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Faults can fundamentally change a groundwater flow regime and represent a major source of uncertainty in groundwater studies. Much research has been devoted to uncertainty around their location and their barrier-conduit behavior. However, fault timing is one aspect of fault uncertainty that appears to be somewhat overlooked. Many faulted models feature consistent layer offsets, thereby presuming that block faulting has occurred recently and almost instantaneously. Additionally, barrier and/or conduit behavior is often shown to extend vertically through all layers when a fault may in fact terminate well below-ground surface. In this study, we create three plausible geological interpretations for a transect in the Perth Basin. Adjacent boreholes show stratigraphic offsets and thickening which indicate faulting; however, fault timing is unknown. Flow modeling demonstrates that the model with the most recent faulting shows profoundly different flow patterns due to aquifer juxtaposition. Additionally, multiple realizations with stochastically generated parameter sets for layer, fault core, and fault damage zone conductivity show that fault timing influences flow more than layer or fault zone conductivity. Finally, fault conduit behavior that penetrates aquitards has significant implications for transport, while fault barrier behavior has surprisingly little. This research advocates for adequate data collection where faults may cause breaches in aquitards due to layer offsets or conduit behavior in the damage zone. It also promotes the use of multiple geological models to address structural uncertainty, and highlights some of the hurdles in doing so such as computational expense and the availability of seamless geological-flow modeling workflows., (© 2024 The Author(s). Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

Cervical cancer is the fourth most common cancer in women worldwide. To determine early treatment for patients, it is critical to accurately classify the cervical intraepithelial lesion status based on a microscopic biopsy. Lesion classification is a 4-class problem, with biopsies being designated as benign or increasingly malignant as class 1-3, with 3 being invasive cancer. Unfortunately, traditional biopsy analysis by a pathologist is time-consuming and subject to intra- and inter-observer variability. For this reason, it is of interest to develop automatic analysis pipelines to classify lesion status directly from a digitalized whole slide image (WSI). The recent TissueNet Challenge was organized to find the best automatic detection pipeline for this task, using a dataset of 1015 annotated WSI slides. In this work, we present our winning end-to-end solution for cervical slide classification composed of a two-step classification model: First, we classify individual slide patches using an ensemble CNN, followed by an SVM-based slide classification using statistical features of the aggregated patch-level predictions. Importantly, we present the key innovation of our approach, which is a novel partial label-based loss function that allows us to supplement the supervised WSI patch annotations with weakly supervised patches based on the WSI class. This led to us not requiring additional expert tissue annotation, while still reaching the winning score of 94.7%. Our approach is a step towards the clinical inclusion of automatic pipelines for cervical cancer treatment planning.Clinical relevance- The explanation of the winning Tis-sueNet AI algorithm for automated cervical cancer classification, which may provide insights for the next generation of computer assisted tools in digital pathology.

Green oat ( Avena sativa ) extracts contain several groups of potentially psychoactive phytochemicals. Previous research has demonstrated improvements in cognitive function following a single dose of these extracts, but not following chronic supplementation. Additionally, whilst green oat extracts contain phytochemicals that may improve mood or protect against stress, for instance species-specific triterpene saponins, to date this possibility has not been examined. The current study investigated the effects of a single dose and four weeks of administration of a novel, Avena sativa herbal extract (cognitaven ® ) on cognitive function and mood, and changes in psychological state during a laboratory stressor. The study adopted a dose-ranging, double-blind, randomised, parallel groups design in which 132 healthy males and females (35 to 65 years) received either 430 mg, 860 mg, 1290 mg green oat extract or placebo for 29 days. Assessments of cognitive function, mood and changes in psychological state during a laboratory stressor (Observed Multitasking Stressor) were undertaken pre-dose and at 2 h and 4 h post-dose on the first (Day 1) and last days (Day 29) of supplementation. The results showed that both a single dose of 1290 mg and, to a greater extent, supplementation for four weeks with both 430 mg and 1290 mg green oat extract resulted in significantly improved performance on a computerised version of the Corsi Blocks working memory task and a multitasking task (verbal serial subtractions and computerised tracking) in comparison to placebo. After four weeks, the highest dose also decreased the physiological response to the stressor in terms of electrodermal activity. There were no treatment-related effects on mood. These results confirm the acute cognitive effects of Avena sativa extracts and are the first to demonstrate that chronic supplementation can benefit cognitive function and modulate the physiological response to a stressor., Competing Interests: The study was sponsored by Anklam Extrakt GmbH, by whom BB and SCL are employed. However, the sponsors had no input into the data-collection, analysis or interpretation of the results of the study. The authors declare no other conflicts of interest.

