Little evidence exists on the impact of diabetes risk scores, e.g. on physicians and patient's behavior, perceived risk of persons, shared-decision making and particularly on patient's health. The ...aim of this study is to investigate the impact of a non-invasive type 2 diabetes risk prediction model in the primary health care setting as component of routine health checks on change in physical activity.
Parallel group cluster randomized controlled trial including 30 primary care physicians (PCPs) and 300 participants in the region of Düsseldorf and surrounding urban and rural municipalities, West Germany. On cluster level, PCPs will be randomized into intervention or control group using a biased coin minimization technique. Participants in the control group are going to have a routine health check "Check-up 35" which is recommended biannually for all people ≥35 years of age in Germany. In the intervention group, the routine health check is expanded by usage of a non-invasive diabetes risk prediction model (German Diabetes Risk Score). Primary outcome is change in physical activity after 1 year. Secondary outcomes include aspects of targeted counseling, motivation of participant's to change lifestyle, perceived and objectively measured diabetes risk, acceptance of diabetes risk scores, quality of life, depression and anxiety. Patients will be followed over 12 months. Hierarchical or mixed models will be conducted, including a random intercept to adjust for cluster, the respective baseline value, and covariates to compare the groups.
This pragmatic cluster randomized controlled trial will enhance our knowledge on the clinical impact of diabetes risk scores for the first time in the real-life primary health care setting.
ClinicalTrials.gov NCT03234322 , registered on July 28, 2017.
There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the ...disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking.
To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset.
This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months.
Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system.
The primary end point was the achievement of motor milestones.
A total of 234 children (123 52.6% female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%).
This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group.
German Clinical Trials Register: DRKS00012699.
Zusammenfassung
Hintergrund
In den letzten Jahren wird verstärkt gefordert, Forschungsdaten gemäß den sog. FAIR-Prinzipien für eine Nachnutzung aufzubereiten. Dadurch könnten zukünftige Projekte auf ...einer breiteren Datengrundlage durchgeführt sowie durch Verknüpfung verschiedener Datenquellen neue Fragestellungen untersucht werden.
Fragestellung
Eruiert werden soll, inwieweit Abrechnungsdaten gesetzlicher Krankenversicherungen mit den Daten der Landeskrebsregister (LKR) überregional verknüpft werden können, um die in den Abrechnungsdaten fehlenden Informationen zu Krebserkrankungen ergänzen und die Validität der dortigen Angaben zur Tumordiagnose beurteilen zu können. Der Fokus liegt dabei auf der Beschreibung der länderspezifischen Anforderungen für einen solchen Datenabgleich.
Material und Methoden
Als Datenquellen wurden die Pharmakoepidemiologische Forschungsdatenbank GePaRD des Leibniz-Instituts für Präventionsforschung und Epidemiologie – BIPS und sechs Krebsregister herangezogen. Zur Verknüpfung wurden vergleichend das logistisch aufwendige direkte Linkage- und ein weniger aufwendiges indirektes Linkage-Verfahren angewandt. Dazu mussten für GePaRD und für jedes LKR die Genehmigungen der jeweils zuständigen Behörde eingeholt werden.
Ergebnisse
Hinsichtlich der Verknüpfung von LKR-Daten mit GePaRD zeigten sich gravierende Unterschiede in der Datenbereitstellung (vollständige Ablehnung bis hin zu einer unkomplizierten Umsetzung).
Diskussion
In Deutschland müssen einheitliche Rahmenbedingungen geschaffen werden, um eine angemessene Nachnutzung und eine Verknüpfung von personenbezogenen Gesundheitsdaten zu Forschungszwecken im Sinne der FAIR-Prinzipien zu ermöglichen. Bezüglich der Verknüpfung von LKR-Daten mit anderen Datenquellen könnte das neue Gesetz zur Zusammenführung von Krebsregisterdaten Abhilfe schaffen.
In recent years, there has been an increasing demand for the reuse of research data in accordance with the so-called FAIR principles. This would allow researchers to conduct projects on a broader ...data basis and to investigate new research questions by linking different data sources.
We explored if nationwide linking of claims data from statutory health insurances (SHI) with data from population-based cancer registries can be used to obtain additional information on cancer that is missing in claims data and to assess the validity of SHI tumour diagnoses. This paper focuses on describing the specific requirements of German federal states for such data linkage.
