Increased somatic mutation burdens in normal human cells due to defective DNA polymerases.

Funder: Wellcome PhD StudentshipFunder: Jean Shank/Pathological Society Intermediate FellowshipFunder: Wellcome Clinical PhD fellowshipMutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life

An extended window of opportunity for G-CSF treatment in cerebral ischemia

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is known as a powerful regulator of white blood cell proliferation and differentiation in mammals. We, and others, have shown that G-CSF is effective in treating cerebral ischemia in rodents, both relating to infarct size as well as functional recovery. G-CSF and its receptor are expressed by neurons, and G-CSF regulates apoptosis and neurogenesis, providing a rational basis for its beneficial short- and long-term actions in ischemia. In addition, G-CSF may contribute to re-endothelialisation and arteriogenesis in the vasculature of the ischemic penumbra. In addition to these trophic effects, G-CSF is a potent neuroprotective factor reliably reducing infarct size in different stroke models. RESULTS: Here, we have further delayed treatment and studied effects of G-CSF on infarct volume in the middle cerebral artery occlusion (MCAO) model and functional outcome in the cortical photothrombotic model. In the MCAO model, we applied a single dose of 60 μg/kg bodyweight G-CSF in rats 4 h after onset of ischemia. Infarct volume was determined 24 h after onset of ischemia. In the rat photothrombotic model, we applied 10 μg/kg bodyweight G-CSF daily for a period of 10 days starting either 24 or 72 h after induction of ischemia. G-CSF both decreased acute infarct volume in the MCAO model, and improved recovery in the photothrombotic model at delayed timepoints. CONCLUSION: These data further strengthen G-CSF's profile as a unique candidate stroke drug, and provide an experimental basis for application of G-CSF in the post-stroke recovery phase

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

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Experiences and views of different key stakeholders on the feasibility of treating cancer-related fatigue

Background Although cancer-related fatigue (CRF) has gained increased attention in the past decade, therapy remains a challenge. Treatment programs are more likely to be effective if the needs and interests of the persons involved are well represented. This can be achieved by stakeholder engagement. In this paper, different key stakeholders’ experiences and views on the feasibility of treating CRF in the context of supportive care in hospital environments are analyzed. Method In a qualitative study with the aim of developing an integrative treatment program for CRF, a total of 22 stakeholders (6 medical oncologists, 5 nurses, 9 patients, 1 patient family member, 1 representative of the Swiss Cancer League) were interviewed either in a face-to-face (n = 12) or focus group setting (n = 2). For data analyses, the method of qualitative content analysis was used. Results The stakeholders referred to different contextual factors when talking about the feasibility of treating CRF in the context of supportive care in hospital environments. These included: assessment, reporting and information; treatability; attitude; infrastructure, time-management, costs and affordability; and integrative approach. Conclusions Key factors of a feasible treatment approach to CRF are a coherent, cost effective integrative treatment program facilitated by an interdisciplinary team of health care providers. Furthermore, the treatment approach should be patient orientated, adopting an individualized approach. The major challenges of making the integrative treatment program feasible for CRF are resources and interprofessional collaboration

Developing an integrative treatment program for cancer-related fatigue using stakeholder engagement - a qualitative study

Background: Although cancer-related fatigue (CRF) has gained increased attention in the past decade, it remains difficult to treat. An integrative approach combining conventional and complementary medicine interventions seems highly promising. Treatment programs are more likely to be effective if the needs and interests of the people involved are well represented. This can be achieved through stakeholder engagement. Objectives: The aim of the study was to develop an integrative CRF treatment program using stakeholder engagement and to compare it to an expert version. Method: In a qualitative study, a total of 22 stakeholders (4 oncologists, 1 radiation-oncologist, 1 psycho-oncologist, 5 nurses/nurse experts, 9 patients, 1 patient family member, 1 representative of a local Swiss Cancer League) were interviewed either face-to-face or in a focus group setting. For data analysis, qualitative content analysis was used. Results: With stakeholder engagement, the integrative CRF treatment program was adapted to usual care using a prioritizing approach and allowing more patient choice. Unlike the expert version, in which all intervention options were on the same level, the stakeholder engagement process resulted in a program with 3 different levels. The first level includes mandatory nonpharmacological interventions, the second includes nonpharmacological choice-based interventions, and the third includes pharmacological interventions for severe CRF. The resulting stakeholder based integrative CRF treatment program was implemented as clinical practice guideline at our clinic (Institute for Complementary and Integrative Medicine, University Hospital Zurich). Conclusion: Through the stakeholder engagement approach, we integrated the needs and preferences of people who are directly affected by CRF. This resulted in an integrative CRF treatment program with graded recommendations for interventions and therefore potentially greater sustainability in a usual care setting

A blockchain-based pattern for confidential and pseudo-anonymous contract enforcement

