Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 ...newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8
T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Abstract Objective To find out what inpatients with advanced cancer who are receiving palliative care think about the effect of thromoprophylaxis on overall quality of life. Design Qualitative study ...using audiotaping of semistructured interviews. Setting Regional cancer centre in Wales. Participants 28 inpatients with advanced metastatic cancer receiving palliative care and low molecular weight heparin. Main outcome measures Recurring themes on the effect of thromboprophylaxis on overall quality of life. Results Major emerging themes showed that patients knew about the risks of venous thromboembolism and the purpose of treatment with heparin. Media coverage had raised awareness about venous thromboembolism, and many had previous experience of thromboprophylaxis. All found low molecular weight heparin an acceptable intervention, and many said that it improved their quality of life by giving them a feeling of safety and reassurance. Antiembolic stockings were considered uncomfortable and had a negative impact on quality of life. Patients were concerned that because they had advanced disease they might not be eligible for thromboprophylaxis. Conclusion Low molecular weight heparin is acceptable to inpatients with advanced cancer receiving palliative care and has a positive impact on overall quality of life. Antiembolic stockings are an unacceptable intervention in this patient group. Guidelines on thromboprophylaxis are urgently needed for palliative care inpatient units and hospices.
Flood Risk Management (FRM) is often essential to reduce the risk of flooding to properties and infrastructure in urban landscapes, but typically degrades the habitats required by many aquatic ...animals for foraging, refuge and reproduction. This conflict between flood risk management and biodiversity is driven by conflicting directives, such as the EU Floods and Water Framework Directives, and has led to a requirement for synergistic solutions for FRM that integrate river restoration actions. Unfortunately, ecological monitoring and appraisal of combined FRM and river restoration works is inadequate. This paper uses a case study from the River Don in Northern England to evaluate the effects of the FRM and subsequent river restoration works on instream habitat and the associated fish assemblage over an 8-year period.
Flood risk management created a homogeneous channel but did not negatively affect fish species composition or densities, specifically brown trout. Densities of adult brown trout were comparable pre and post-FRM, while densities of juvenile bullhead and brown trout increased dramatically post FRM. River restoration works created a heterogeneous channel but did not significantly improve species composition or brown trout density. Species composition post-river restoration works returned to that similar to pre-FRM over a short-term period, but with improved numbers of juvenile bullhead. Although habitat complexity increased after river restoration works, long-term changes in species composition and densities were marginal, probably because the river reset habitat complexity within the time framework of the study.
•Flood risk management created a wide and shallow homogenous channel•Flood risk management had no negative impact on fish species composition•Restoration created a heterogeneous channel increasing flow and substrate diversity•Post restoration species composition did not return to the baseline pre-flood works•Flood risk management planning should integrate river restoration
Natural hydrological regimes encompass varying seasonal flow characteristics that provide fish with cues and opportunities for upstream spawning migrations, but these flows are often modified/absent ...in regulated rivers. Compensatory artificial flows (freshets) can be released from reservoirs to replicate these characteristics, but studies testing their effectiveness are limited. To address this, river‐resident brown trout, a species known to undertake spawning migrations, were manually tracked using radio telemetry in a regulated upland river in northern England in response to 11 freshet releases of differing timing, magnitude, and duration. Spawning migrations were not observed because extent of movement during freshets was generally small and the pattern of movement (i.e., directionality and relocation indices) was comparable between impact/control reaches. Movements during freshets were comparable with those observed the days immediately before/after and were small relative to the entire tracking period. In conclusion, freshet characteristic of those recommended to produce “naturalized” autumn/winter flow elevations did not stimulate/facilitate spawning migrations of river‐resident brown trout under the given seasonal conditions. Outside freshets, longer unidirectional movements occurred during low‐flow periods and elevated river level due to rainfall, including during periods of reservoir overtopping. Notwithstanding, fish in experimental reaches were significantly more active (total distance moved) and occupied a larger extent of river (range during freshet) than those in control reaches during short‐duration freshets. Therefore, during dry years/when (autumn/winter) reservoir overtopping events are unlikely, small‐magnitude freshets providing flows that allow fish short opportunities to search for/find superior local habitat while minimizing total water released are recommended.