In our previous investigation, delphinidin, one of the most abundant anthocyanins found in vegetables and berry fruits, had been shown to inhibit osteoclasts and prevent bone loss in mouse models of osteoporosis. In the present study, we investigated whether a delphinidin glycoside-enriched maqui berry extract (MBE, Delphinol ® ) exhibits beneficial effects on bone metabolism both in vitro and in vivo. MBE stimulated the osteoblastic differentiation of MC3T3-E1 cells, as indicated by enhanced mineralized nodule formation, and increased alkaline phosphatase activity, through the upregulation of bone morphogenetic protein 2 ( Bmp2 ), runt-related transcription factor 2 ( Runx2 ), Osterix ( Osx ), osteocalcin ( Ocn ), and matrix extracellular phosphoglycoprotein ( Mepe ) mRNA expression. Immunostaining and immunoprecipitation assays demonstrated that MBE suppressed NF-κB transnucleation through acting as a superoxide anion/peroxynitrite scavenger in MC3T3-E1 cells. Simultaneously, MBE inhibited both osteoclastogenesis in primary bone marrow macrophages and pit formation by maturated osteoclasts on dentine slices. Microcomputed tomography (micro-CT) and bone histomorphometry analyses of femurs demonstrated that the daily ingestion of MBE significantly increased BV/TV (ratio of bone volume to tissue volume), Tb.Th (trabecular thickness), Tb.N (trabecular number), N.Nd/N.Tm (node to terminus ratio), OV/TV (ratio of osteoid volume to tissue volume), BFR/TV (bone formation rate per tissue volume), and significantly decreased Tb.Sp (trabecular separation), ES/BS (ratio of eroded surface to bone surface) and N.Oc/BS (number of osteoclast per unit of bone surface, compared to vehicle controls in osteopenic mouse models. These findings suggest that MBE can be a promising natural agent for the prevention of bone loss in osteopenic conditions by not only inhibiting bone resorption, but also stimulating bone formation.

Sediment cores and bottom water samples from across the Baltic Sea region were analyzed for freely dissolved concentrations (C free ), total sediment concentrations (C T ) and the dissolved aqueous fraction in water of seven indicator PCBs. Ex-situ equilibrium sampling of sediment samples was conducted with polydimethylsiloxane (PDMS) coated glass fibers that were analyzed by automated thermal desorption GC-MS, which yielded PCB concentrations in the fiber coating (C PDMS ). Measurements of C PDMS and C T were then applied to determine (i) spatially resolved freely dissolved PCB concentrations; (ii) baseline toxicity potential based on chemical activities (a); (iii) site specific mixture compositions; (iv) diffusion gradients at the sediment water interface and within the sediment cores; and (vi) site specific distribution ratios (K D ). The contamination levels were low in the Gulf of Finland and moderate to elevated in the Baltic Proper, with the highest levels observed in the western Baltic Sea. The SPME method has been demonstrated to be an appropriate and sensitive tool for area surveys presenting new opportunities to study the in-situ distribution and thermodynamics of hydrophobic organic chemicals at trace levels in marine environments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Periarticular bone loss is a long known but yet insufficiently understood phenomenon in patients with rheumatoid arthritis. This study investigated whether autoimmunity against citrullinated proteins is causally involved in triggering periarticular bone loss. Periarticular bone loss was studied in the standard antigen-induced arthritis (AIA) mouse model with methylated bovine serum albumin (mBSA) as well as a modified model with mutated citrullinated vimentin (MCV) alone or in combination with mBSA. Periarticular bone loss, subchondral osteoclastogenesis, as well as local expression of cytokines, osteoclast genes, and peptidyl-arginine deiminase (PAD) enzymes were assessed after arthritis induction. Immune cell and osteoclast precursor infiltration were detected in the periarticular bone marrow and local lymph nodes. In addition, periarticular bone loss was assessed upon challenge of mice with purified anti-MCV antibody. Despite inducing a milder form of arthritis than mBSA, MCV triggered significant periarticular bone loss associated with an increased infiltration of osteoclast precursors and mature osteoclasts in the periarticular bone marrow. MCV enhanced the expression of the osteoclast inducers RANKL and M-CSF, the cytokines IL-8, IL-1, IL-6, and TNF-α, as well as PAD2 and PAD4 enzymes in the periarticular bone marrow. Furthermore, also anti-MCV antibody challenge induced significant periarticular bone loss and local osteoclastogenesis in the mice. Autoimmunity against citrullinated vimentin triggers periarticular bone loss by osteoclast activation in the bone marrow. These findings may explain why periarticular bone loss is already found very early in the disease course of patients with rheumatoid arthritis. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: The purpose of this study was to assess the relationship between emergency medicine (EM) resident and attending physician patient satisfaction scores., Methods: We added four resident questions to the standard Press Ganey survey used at a large, urban, university hospital with a PGY-1 to -4 EM residency. The resident questions were identical to the traditional attending questions. Press Ganey distributed the modified survey to a random sample of 30% of discharged patients. We assessed the correlation between resident and attending top-box Press Ganey scores using Pearson's coefficients. Two-tailed two-sample comparisons of proportions were used to compare top-box responses between residents and attendings., Results: From September 1, 2012, to August 31, 2015, a total of 66,216 patients received surveys, and 7,968 responded, resulting in a 12.03% response rate, similar to Press Ganey survey response rate at comparable peer institutions. Patients were able to discriminate between residents and attendings; however, 751 surveys did not contain responses for residents, resulting in a total number of 6,957. All 64 of the EM residents had a minimum of 5 or more surveys returned. There was a high degree of correlation between resident and attending top-box scores with correlation coefficients ranging from 0.75 to 0.80. However, the proportion of top-box scores was consistently higher for residents (p < 0.05)., Conclusions: There is a high degree of correlation between resident and attending top-box scores on Press Ganey surveys, with residents scoring slightly higher than attendings. The addition of resident questions to the standard Press Ganey survey does not appear to decrease overall attending scores.

