Colorectal cancer screening with faecal immunochemical testing, sigmoidoscopy or colonoscopy: a microsimulation modelling study

OBJECTIVE: To estimate benefits and harms of different colorectal cancer screening strategies, stratified by (baseline) 15-year colorectal cancer risk. DESIGN: Microsimulation modelling study using MIcrosimulation SCreening ANalysis-Colon (MISCAN-Colon). SETTING: A parallel guideline committee (BMJ Rapid Recommendations) defined the time frame and screening interventions, including

Ultra-processed food consumption and associations with biomarkers of nutrition and inflammation in pregnancy: The Norwegian Environmental Biobank

BackgroundA high consumption of ultra-processed foods (UPFs) is often associated with low nutritional quality, but data on associations with biomarkers are scarce. We aimed to explore associations between UPF intake, diet quality, and concentrations of biomarkers of nutrition and inflammation measured in mid-pregnancy.MethodsThis cross-sectional study included n = 2,984 pregnant women recruited during 2002–2008 in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Concentrations of C-reactive protein (CRP) and 21 nutritional biomarkers including carotenes (α-carotene, β-carotene, γ-carotene, α-cryptoxanthin, β-cryptoxanthin, lutein, lycopene), vitamins [α-tocopherol, γ-tocopherol, 25-hydroxyvitamin D (25-OH-D), retinol], creatinine, elements (K, Na, Co, Cu, Mn, Mo, Se, Zn), and ferritin (Fe) were measured in blood and urine collected in mid-pregnancy. Habitual diet in pregnancy was assessed using a validated semi-quantitative food frequency questionnaire. We calculated the relative (%) energy contribution of UPF to overall intake according to the NOVA classification. We also applied a diet quality index (DQI) adapted to assess adherence to Norwegian dietary guidelines (DQI; min–max: 0–110, higher score meaning higher adherence). We present summary statistics for biomarker concentrations and explored associations between UPF intake or the DQI and measured biomarkers using adjusted linear, logistic, and generalized additive regression models.ResultsUltra-processed food intake was positively associated with biomarker concentrations of vitamin E (γ-tocopherol), creatinine, K, and Na [βs: 5.6 to 17% increase in biomarker concentration per interquartile range (IQR) increase in UPF intake] and negatively associated with carotenoids (α-carotene, β-carotene, γ-carotene, α-cryptoxanthin, β-cryptoxanthin, lutein, lycopene), vitamin A, Mo, and Se (βs: −2.1 to −18%). Inversely, high diet quality (i.e., the DQI) was positively associated with concentrations of carotenoids, vitamins [vitamin A (retinol) and D (25-OH-D)], and Se (β: 1.5 to 25%) and negatively associated with vitamin E (γ-tocopherol), creatinine, and Na (β: −4.8 to −8.3%). A weak, positive association was found between UPF and CRP (β: 5.4%, 95% CI 0.12–11%).ConclusionHigh UPF intake was associated with reduced concentrations of nutrition biomarkers in mid-pregnancy. Associations in the opposite direction were found with high adherence to the Norwegian dietary guidelines, suggesting that the two dietary scoring systems capture diet quality in a mirrored manner in this population

Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative

Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases

Socio-cultural determinants of adiposity and physical activity in preschool children: A cross-sectional study

