always adhere to the tailored prevention advice.
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http://dx.doi.org/10.1177/07334648211004037DOI Listing
April 2021

Does Late-Life Depression Counteract the Beneficial Effect of Physical Activity on Cognitive Decline? Results From the NESDO Study.

J Geriatr Psychiatry Neurol 2021 Apr 1:8919887211002658. Epub 2021 Apr 1.

LUMC, Leiden, Zuid-Holland, Netherlands.

Objectives: Depression both affects physical activity (PA) and cognition in older persons, yet its impact on the association between PA and cognitive decline is to be determined. We aimed to investigate the association between baseline PA and cognitive functioning over time, stratified for depression.

Methods: We used data of the Netherlands Study of Depression in Older persons (NESDO), a multi-site cohort study with 6-years follow-up. Patients with complete data on PA and cognitive functioning at baseline were included, yielding 394 participants for the analyses of whom 297 were depressed and 97 non-depressed. PA (continuous) was measured with the International Physical Activity Questionnaire. Linear mixed models were used to determine differential effects of baseline PA on the rate of decline of 5 standardized outcomes of cognitive functioning over 6-year follow-up. For this purpose, we examined the significance of the interaction-term (PA*time) in both basic and adjusted models. We also assessed the association between time and cognitive functioning. All analyses were stratified for depression.

Results: In both groups, no robust significant interactions of PA with time were found. Furthermore, only decline in working memory was significantly worse in the depressed compared to the non-depressed.

Conclusion: At older age, the impact of a more inactive lifestyle on cognitive decline was shown to be limited, irrespective of depression that appeared to worsen age-related decline of working memory only. As a higher PA-level at older age has a positive effect on a multitude of other health outcomes, PA should still be encouraged in this population.
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http://dx.doi.org/10.1177/08919887211002658DOI Listing
April 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk): a Delphi study by the EuGMS Task and Finish Group on Fall-Risk-Increasing Drugs.

Age Ageing 2021 06;50(4):1189-1199

Department of Internal Medicine, Section of Geriatric Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group.

Methods: STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed.

Results: The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes.

Conclusion: STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.
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http://dx.doi.org/10.1093/ageing/afaa249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244563PMC
June 2021

Potentially inappropriate prescribing in older hospitalized Dutch patients according to the STOPP/START criteria v2: a longitudinal study.

Eur J Clin Pharmacol 2021 May 2;77(5):777-785. Epub 2020 Dec 2.

Amsterdam UMC, Department of Medical Informatics, Amsterdam Public Health Research Institute, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Purpose: To investigate prevalence, independent associations, and variation over time of potentially inappropriate prescriptions in a population of older hospitalized patients.

Methods: A longitudinal study using a large dataset of hospital admissions of older patients (≥ 70 years) based on an electronic health records cohort including data from 2015 to 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) prevalence during hospital stay were identified based on the Dutch STOPP/START criteria v2. Univariate and multivariate logistic regression were used for analyzing associations and trends over time.

Results: The data included 16,687 admissions. Of all admissions, 56% had ≥ 1 PIM and 58% had ≥ 1 PPO. Gender, age, number of medications, number of diagnoses, Charlson score, and length of stay were independently associated with both PIMs and PPOs. Additionally, number of departments and number of prescribing specialties were independently associated with PIMs. Over the years, the PIM prevalence did not change (OR = 1.00, p = .95), whereas PPO prevalence increased (OR = 1.08, p < .001). However, when corrected for changes in patient characteristics such as number of diagnoses, the PIM (aOR = 0.91, p < .001) and PPO prevalence (aOR = 0.94, p < .001) decreased over the years.

Conclusion: We found potentially inappropriate prescriptions in the majority of admissions of older patients. Prescribing relatively improved over time when considering complexity of the admissions. Nevertheless, the high prevalence shows a clear need to better address this issue in clinical practice. Studies seeking effective (re)prescribing interventions are warranted.
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http://dx.doi.org/10.1007/s00228-020-03052-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032616PMC
May 2021

Genetic basis of falling risk susceptibility in the UK Biobank Study.

