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• Liver disease with portal hypertension developed almost always in children under 10 years of age. • Children who had no evidence of liver disease by 10 years of age did not develop CFLD during follow up. • Most children with nonspecific liver abnormalities will not progress to advanced liver disease. • CFLD was associated with increased mortality rates and shortened life expectancy. Our understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. to determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). The Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) 480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99–10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD. During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59–12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44–3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77–1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. The incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children. [Display omitted] [ABSTRACT FROM AUTHOR]

• Pathogens were quantified in the benthic sediment during low baseflow conditions. • We present a flow-dependent mobile-immobile particle tracking model for pathogens. • Longitudinal transport of pathogens during dynamic flow conditions simulated by model. • Benthic sediments are potential stores and sources of pathogens during storm events. • Transport into and out of benthic sediment regulates pathogen presence in the stream. The presence of bacteria and viruses in freshwater represents a global health risk. The substantial spatial and temporal variability of microbes leads to difficulties in quantifying the risks associated with their presence in freshwater. Fine particles, including bacteria and viruses are transported and accumulated into shallow streambed (i.e., benthic) sediment, delaying the downstream transmission during baseflow conditions but contributing to their resuspension and transport downstream during stormflow events. Direct measurements of pathogen accumulation in benthic sediments are rare. Until now, the dynamic role of benthic sediment as both a store and source of microbes, has not been quantified. In this study, we analyze microbial abundance in benthic sediment along a 1 km reach of an intermittent Mediterranean stream receiving inputs from the effluent of a wastewater treatment plant, a known point source of microbes in streams. We sampled benthic sediment during a summer drought when the wastewater effluent constituted 100 % of the stream flow, and thus, large accumulation and persistence of pathogens along the streambed was expected. We measured the abundance of total bacteria, Escherichia coli (as a fecal indicator) , and presence of enteric rotavirus (RoV) and norovirus (NoV). The abundance of E. coli , based on qPCR detection, was high (4.99∙102 gc /cm2) along the first 100 m downstream of the wastewater effluent input and in general decreased with distance from the source, with presence of RoV and NoV along the study reach. A particle tracking model was applied, that uses stream water velocity as an input, and accounts for microbial exchange into, immobilization, degradation, and resuspension out of benthic sediment during baseflow and stormflow. Rates of exchange into benthic sediment were 3 orders of magnitude higher during stormflow, but residence times were proportionately lower, resulting in increased longitudinal connectivity from up to downstream during stormflow. Model simulations demonstrated mechanistically how the rates of exchange into and out of the benthic sediment resulted in benthic sediment to act as a store during baseflow and a source during stormflow. [Display omitted] [ABSTRACT FROM AUTHOR]

Water level fluctuations in surface water bodies, and in particular low flow drought conditions, are expected to become more frequent and more severe in the future due to the impacts of global environmental change. Variations in water level, and therefore in-channel water volume, not only have the potential to directly impact stream temperature, but also aquatic vegetation coverage which, in turn, may affect stream temperature patterns and dynamics. Manipulation experiments provide a systematic approach to investigate the multiple environmental controls on stream temperature patterns. This study aims to use temperature data loggers and fibre optic distributed temperature sensing (FO-DTS) to investigate potential drought impacts on patterns in surface water and streambed temperature as a function of change in water column depth. To quantify the joint impacts of water level and associated vegetation coverage on stream temperatures, investigations were conducted in outdoor flumes using identical pool-riffle-pool features, but with spatially variable water levels representative of different drought severity conditions. Naturally evolved vegetation growth in the flumes ranged from sparse vegetation coverage in the shallow flumes to dense colonization in the deepest. Observed surface water and streambed temperature patterns differed significantly within the range of water levels and degrees of vegetation coverage studied. Streambed temperature patterns were more pronounced in the shallowest flume, with minimum and maximum temperature values and diurnal temperature variation being more intensively affected by variation in meteorological conditions than daily average temperatures. Spatial patterns in streambed temperature correlated strongly with morphologic features in all flumes, with riffles coinciding with the highest temperatures, and pools representing areas with the lowest temperatures. In particular, the shallowest flume (comprising multiple exposed features) exhibited a maximum upstream-downstream temperature warming of 3.3 °C (T in = 10.3 °C, T out = 13.5 °C), exceeding the warming observed in the deeper flumes by ∼2 °C. Our study reveals significant streambed and water temperature variation caused by the combined impacts of water level and related vegetation coverage. These results highlight the importance of maintaining minimum water levels in lowland rivers during droughts for buffering the impacts of atmospheric forcing on both river and streambed water temperatures. [ABSTRACT FROM AUTHOR]