Key Points
Artificial freshets from reservoirs are promoted in international guidance to stimulate spawning migrations of fish
River‐resident brown trout did not perform spawning migrations during freshets of differing timing, magnitude, and duration
These findings are important for water resource managers when designing ecologically appropriate flow regimes for regulated rivers
Venous thromboembolism (VTE) is common in patients with terminal cancer. Current treatment practice with warfarin has a high incidence of complications, including bleeding, poor control and recurrent ...VTE. Long-term low-molecular-weight heparin (LMWH) therapy is safer and more efficacious in this patient group, but there are concerns that daily therapy may have a negative impact on quality of life. A qualitative study was carried out to determine whether LMWH was acceptable in palliative care patients, both in the community and in-patient units. Forty palliative care patients receiving LMWH for VTE were interviewed. Participants found LMWH to be an acceptable intervention, allowing them freedom from blood tests and optimism regarding their care. It was considered a preferable therapy to warfarin, which had a negative impact on participant's quality of life. The findings of this study support the use of LMWH, first line in the treatment of established VTE in the palliative care setting.
Background
Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20–30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is ...difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches.
Methods
Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model.
Results
A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal–external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent).
Conclusion
The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.
Antecedentes
la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20‐30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático.
Métodos
Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo.
Resultados
En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna‐externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%).
Conclusión
El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.
Early recurrence after surgery for adenocarcinoma of the oesophagus is common. A risk prediction model was derived using modern machine learning methods that accurately predicts risk of early recurrence using postoperative pathology.
Machine learning may help
The functional ecological guild approach is the cornerstone for the development of Indices of Biotic Integrity and multi‐metric indices to assess the ecological status of aquatic systems. These ...indices combine metrics (unit‐specific measures of a functional component of the fish community known to respond to degradation) into a single measure of ecological assessment. The guild approach provides an operational unit linking individual species characteristics with the community as a whole. Species are grouped into guilds based on some degree of overlap in their ecological niches, regardless of taxonomic relationships. Despite European fish species having been classified into ecological guilds, classification has not been standardised Europe‐wide or within the context of classifying species into guilds from which metrics can be developed for ecological assessment purposes. This paper examines the approach used by the EU project FAME to classify European fish species into consistent ecological guilds and to identify suitable metrics as basic tools for the development of a standardised ecological assessment method for European rivers to meet the requirements of the Water Framework Directive.
Cosmic microwave background (CMB) measurements are fundamentally limited by photon statistics. Therefore, ground-based CMB observatories have been increasing the number of detectors that are ...simultaneously observing the sky. Thanks to the advent of monolithically fabricated transition edge sensor arrays, the number of on-sky detectors has been increasing exponentially for over a decade. The next-generation experiment CMB-S4 will increase this detector count by more than an order of magnitude from the current state of the art to 500,000. The readout of such a huge number of exquisitely precise sub-Kelvin sensors is feasible using an existing technology: frequency-domain multiplexing. To further optimize this system and reduce complexity and cost, we have recently made significant advances including the elimination of 4 K electronics, a massive decrease in parasitic in-series impedances, and a significant increase in multiplexing factor.
Background: Terminal haemorrhage is a rare but devastating event that may occur in certain advanced cancers. The focus of management involves administration of ‘crisis medicine’ with the intention of ...relieving patient distress through sedative doses of anxiolytics or opioids. This practice, whilst widely accepted, is based on limited evidence and has never been formally evaluated.
Aim: To evaluate the utility of crisis medication in the management of terminal haemorrhage, through the experiences of nurses who had personally managed such events.
Method: Semi-structured interviews exploring the experiences of palliative care and head and neck oncology nurses were recorded, transcribed verbatim and analysed using interpretative phenomenological analysis. Saturation of themes occurred after interviewing 11 nurses with cumulative experience of managing 37 terminal haemorrhages.
Results: Participants reported crisis medication to have little, if any, role in the management of terminal haemorrhage, which was such a rapid event that patients died before it could be administered. As many events had not been predicted, anticipatory prescribing of crisis medication did not always occur. Staying with and supporting the patient, and using dark-coloured towels to camouflage blood were reported to be of more practical use. A focus on accessing crisis medicines had often been to the detriment of these simple yet beneficial measures.
Conclusion: Anticipatory prescribing of crisis medication rarely benefits the patient and may unintentionally detract from nursing care. Guidelines on the management of terminal haemorrhage should reconsider the emphasis on crisis medication and focus on non-pharmacological approaches to this invariably fatal event.
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