Commun Biol 2020 09 30;3(1):543. Epub 2020 Sep 30.

Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual's fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (P ≤ 5 × 10). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics.
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http://dx.doi.org/10.1038/s42003-020-01256-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527955PMC
September 2020

Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial.

Clin Nutr 2021 03 5;40(3):1199-1206. Epub 2020 Aug 5.

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands; Amsterdam UMC, (University) of Amsterdam, Section of Geriatric Medicine, Department of Internal Medicine, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Background & Aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk.

Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 μg) and vitamin-B12 (500 μg) versus placebo (n = 2,919). Primary outcome was verified self-reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease.

Results: A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic- and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 μmol/l). No age-dependent effects were present.

Conclusions: This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated.
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http://dx.doi.org/10.1016/j.clnu.2020.07.033DOI Listing
March 2021

Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials.

Eur J Clin Pharmacol 2021 Jan 7;77(1):1-12. Epub 2020 Aug 7.

Internal Medicine Department 7.2, Hospital Curry Cabral - Centro Hospitalar Universitário Lisboa Central, EPE, Lisbon, Portugal.

Background: Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty.

Methods: A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019.

Results: Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty.

Conclusion: So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.
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http://dx.doi.org/10.1007/s00228-020-02951-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197722PMC
January 2021

Research with older people in a world with COVID-19: identification of current and future priorities, challenges and opportunities.

Age Ageing 2020 10;49(6):901-906

AGE Research Group, Translational and Clinical Research Institute, Biomedical Research Building, Campus for Ageing & Vitality, NIHR Newcastle Biomedical Research Centre, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Older people are disproportionately affected by the COVID-19 pandemic, which has had a profound impact on research as well as clinical service delivery. This commentary identifies key challenges and opportunities in continuing to conduct research with and for older people, both during and after the current pandemic. It shares opinions from responders to an international survey, a range of academic authors and opinions from specialist societies. Priorities in COVID-19 research include its specific presentation in older people, consequences for physical, cognitive and psychological health, treatments and vaccines, rehabilitation, supporting care homes more effectively, the impact of social distancing, lockdown policies and system reconfiguration to provide best health and social care for older people. COVID-19 research needs to be inclusive, particularly involving older people living with frailty, cognitive impairment or multimorbidity, and those living in care homes. Non-COVID-19 related research for older people remains of critical importance and must not be neglected in the rush to study the pandemic. Profound changes are required in the way that we design and deliver research for older people in a world where movement and face-to-face contact are restricted, but we also highlight new opportunities such as the ability to collaborate more widely and to design and deliver research efficiently at scale and speed.
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http://dx.doi.org/10.1093/ageing/afaa149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454250PMC
October 2020

Impact of Altering Data Granularity Levels on Predictive Modelling: A Case Study of Fall Risk Prediction in Older Persons.

Stud Health Technol Inform 2020 Jun;270:257-261

Amsterdam UMC, University of Amsterdam, Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam, Netherlands.

Classification systems are widely used in medicine for knowledge representation. The hierarchical relationships between concepts in a classification system can be exploited in prediction models by looking for the optimal predictive granularity level. In this study, we used the Anatomical Therapeutic Chemical (ATC) classification system to cluster medications in the context of predicting medication-related falls in older persons. We compared the performance of fall risk prediction by describing medications at varying granularity levels of the ATC classification system. We found that the level of abstraction significantly affects the predictive performance in terms of both discrimination (measured by the receiver operating characteristic curve AUC-ROC) and calibration. An implication of these findings to the researchers is that data representation at different granularity levels can influence the predictive performance. The optimal granularity level can be determined by experimentation.
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http://dx.doi.org/10.3233/SHTI200162DOI Listing
June 2020

The impact of thiazide diuretics on bone mineral density and the trabecular bone score: the Rotterdam Study.

Bone 2020 09 9;138:115475. Epub 2020 Jun 9.

Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands.