Summary On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset. [ABSTRACT FROM AUTHOR]

Summary The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis. [ABSTRACT FROM AUTHOR]

Microplastics are ubiquitous in the environment, with high concentrations being detected now also in river corridors and sediments globally. Whilst there has been increasing field evidence of microplastics accumulation in the guts and tissues of freshwater and marine aquatic species, the uptake mechanisms of microplastics into freshwater food webs, and the physical and geological controls on pathway-specific exposures to microplastics, are not well understood. This knowledge gap is hampering the assessment of exposure risks, and potential ecotoxicological and public health impacts from microplastics. This review provides a comprehensive synthesis of key research challenges in analysing the environmental fate and transport of microplastics in freshwater ecosystems, including the identification of hydrological, sedimentological and particle property controls on microplastic accumulation in aquatic ecosystems. This mechanistic analysis outlines the dominant pathways for exposure to microplastics in freshwater ecosystems and identifies potentially critical uptake mechanisms and entry pathways for microplastics and associated contaminants into aquatic food webs as well as their risk to accumulate and biomagnify. We identify seven key research challenges that, if overcome, will permit the advancement beyond current conceptual limitations and provide the mechanistic process understanding required to assess microplastic exposure, uptake, hazard, and overall risk to aquatic systems and humans, and provide key insights into the priority impact pathways in freshwater ecosystems to support environmental management decision making. Image 1 • Environmental risks are affected by pathway-specific exposures to microplastics. • Particle properties and flow dynamics control exposure to microplastics. • We identify uptake mechanisms and microplastic entry points into aquatic food webs. • Ecotoxicological impacts are controlled by fate and transport of microplastics. [ABSTRACT FROM AUTHOR]

Wastewater treatment plant (WWTP) effluents alter stream water chemistry and metabolic activity. Yet, essential aspects influencing the biogeochemical response of receiving streams such as hydrology and diel oscillations of light and temperature remain largely unexplored. We measured day vs night water chemistry and in-stream net nutrient uptake velocity (V f) in an intermittent forested stream, upstream and downstream of a WWTP effluent under contrasting hydrological conditions. The WWTP effluent negatively influenced stream water chemistry, especially during the dry period. Despite large diel oscillations in light inputs, day-night differences in nutrient and oxygen concentrations were small, suggesting that heterotrophic respiration drove stream metabolism with a minor contribution of gross primary production. The magnitude of V f was similar between day and night at the two reaches. Yet, at the downstream reach, in-stream net DIN uptake occurred more often at night, and values of V f for ammonia and nitrite indicated enhanced in-stream nitrification. The two reaches showed a small capacity to retain DIN and soluble reactive phosphorus from the water column. Positive values of in-stream net nutrient uptake (i.e. uptake > release) occurred mostly during the dry period, highlighting that in-stream biogeochemical processing can contribute to improve water quality in streams receiving point-sources effluents in regions with low water availability. Unlabelled Image • WWTP effluents impair stream water chemistry, especially during low flow periods. • Urban stream biota removes small amounts of nutrients from the water column. • Small day-night variations reveal heterotrophs drive stream biogeochemical activity. • Nighttime denitrification can contribute to decrease stream nitrogen concentrations. [ABSTRACT FROM AUTHOR]