The Dutch LATER physical outcomes set for self-reported data in survivors of childhood cancer

Purposes: Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods: First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results: A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors: This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine:A Pragmatic Randomized Controlled Trial (CYSCE Trial)

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression

The rate of telomere loss is related to maximum lifespan in birds

Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.This article is part of the theme issue 'Understanding diversity in telomere dynamics'

What Role Do Traditional Beliefs Play in Treatment Seeking and Delay for Buruli Ulcer Disease?–Insights from a Mixed Methods Study in Cameroon

Victims of Buruli ulcer disease (BUD) frequently report to specialized units at a late stage of the disease. This delay has been associated with local beliefs and a preference for traditional healing linked to a reportedly mystical origin of the disease. We assessed the role beliefs play in determining BUD sufferers' choice between traditional and biomedical treatments.Anthropological fieldwork was conducted in community and clinical settings in the region of Ayos and Akonolinga in Central Cameroon. The research design consisted of a mixed methods study, triangulating a qualitative strand based on ethnographic research and quantitative data obtained through a survey presented to all patients at the Ayos and Akonolinga hospitals (N = 79) at the time of study and in four endemic communities (N = 73) belonging to the hospitals' catchment area.The analysis of BUD sufferers' health-seeking behaviour showed extremely complex therapeutic itineraries, including various attempts and failures both in the biomedical and traditional fields. Contrary to expectations, nearly half of all hospital patients attributed their illness to mystical causes, while traditional healers admitted patients they perceived to be infected by natural causes. Moreover, both patients in hospitals and in communities often combined elements of both types of treatments. Ultimately, perceptions regarding the effectiveness of the treatment, the option for local treatment as a cost prevention strategy and the characteristics of the doctor-patient relationship were more determinant for treatment choice than beliefs.The ascription of delay and treatment choice to beliefs constitutes an over-simplification of BUD health-seeking behaviour and places the responsibility directly on the shoulders of BUD sufferers while potentially neglecting other structural elements. While more efficacious treatment in the biomedical sector is likely to reduce perceived mystical involvement in the disease, additional decentralization could constitute a key element to reduce delay and increase adherence to biomedical treatment

Towards an integrative understanding of soil biodiversity

Soil is one of the most biodiverse terrestrial habitats. Yet, we lack an integrative conceptual framework for understanding the patterns and mechanisms driving soil biodiversity. One of the underlying reasons for our poor understanding of soil biodiversity patterns relates to whether key biodiversity theories (historically developed for aboveground and aquatic organisms) are applicable to patterns of soil biodiversity. Here, we present a systematic literature review to investigate whether and how key biodiversity theories (species-energy relationship, theory of island biogeography, metacommunity theory, niche theory and neutral theory) can explain observed patterns of soil biodiversity. We then discuss two spatial compartments nested within soil at which biodiversity theories can be applied to acknowledge the scale-dependent nature of soil biodiversity.Peer reviewe

Chromatic periodic activity down to 120 MHz in a Fast Radio Burst

Fast radio bursts (FRBs) are extragalactic astrophysical transients whose brightness requires emitters that are highly energetic, yet compact enough to produce the short, millisecond-duration bursts. FRBs have thus far been detected between 300 MHz and 8 GHz, but lower-frequency emission has remained elusive. A subset of FRBs is known to repeat, and one of those sources, FRB 20180916B, does so with a 16.3 day activity period. Using simultaneous Apertif and LOFAR data, we show that FRB 20180916B emits down to 120 MHz, and that its activity window is both narrower and earlier at higher frequencies. Binary wind interaction models predict a narrower periodic activity window at lower frequencies, which is the opposite of our observations. Our detections establish that low-frequency FRB emission can escape the local medium. For bursts of the same fluence, FRB 20180916B is more active below 200 MHz than at 1.4 GHz. Combining our results with previous upper-limits on the all-sky FRB rate at 150 MHz, we find that there are 3-450 FRBs/sky/day above 50 Jy ms at 90% confidence. We are able to rule out the scenario in which companion winds cause FRB periodicity. We also demonstrate that some FRBs live in clean environments that do not absorb or scatter low-frequency radiation.Comment: 50 pages, 14 figures, 3 tables, submitte

InterPro: the integrative protein signature database

The InterPro database (http://www.ebi.ac.uk/interpro/) integrates together predictive models or ‘signatures' representing protein domains, families and functional sites from multiple, diverse source databases: Gene3D, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY and TIGRFAMs. Integration is performed manually and approximately half of the total ∼58 000 signatures available in the source databases belong to an InterPro entry. Recently, we have started to also display the remaining un-integrated signatures via our web interface. Other developments include the provision of non-signature data, such as structural data, in new XML files on our FTP site, as well as the inclusion of matchless UniProtKB proteins in the existing match XML files. The web interface has been extended and now links out to the ADAN predicted protein-protein interaction database and the SPICE and Dasty viewers. The latest public release (v18.0) covers 79.8% of UniProtKB (v14.1) and consists of 16 549 entries. InterPro data may be accessed either via the web address above, via web services, by downloading files by anonymous FTP or by using the InterProScan search software (http://www.ebi.ac.uk/Tools/InterProScan/