The decreased risk of osteoporotic fractures in thiazide diuretics (TD) users is possibly not only caused by an increase in bone mineral density (BMD), but by an increase in other determinants of bone strength as well, such as the trabecular bone score (TBS). To test this hypothesis, we studied the association between TD use and both lumbar spine BMD (LS-BMD) and lumbar spine TBS (LS-TBS) cross-sectionally in 6096 participants from the Rotterdam Study, as well as the association between TD use and bone turnover estimated by serum osteocalcin levels. We found that past and current use of TD were associated with an increase of LS-BMD (β = 0.021 g/cm (95% CI: 0.006;0.036) and β = 0.016 g/cm (95% CI: 0.002;0.031), respectively). Use of ≥1 defined daily dose (DDD) (β = 0.028, 95% CI: 0.010;0.046; p for trend within DDD of use <0.001) and use of >365 days (β = 0.033, 95% CI: 0.014;0.052; p for trend within duration of use <0.001) were positively associated with LS-BMD. No significant association between TD use and LS-TBS was observed. Mean serum osteocalcin levels were significantly different between users and non-users of TD (20.2 ng/ml (SD 8.3) and 22.5 ng/ml (SD 17.0), respectively, p < 0.001). Furthermore, linear regression analysis showed that the use of TD was associated with a 3.2 ng/l (95% CI: -4.4.; -2.0) lower serum osteocalcin level compared to non-use of TD, when adjusted for Rotterdam Study cohort, age, and sex. Our results may implicate that the decreased fracture risk in TD users is explained by increased bone mass rather than by improved bone microarchitecture. Alternatively, changes in bone microarchitecture might not be detected through TBS and more sophisticated techniques are possibly needed to study a potential effect of TD on bone microarchitecture.
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http://dx.doi.org/10.1016/j.bone.2020.115475DOI Listing
September 2020

Translation of mouse model to human gives insights into periodontitis etiology.

Sci Rep 2020 03 17;10(1):4892. Epub 2020 Mar 17.

Department of Clinical. Microbiology and Immunology, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10) and RNASE2 (rs2771342, P = 2.84×10) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA-DQH1 (rs9271850, P = 2.52×10) and HLA-DPA1 (rs17214512, P = 5.14×10). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.
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http://dx.doi.org/10.1038/s41598-020-61819-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078197PMC
March 2020

Orthostatic Drop in Diastolic but Not Systolic Blood Pressure Is Associated With Fear of Falling in Older Fallers.

J Am Med Dir Assoc 2020 03 6;21(3):429-431. Epub 2020 Jan 6.

Section of Geriatric Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.jamda.2019.11.030DOI Listing
March 2020

Psychosocial and Health-Related Factors Associated With Discordance Between 13-Year Trajectories of Self-Reported Functional Limitations and Performance-Based Physical Functioning in Old Age.

J Aging Health 2020 10 5;32(9):1084-1097. Epub 2019 Nov 5.

Amsterdam UMC-Vrije Universiteit Amsterdam, The Netherlands.

The objective of this study was to examine correlates of discordance between 13-year trajectories of self-reported functional limitations and performance-based physical functioning in older adults. We included 2,135 participants from the population-based Longitudinal Aging Study Amsterdam, the Netherlands, followed across 1995-2008. Self-reported functional limitations included six (instrumental) activities of daily living. Performance-based functioning was a composite of four tests. We used latent class growth analysis and multinomial logistic regression to examine discordance and its correlates. Patterns of discordance and concordance (41% concordance, 46% "overestimation" of daily functioning, 13% "underestimation") appeared to be persistent over 13 years. Older age, male sex, cognitive impairment, absence of pain, and light alcohol use were associated with overestimation. Younger age, female sex, and lower self-rated health were associated with underestimation. Factors associated with overestimation partly differ from those associated with underestimation. Factors that are highly stable over time are particularly good indicators of persistent discordance.
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http://dx.doi.org/10.1177/0898264319884404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731649PMC
October 2020

Do Vitamin D Level and Dietary Calcium Intake Modify the Association Between Loop Diuretics and Bone Health?

Calcif Tissue Int 2020 02 14;106(2):104-114. Epub 2019 Oct 14.