The Pharmacoepidemiological Research Database GePaRD at the Leibniz Institute for Prevention Research and Epidemiology - BIPS and six cancer registries were used as data sources. The logistically complex direct linkage was compared with a less complex indirect linkage. For this purpose, permission had to be obtained for GePaRD and for each cancer registry from the respective responsible authority.
Regarding the linkage of cancer registry data with GePaRD, the cancer registries showed profound differences in the modalities for data provision, ranging from a complete rejection to an uncomplicated implementation of linkage procedures.
In Germany, a consistent legal framework is needed to adequately enable the reuse and record linkage of personal health data for research purposes according to the FAIR principles. The new law on the consolidation of cancer registry data could provide a remedy regarding the linkage of cancer registry data with other data sources.
Abstract
Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels ...and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.
As a rule, acetylides and sulfonyl azides do not undergo electrophilic azide transfer because 1,2,3‐triazoles are usually formed. We show now that treatment of tritylethyne with butyllithium followed ...by exposure to 2,4,6‐triisopropylbenzenesulfonyl azide leads to products that are easily explained through the generation of short‐lived tritylethynyl azide and its secondary product cyanotritylcarbene. Furthermore, it is demonstrated that tritylcarbenes generally do not produce triphenylethenes exclusively, as was stated in the literature. Instead, these carbenes always yielded also (diphenylmethylidene)cycloheptatrienes (heptafulvenes) as side products. This result is supported by static DFT, coupled cluster, and ab initio molecular dynamics calculations. From these investigations, the fused bicyclobutane intermediate was found to be essential for heptafulvene formation. Although the bicyclobutane is also capable of rearranging to the triphenylethene product, only the heptafulvene pathway is reasonable from the energetics. The ethene is formed straight from cyanotritylcarbene.
A bit on the side: Tritylcarbenes do not produce triphenylethenes exclusively; in a side reaction, heptafulvenes are generated via a fused bicyclobutane (see scheme). The latter is not an intermediate in the formation of the triphenylethene, as shown by quantum chemistry.
Preclinical experiments on animal models are essential to understand the mechanisms of cardiovascular disease (CVD). Metabolomics allows access to the metabolic perturbations associated with CVD in ...heart and vessels. Here we assessed which potential animal CVD model most closely mimics the serum metabolite signature of increased carotid intima-media thickness (cIMT) in humans, a clinical parameter widely accepted as a surrogate of CVD.
A targeted mass spectrometry assay was used to quantify and compare a series of blood metabolites between 1362 individuals (KORA F4 cohort) and 5 animal CVD models: ApoE−/−, Ldlr−/−, and klotho-hypomorphic mice (kl/kl) and SHRSP rats with or without salt feeding. The metabolite signatures were obtained using linear regressions adjusted for various co-variates.
In human, increased cIMT quartile Q4 vs. Q1 was associated with 26 metabolites (9 acylcarnitines, 2 lysophosphatidylcholines, 9 phosphatidylcholines and 6 sphingomyelins). Acylcarnitines correlated preferentially with serum glucose and creatinine. Phospholipids correlated preferentially with cholesterol (total and LDL). The human signature correlated positively and significantly with Ldlr−/− and ApoE−/− mice, while correlation with kl/kl mice and SHRP rats was either negative and non-significant. Human and Ldlr−/− mice shared 11 significant metabolites displaying the same direction of regulation: 5 phosphatidylcholines, 1 lysophosphatidylcholines, 5 sphingomyelins; ApoE−/− mice shared 10.
The human cIMT signature was partially mimicked by Ldlr−/− and ApoE−/− mice. These animal models might help better understand the biochemical and molecular mechanisms involved in the vessel metabolic perturbations associated with, and contributing to metabolic disorders in CVD.
•Metabolomics allows access to the metabolic perturbations associated with cardiovascular disease (CVD).•Increased carotid intima-media thickness (cIMT) is a surrogate of CVD.•Human blood metabolite signature of increased cIMT is made of acylcarnitines and phospholipids.•LDLR−/− and ApoE−/− mice mimicked the phospholipid part of cIMT signature.
Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional ...epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = −0.0264,
p
value = 3.5 × 10
–8
) in the discovery panel and was replicated in replication panel (beta = −0.07,
p
value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (
AHRR
). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of
ALOX12
showed the strongest association with cIMT (
p
value = 1.4 × 10
–13
)
.
In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
Abstract Background Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher ...risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. Objective Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). Design Data of 1601 participants aged 50–81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and β-estimates (p-values), respectively. Results Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28–11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (β = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. Conclusions Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies.
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