BACKGROUND: Both individual socio-cultural determinants such as selected parental characteristics (migrant background, low educational level and workload) as well as the regional environment are related to childhood overweight and physical activity (PA). The purpose of the study was to compare the impact of distinct socio-cultural determinants such as the regional environment and selected parental characteristics on adiposity, PA and motor skills in preschool children. METHODS: Forty preschools (N = 542 children) of two culturally different urban regions (German and French speaking part of Switzerland) participated in the study (Ballabeina Study). Outcome measures included adiposity (BMI and skinfold thickness), objectively measured sedentary activities and PA (accelerometers) and agility performance (obstacle course). Parental characteristics (migrant status, educational level and workload) were assessed by questionnaire. RESULTS: Children from the French speaking areas had higher adiposity, lower levels of total and of more intense PA, were more sedentary and less agile than children from the German speaking regions (percent differences for all outcome parameters except for BMI ≥10%; all p ≤ 0.04). Differences in skinfold thickness, sedentary activities and agility, but not in PA, were also found between children of Swiss and migrant parents, though they were ≤8% (p ≤ 0.02). While paternal workload had no effect, maternal workload and parental education resulted in differences in some PA measures and/or agility performance (percent differences in both: ≤9%, p ≤ 0.008), but not in adiposity or sedentary activities (p = NS). Regional differences in skinfold thickness, PA, sedentary activities and agility performance persisted after adjustment for parental socio-cultural characteristics, parental BMI and, where applicable, children's skinfolds (all p ≤ 0.01). CONCLUSIONS: The regional environment, especially the broader social environment, plays a prominent role in determining adiposity, PA and motor skills of young children and should be implicated in the prevention of obesity and promotion of PA in children

Framework and baseline examination of the German National Cohort (NAKO)

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19–74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2–3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4–5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10654-022-00890-5

Coronavirus-Pandemie: Die Feiertage und den Jahreswechsel für einen harten Lockdown nutzen : 7. Ad-hoc-Stellungnahme zr Coronavirus-Pandemie - 08.Dezember 2020

Die gegenwärtige Situation ist nach wie vor ernst und droht sich weiter zu verschärfen. Trotz des seit Anfang November in Deutschland geltenden Teil-Lockdowns sind die Infektionszahlen auf einem sehr hohen Niveau. Jeden Tag sterben mehrere Hundert Menschen. Die Krankenhäuser und insbesondere das medizinische Personal sind bereits jetzt an ihren Grenzen und die Gesundheitsämter überlastet. Um die Kontrolle über das Infektionsgeschehen zurückzuerlangen, empfiehlt die Nationale Akademie der Wissenschaften Leopoldina in der Ad-hoc-Stellungnahme „Coronavirus-Pandemie: Die Feiertage und den Jahreswechsel für einen harten Lockdown nutzen“ ein zweistufiges Vorgehen. Die Rahmenbedingungen ‒ Weihnachtsferien in Bildungseinrichtungen und eingeschränkter Betrieb in vielen Unternehmen und Behörden – bieten die Chance, in der Eindämmung der Pandemie ein großes Stück voranzukommen

Streptomyces coelicolor A3(2) plasmid SCP2* : deductions from the complete sequence

SCP2 war das erste aus Streptomyces coelicolor A3(2) isolierte zirkuläre Plasmid, ein Fertilitätsfaktor ähnlich dem F-Plasmid aus Escherichia coli mit einer Kopienzahl von eins bis vier Plasmiden pro Chromosom. Das in dieser Arbeit untersuchte SCP2*-Plasmid ist ein spontan aufgetretenes Derivat von SCP2, welches sich durch erhöhte Fertilität und Mobilisierung chromosomaler DNA auszeichnet. Beide Plasmide sind seit langem Grundlage wichtiger Vektoren in der Streptomyceten-Genetik, die sich vor allem durch ihre Fähigkeit auszeichnen, große, insertierte Fragmente stabil weiterzugeben. Die Gesamtsequenz von SCP2* wurde ermittelt und ist in der GenBank unter der Nummer AL645771 hinterlegt. Teilsequenzen waren bereits vorher von anderen publiziert worden. Bei der Analyse der 31317 bp langen Sequenz von SCP2* wurden 34 offene Leserahmen identifiziert, deren abgeleitete Proteinsequenzen von 31 bis 710 Aminosäuren reichen. Den meisten dieser Proteine kann keine bekannte Funktion oder Verwandtschaft zu anderen Proteinen zugeordnet werden. Drei funktionelle Regionen waren bereits vorher identifiziert worden: die Stabilitäts-, die Transfer- und die Replikationsregion. Des Weiteren konnten zwei transponierbare Elemente identifiziert werden, IS1648 und Tn5417. Die Stabilitätsregion, welche zwischen den beiden transponierbaren Elementen positioniert ist, enthält zwei funktionelle Einheiten. Bei der ersten handelt es sich um das Protein MrpA (multimer resolution protein A), das ein neues Mitglied der l-Integrasen darstellt. Das Gen mrpA wurde in E. coli exprimiert und die Aktivität der Integrase untersucht. Die Erkennungssequenz mrpS der Integrase wurde über Mobility Shift-Experimente und durch Footprinting identifiziert. Sie besteht aus zwei 9 bp langen invers orientierten Sequenz-wiederholungen, die eine 18 bp große Kernregion flankieren. Zwei Integrase-Moleküle binden nicht-kooperativ in mrpS und induzieren dabei eine Beugung der DNA. Durch Expressionsstudien mit Hilfe einer Transkriptionsfusion mit xylE als Reportergen wurde eine Autoregulation durch MrpA nachgewiesen. In vivo Untersuchungen in E. coli zeigten die Fähigkeit von MrpA, in trans aus Plasmiden, die eine mrpS-Sequenz tragen, Multimere zu bilden und diese auch in Monomere aufzulösen. Liegen zwei mrpS-Sequenzen auf einem Plasmid vor, kommt es bei Zugabe von MrpA zur Deletion bzw. Inversion der DNA-Fragmente, die sich zwischen den cis-aktiven Erkennungssequenzen der Integrase befinden. Die zweite funktionelle Einheit der Stabilitätsregion bilden die Partitionsgene parA und parB, die zur Stabilität von SCP2* beitragen. Das Partitionssystem gehört zur Familie des Walker Ib-Typs. Das parA-Gen codiert eine ATPase. Das Gen wurde in E. coli exprimiert und die Magnesium-abhängige ATPase-Aktivität in Rohextrakt und gereinigtem Enzym untersucht. Das parB-Gen von SCP2* zeigt keine Verwandtschaft zu anderen parB-Genen und konnte in E. coli nur in sehr geringen Mengen exprimiert werden. Mit eGFP-Fusionen konnte die Verteilung von ParA und ParB in E. coli sichtbar gemacht werden. Expressionsstudien mit Hilfe von xylE-par-Fusionen in Streptomyces lividans deuten auf eine Regulation des par-Operons durch ParB hin. Der Beitrag, den die einzelnen Gene aus der Stabilitätsregion zur Stabilität des Plasmids SCP2* leisten, wurde untersucht, indem die Gene einzeln oder in Gruppen in Vektoren eingefügt wurden. Befinden sich alle drei Stabilitätsgene (mrpA, parA, parB) auf einem Plasmid, werden die Plasmide mit einer Wahrscheinlichkeit von 96 % in die Sporen segregiert. MrpA leistet dabei den wichtigsten Beitrag. Durch die Ermittlung der SCP2*-Sequenz konnten im Replikationsbereich von SCP2* zwei offene Leserahmen und eine nicht-codierende Region von 650 bp identifiziert werden, welche notwendig und ausreichend für die Replikation des Plasmids sind. Die entsprechenden Proteine RepI (161 Aminosäuren) und RepII (136 Aminosäuren) konnten in E. coli exprimiert werden. Die Interaktion von RepI mit dem nicht-codierenden DNA-Bereich aus der Replikationsregion von SCP2* wurde durch Mobility Shift-Experimente und Footprint-Untersuchungen gezeigt. Die Bindung erfolgt an drei Sequenzwiederholungen. Weiterhin können die Rep-Proteine in S. lividans ein Plasmid in trans komplementieren, welches nur den nicht-codierenden Bereich aus der Replikationsregion von SCP2* enthält und folglich alleine replikationsdefizient ist. Mit diesen Ergebnissen als Basis wurden verschiedene SCP2-Shuttle-Vektoren konstruiert, die in E. coli eine hohe Kopienzahl und in S. lividans wie auch das Ausgangsplasmid SCP2 eine niedrige Kopienzahl haben. Diese sollten besonders für die Klonierung großer Fragmente geeignet sein, unterscheiden sich aber durch die viel geringere Größe und damit bessere Handhabung von den bisher verwendeten SCP2-Vektoren.The first circular plasmid isolated from streptomycetes was SCP2 from Streptomyces coelicolor A3(2). It is a conjugative low copy number plasmid present in one to four copies per chromosome. Later, the spontaneous derivative SCP2* was isolated which exhibits higher fertility and mobilisation of chromosomal DNA. Both plasmids are stably inherited, being retained by 99.5 % of spores after a single spore to spore cycle. For that reason the plasmids are frequently used as cloning vectors. As a first step in elucidating the biology of SCP2* the full sequence of plasmid SCP2* was determined in this work. The sequence was deposited at GenBank under the accession number AL645771. It should be noticed that parts of the sequence have been published before. A total of 34 open reading frames were identified in the 31317 bp sequence of SCP2* encoding putative proteins between 31 and 710 amino acids, most of them without known function. Three functional regions had been identified before, namely the stability region, the transfer and spreading region and the replicational region. Likewise two transposable elements, Tn5417 and IS1648, were found. The region necessary for stable inheritance of SCP2* comprises three genes resembling known plasmid stability functions. The first gene mrpA (multimere resolution protein A) encodes a new member of the l-integrase family of site specific recombinases of 371 amino acids. It was expressed in E. coli and the protein was purified. The recombination site mrpS recognized by MrpA was identified via mobility shift experiments and footprinting. The site is organized in two perfect inverted repeats of 9 bp flanking an 18 bp core region. Two molecules of MrpA are binding non-cooperatively to mrpS and induce a bend in the DNA. Examination with transcriptional fusions of mrpA and the reporter gene xylE indicated that MrpA is a transcription autoregulatory protein. In vivo experiments in E. coli with mrpS on plasmids and MrpA provided in trans revealed that MrpA is able to perform inter- and intramolecular recombinations, being able to resolve and build multimeric plasmids as well as to invert or delete DNA between mrpS sites depending on the orientation of the sites in the plasmids. The two other genes in the stability region were called parA and parB. ParA (310 aa) is an ATPase belonging to the Walker-type Ib. ParA was expressed in E. coli, purified and its ATPase activity established. The parB gene could only be expressed at a very low level in E. coli. By means of a translational fusions of parA and parB to eGFP, the distribution of the fusion proteins in E. coli were monitored. ParA-eGFP was homogeneously distributed over the whole cell whereas the ParB-eGFP was localised near the cell poles of the cells. The expression of both par-genes on SCP2* seems to be repressed by ParB as shown by transcriptional fusions of the par-operon with the xylE-reporter gene. To determine the contribution of the stability genes mrpA, parA and parB to the stabilisation of plasmids, the genes were inserted single or in groups into a SCP2* vector and the retention of the plasmids in spores after one or two cycles of growth without antibiotic selection was measured. Plasmid constructs containing all three stability genes were segregated in spores with a frequency of 96 %, with the highest impact coming from mrpA. The minimal replication region was confined to a 1.4 kb region, containing the genes repI and repII and an essential noncoding region of 650 bp. In S. lividans, the rep-genes were able to complement a plasmid containing only the noncoding region in trans. The deduced proteins of 161 aa (RepI) and 136 aa (RepII) shared significant similarity to each other but only in RepI a helix-turn-helix motif for DNA binding could be identified. Both genes were expressed in E. coli. The interaction of RepI with the noncoding replication region was demonstrated via mobility shift experiments and footprint assays. Three binding sites were identified. The knowledge gained on the stability and the replication of SCP2* during this work was used to develop a variety of shuttle vectors for streptomycetes. These vectors are much smaller in size compared to other SCP2 vectors used so far and should be useful for cloning large DNA fragments