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002-2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20-50 nmol/l (β = - 0.036, 95% CI - 0.060; - 0.013 vs. β = - 0.012, 95% CI - 0.036; 0.013 and β = - 0.031, 95% CI - 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake.
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http://dx.doi.org/10.1007/s00223-019-00621-1DOI Listing
February 2020

Value of a comprehensive geriatric assessment for predicting one-year outcomes in patients undergoing transcatheter aortic valve implantation: results from the CGA-TAVI multicentre registry.

J Geriatr Cardiol 2019 Jun;16(6):468-477

Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: In a three-month report from the CGA-TAVI registry, we found the Multidimensional Prognostic Index (MPI) and Short Physical Performance Battery (SPPB) to be of value for predicting short-term outcomes in elderly patients undergoing transcatheter aortic valve implantation (TAVI). In the present analysis, we examined the association of these tools with outcomes up to one year post-TAVI.

Methods: CGA-TAVI is an international, observational registry of geriatric patients undergoing TAVI. Patients were assessed using the MPI and SPPB. Efficacy of baseline values and any postoperative change for predicting outcome were established using logistic regression. Kaplan-Meier analysis was carried out for each comprehensive geriatric assessment tool, with survival stratified by risk category.

Results: One year after TAVI, 14.1% of patients deceased, while 17.4% met the combined endpoint of death and/or non-fatal stroke, and 37.7% the combined endpoint of death and/or hospitalisation and/or non-fatal stroke. A high-risk MPI score was associated with an increased risk of all-cause mortality (aOR = 36.13, 95% CI: 2.77-470.78, = 0.006) and death and/or non-fatal stroke (aOR = 10.10, 95% CI: 1.48-68.75, = 0.018). No significant associations were found between a high-risk SPPB score and mortality or two main combined endpoints. In contrast to a worsening SPPB, an aggravating MPI score at three months post-TAVI was associated with an increased risk of death and/or non-fatal stoke at one year (aOR = 95.16, 95% CI: 3.41-2657.01).

Conclusions: The MPI showed value for predicting the likelihood of death and a combination of death and/or non-fatal stroke by one year after TAVI in elderly patients.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612614PMC
June 2019

Melatonin, temazepam and placebo in hospitalised older patients with sleeping problems (MATCH): a study protocol of randomised controlled trial.

BMJ Open 2019 05 22;9(5):e025514. Epub 2019 May 22.

Department of Geriatric Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Introduction: Hospitalised older patients frequently suffer from inadequate sleep, which can lead to patient distress and delayed recovery from acute illness or surgical procedure. Currently, no evidence-based treatments exist for sleeping problems in hospitalised older patients. Benzodiazepines, such as temazepam, are regularly prescribed by physicians, although they have serious side effects; for older patients in particular. Melatonin is proposed as a safe alternative for sleeping problems in hospitalised older patients, but the efficacy of melatonin is unclear in this population. Therefore, the aim of this study is to investigate the effects of melatonin and temazepam compared with placebo on sleep quality among hospitalised older patients with sleeping problems.

Methods And Analysis: This study is a multicentre, randomised, placebo-controlled trial. A total of 663 patients will be randomised in a 1:1:1 fashion to receive either melatonin (n=221), temazepam (n=221) or placebo (n=221). The study population consists of hospitalised patients aged 60 years and older, with new or aggravated sleeping problems for which an intervention is needed. The primary outcome is sleep quality measured with the Leeds Sleep Evaluation Questionnaire (LSEQ). Secondary outcomes include sleep parameters measured with actigraphy and medication-related adverse effects.

Ethics And Dissemination: This study was approved by the Medical Ethics Committee of the Academic Medical Centre Amsterdam, (No 2015_302). Study findings will be disseminated through presentations at professional and scientific conferences and publications in peer-reviewed journals.

Trial Registration Number: NTR6908; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537975PMC
May 2019

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Nat Commun 2019 05 15;10(1):2176. Epub 2019 May 15.

School of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, 2000, South Africa.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.
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http://dx.doi.org/10.1038/s41467-019-09976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520353PMC
May 2019
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