International audienceBlockchain has been praised for its capacity to hold data in a decentralized and tamper-proof way. It also supports the execution of code through blockchain’s smart contracts, adding automation of actions to the network with high trustability. However, as smart contracts are visible by anybody on the network, the business data and logic may be at risk, thus companies could be reluctant to use such technology. This paper aims to propose a pattern that allows the execution of automatable legal contract clauses, where its execution states are stored in an on-chain smart-contract and the logic needed to enforce it wraps it off-chain. An engine completes this pattern by running a business process that corresponds to the legal contract. We then propose a pattern-based solution based on a real-life use case: transportation of refrigerated goods. We argue that this pattern guarantees companies pseudonymity and data confidentiality while ensuring that an audit trail can be reconstituted through the blockchain smart-contract to identify misbehavior or errors. This paper paves the way for a future possible implementation of the solution described, as well as its evaluation

Supplementenkonsum bei Jugendlichen in Deutschland

Im Jahr 2006 nahmen 20 % der Jugendlichen im Alter von 12–17 Jahren Supplemente ein. Supplemente wurden häufiger von körperlich-sportlich Aktiven sowie von Gymnasiasten eingenommen. Ein Großteil der Supplementnehmer verwendete ein einziges Präparat mit nur einem Nährstoff. Es war aber auch häufig die Einnahme eines Präparates mit mehreren Nährstoffen festzustellen. Am meisten wurde Vitamin C supplementiert, gefolgt von Magnesium, B-Vitaminen, Vitamin E und Kalzium.In 2006, 20 % of adolescents aged 12–17 years used dietary supplements. Persons with high physical activity levels as well as those with high education levels consumed dietary supplements more often than others. Many supplement users used only one single-nutrient supplement. A similarly large proportion of users consumed one supplement with multiple nutrients. Most often supplements containing vitamin C, magnesium, B-vitamins, vitamin E and calcium were used

EsKiMo – Das Ernährungsmodul im Kinder- und Jugendgesundheitssurvey (KiGGS)

Im Rahmen des bundesweiten Kinder- und Jugendgesundheitssurveys (KiGGS) wurde von Januar bis Dezember 2006 in einem Modul das Ernährungsverhalten von 6- bis 17-Jährigen erfasst. Die Studie mit dem Namen EsKiMo (Ernährungsstudie als KiGGS-Modul) wurde vom Robert Koch-Institut (RKI) gemeinsam mit der Universität Paderborn, Fachgruppe Ernährung und Verbraucherbildung, durchgeführt und vom Bundesministerium für Ernährung, Lebensmittel und Verbraucherschutz finanziert. Die Eltern der teilnehmenden Kinder unter 12 Jahren wurden gebeten, gemeinsam mit ihrem Kind ein 3-Tage-Verzehrsprotokoll zu führen. Die älteren Kinder wurden persönlich mit Hilfe von DISHES (Dietary Interview Software for Health Examination Studies) zu ihrer Ernährung in den letzten 4 Wochen befragt. Außerdem sollten sie einen bereits im KiGGS eingesetzten Ernährungsfragebogen (Food Frequency Questionnaire) ein zweites Mal ausfüllen. Zusätzlich kam bei allen Teilnehmern ein Kurzfragebogen zum Einsatz, in dem unter anderem soziodemographische Daten, Aspekte der Freizeitgestaltung, Supplementeinnahme, Verpflegung in der Schule sowie Körpergröße und -gewicht erhoben wurden. Die Studie wird aktuelle, repräsentative Daten zur Ernährung von Kindern und Jugendlichen in Deutschland liefern. Diese werden sowohl hinsichtlich der Lebensmittelverzehrsmengen als auch Nährstoffversorgung ausgewertet. Durch die Verbindung der Ernährungsdaten mit den im KiGGS erhobenen Gesundheitsdaten sind außerdem umfangreiche Analysen zum Zusammenhang zwischen Ernährung und Gesundheit möglich. Schlüsselwörter Gesundheitssurvey - Kinder - Jugendliche - Ernährungsepidemiologie - ErnährungserhebungsmethodenIn a module of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), the dietary behaviour of 6–17-year-olds was assessed from January to December 2006. The study, named EsKiMo (Eating Study as a KiGGS Module), was performed by the Robert Koch Institute together with the division of nutrition and consumer education at the University of Paderborn. It was funded by the Federal Ministry of Food, Agriculture and Consumer Protection. Parents of participants younger than 12 years were asked to conduct a 3-day dietary record. Participants of 12 years and older were personally interviewed about their eating behaviour during the last four weeks using DISHES (Dietary Interview Software for Health Examination Studies). In addition, they were asked to fill in the KiGGS food frequency questionnaire a second time. Furthermore, all participants were asked about their socio-demographic background, leisure time activities, supplement use, meals at school, body weight and height. The study will provide up-to-date, representative data on the nutrition of children and adolescents in Germany. The analyses will include the amounts of foods and food groups consumed as well as the nutrient intake. By connecting these nutrition data with other health data from KiGGS, comprehensive analyses of relationships between nutrition and health are possible. Keywords Health survey - Children - Adolescents - Nutritional epidemiology - Dietary assessment method