Development of new non-invasive tests for colorectal cancer screening: The relevance of information on adenoma detection

Researchers are actively pursuing the development of a new non-invasive test (NIT) for colorectal cancer (CRC) screening as an alternative to fecal occult blood tests (FOBTs). The majority of pilot studies focus on the detection of invasive CRC rather than precursor lesions (i.e., adenomas). We aimed to explore the relevance of adenoma detection for the viability of an NIT for CRC screening by considering a hypothetical test that does not detect adenomas beyond chance. We used the Simulation Model of Colorectal Cancer (SimCRC) to estimate the effectiveness of CRC screening and the lifetime costs (payers' perspective) for a cohort of US 50-years-old persons to whom CRC screening is offered from age 50–75. We compared annual screening with guaiac and immunochemical FOBTs (with sensitivities up to 70 and 24% for CRC and adenomas, respectively) to annual screening with a hypothetical NIT (sensitivity of 90% for CRC, no detection of adenomas beyond chance, specificity and cost similar to FOBTs). Screening with the NIT was not more effective, but was 29–44% more costly than screening with FOBTs. The findings were robust to varying the screening interval, the NIT's sensitivity for CRC, adherence rates favoring the NIT, and the NIT's unit cost. A comparative modelling approach using a model that assumes a shorter adenoma dwell time (MISCAN-COLON) confirmed the superiority of the immunochemical FOBT over an NIT with no ability to detect adenomas. Information on adenoma detection is crucial to determine whether a new NIT is a viable alternative to FOBTs for CRC screening. Current evidence thus lacks an important piece of information to identify marker candidates that hold real promise and deserve further (large-scale) evaluation

Epidemiologische Ansätze zur Klärung wichtiger Forschungsfragen zu COVID-19 – eine Übersicht

Die Epidemiologie als wissenschaftliche Disziplin ist prädestiniert dafür, Kernfragen der COVID-19-Pandemie zu bearbeiten. Hierzu werden klassische und neue Methoden eingesetzt, es stellen sich jedoch auch neue Herausforderungen. Der Beitrag bezieht sich auf die verschiedenen Phasen des bevölkerungsbezogenen Verlaufs der SARS-CoV-2-Infektion und COVID-19-Erkrankung. Basierend auf einer selektiven Literaturrecherche werden Beispielfragestellungen anhand von in Deutschland und international durchgeführten Studien vorgestellt und die jeweiligen epidemiologischen Ansätze diskutiert, aber auch Forschungslücken beschrieben. Wissenschaftliche Fragen, die mit epidemiologischen Daten und Forschungsansätzen zu beantworten sind, stellen sich in jeder Phase des Infektions- und Krankheitsgeschehens. Beschreibende Daten werden vielfach über (wiederholte) Querschnittsstudien generiert. Für analytische Fragestellungen etwa zur Identifikation von Risikogruppen hätten besonders in der frühen Phase der Pandemie Fallkontrollstudien wertvolle Ergebnisse liefern können, wurden aber selten durchgeführt. Daten der Krankenkassen kommt eine wichtige Funktion in der Analyse von Verläufen zu; das Potenzial dieser Datenquelle in Bezug auf Fragestellungen zur Impfung kann jedoch vermutlich kaum genutzt werden. Eine verbesserte Koordination der diversen Studien sowie eine stärker auf frei zugängliche Daten (Open Data) ausgerichtete Forschungsinfrastruktur können den Beitrag der Epidemiologie zur Kontrolle dieser und zukünftiger Pandemien weiter stärken.Epidemiology as a scientific discipline is predestined to address key problems in the COVID-19 pandemic. In order to do so, classic and new methods are used, and new challenges are emerging. This paper addresses the various phases of the population-based progression of SARS-CoV‑2 infection and COVID-19. Based on a selective literature search, sample questions from studies conducted in Germany and internationally are presented, their respective epidemiological approaches discussed, and research gaps described. Scientific questions to be answered with epidemiological data and research approaches arise in every phase of infection and disease. Descriptive data are often generated via (repeated) cross-sectional studies. For analytical questions, such as the identification of risk groups, case-control studies could have provided valuable results, especially in the early phase of the pandemic, but were rarely conducted. Data from health insurance companies have an important function in the analysis of the course of disease; however, the potential of this data source with regard to questions on vaccination can probably hardly be used. Improved coordination of the various studies and a more “open data” oriented research infrastructure can further strengthen the contribution of epidemiology to the control of the current and future pandemics