The prevalence of neurodegenerative disease and arthritis increases with age. Despite both processes being associated with immune activation and inflammation, little is known about the mechanistic interactions between neurodegenerative disease and arthritis. In this article, we show that tau-transgenic (tau-tg) mice that develop neurodegenerative disease characterized by deposition of tau tangles in the brain are highly susceptible to developing arthritis. Already at steady-state conditions, tau-tg mice exhibit peripheral immune activation that is manifested by higher numbers of granulocytes, plasmablasts, and inflammatory Ly6C hi CCR2 + monocytes, as well as increased levels of proinflammatory cytokines, such as TNF-α and IL-17. Upon induction of collagen-induced arthritis (CIA), tau-tg mice displayed an increased incidence and an earlier onset of CIA that was associated with a more pronounced inflammatory cytokine response. Furthermore, induction of CIA led to significantly elevated numbers of Iba-1-expressing cells in the brain, indicative of microglia activation, and the formation of anti-tau Abs in tau-tg mice. These changes were accompanied by the resolution of tau tangles and significantly decreased neurodegenerative pathology. In summary, these data show that neurodegenerative disease enhances the development of arthritis. In addition, arthritis, once induced, triggers innate immune responses in the brain, leading to resolution of neurodegenerative changes., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Delivering access to sufficient food, energy and water resources to ensure human wellbeing is a major concern for governments worldwide. However, it is crucial to account for the 'nexus' of interactions between these natural resources and the consequent implications for human wellbeing. The private sector has a critical role in driving positive change towards more sustainable nexus management and could reap considerable benefits from collaboration with researchers to devise solutions to some of the foremost sustainability challenges of today. Yet opportunities are missed because the private sector is rarely involved in the formulation of deliverable research priorities. We convened senior research scientists and influential business leaders to collaboratively identify the top forty questions that, if answered, would best help companies understand and manage their food-energy-water-environment nexus dependencies and impacts. Codification of the top order nexus themes highlighted research priorities around development of pragmatic yet credible tools that allow businesses to incorporate nexus interactions into their decision-making; demonstration of the business case for more sustainable nexus management; identification of the most effective levers for behaviour change; and understanding incentives or circumstances that allow individuals and businesses to take a leadership stance. Greater investment in the complex but productive relations between the private sector and research community will create deeper and more meaningful collaboration and cooperation., Competing Interests: Compliance with ethical standardsThis exercise was explicitly devised to take into account the interests of scientists, businesses and civil society. Those who took part in the prioritisation process (voting and workshop stages) are all listed as co-authors in this study except Monica Contestabile (Nature Publishing Group). Whilst the individuals who participated represented their own opinions, please note in the author details the companies and organisations whose employees have helped to shape and prioritise these research questions.

Solid Phase Microextraction (SPME) was applied to provide the first large scale dataset of freely dissolved concentrations for 9 polycyclic aromatic hydrocarbons (PAHs) in Baltic Sea sediment cores. Polydimethylsiloxane (PDMS) coated glass fibers were used for ex-situ equilibrium sampling followed by automated thermal desorption and GC-MS analysis. From the PAH concentrations in the fiber coating we examined (i) spatially resolved freely dissolved PAH concentrations (Cfree); (ii) baseline toxicity potential on the basis of chemical activities (a); (iii) site specific mixture compositions; (iv) diffusion gradients at the sediment water interface and within the sediment cores and (v) site specific distribution ratios. Contamination levels were low in the northern Baltic Sea, moderate to elevated in the Baltic Proper and highest in the Gulf of Finland. Chemical activities were well below levels expected to cause narcosis to benthos organisms. The SPME method is a very sensitive tool that opens new possibilities for studying the PAHs at trace levels in marine environments., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss.