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Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.

Bayesian optimization (BO) provides an effective method to optimize expensive-to-evaluate black box functions. It has been widely applied to problems in many fields, including notably in computer science, e.g., in machine learning to optimize hyperparameters of neural networks, and in engineering, e.g., in fluid dynamics to optimize control strategies that maximize drag reduction. This paper empirically studies and compares the performance and the robustness of common BO algorithms on a range of synthetic test functions to provide general guidance on the design of BO algorithms for specific problems. It investigates the choice of acquisition function, the effect of different numbers of training samples, the exact and Monte Carlo (MC) based calculation of acquisition functions, and both single-point and multi-point optimization. The test functions considered cover a wide selection of challenges and therefore serve as an ideal test bed to understand the performance of BO to specific challenges, and in general. To illustrate how these findings can be used to inform a Bayesian optimization setup tailored to a specific problem, two simulations in the area of computational fluid dynamics (CFD) are optimized, giving evidence that suitable solutions can be found in a small number of evaluations of the objective function for complex, real problems. The results of our investigation can similarly be applied to other areas, such as machine learning and physical experiments, where objective functions are expensive to evaluate and their mathematical expressions are unknown.

Background: Persistent posttraumatic symptoms (PPS) may manifest after a mild-moderate traumatic brain injury (mmTBI) even when standard brain imaging appears normal. Transcranial direct current stimulation (tDCS) represents a promising treatment that may ameliorate pathophysiological processes contributing to PPS.Objective/Hypothesis: We hypothesized that in a mmTBI population, active tDCS combined with training would result in greater improvement in executive functions and post-TBI cognitive symptoms and increased resting state connectivity of the stimulated region, i.e., left dorsolateral prefrontal cortex (DLPFC) compared to control tDCS.Methods: Thirty-four subjects with mmTBI underwent baseline assessments of demographics, symptoms, and cognitive function as well as resting state functional magnetic resonance imaging (rsfMRI) in a subset of patients (n = 24). Primary outcome measures included NIH EXAMINER composite scores, and the Neurobehavioral Symptom Inventory (NSI). All participants received 10 daily sessions of 30 min of executive function training coupled with active or control tDCS (2 mA, anode F3, cathode right deltoid). Imaging and assessments were re-obtained after the final training session, and assessments were repeated after 1 month. Mixed-models linear regression and repeated measures analyses of variance were calculated for main effects and interactions.Results: Both active and control groups demonstrated improvements in executive function (EXAMINER composite: p < 0.001) and posttraumatic symptoms (NSI cognitive: p = 0.01) from baseline to 1 month. Active anodal tDCS was associated with greater improvements in working memory reaction time compared to control (p = 0.007). Reaction time improvement correlated significantly with the degree of connectivity change between the right DLPFC and the left anterior insula (p = 0.02).Conclusion: Anodal tDCS improved reaction time on an online working memory task in a mmTBI population, and decreased connectivity between executive network and salience network nodes. These findings generate important hypotheses for the mechanism of recovery from PPS after mild-moderate TBI.

Abstract This interpretative phenomenological analysis explores aid workers’ understanding of identity and belonging through the transition from working in humanitarian aid to returning home. Semi-structured interviews were conducted with 10 participants who had returned to the UK after working in recently founded non-governmental organisations in Northern France between 2016 and 2019. Analysis of interview data identified four superordinate themes: (1) shared humanitarian identity, (2) limits and borders, (3) holding on to humanitarian identity and (4) redefining belonging and identity. Aid workers’ belonging in humanitarian work settings is rooted in shared moral values and being able to fulfil a clearly defined role. Upon returning, aid workers struggled to reintegrate, manifesting as denial of having left humanitarian work, re-creation of the social setting and moral demarcation. Participants formed a new sense of belonging through redefining their social in-group. The study sheds light on a previously unexplored area of research, specifically characterised through the closeness of the international humanitarian setting and participants’ homes. Findings suggest organisations can assist aid workers’ re-entry by supporting professional distance in the field, and through opportunities that allow to sustain moral values post-mission. Future research should focus on the role of peer support in the re-entry process and the re-entry experiences of aid workers returning from comparable settings further afield (e.g. Greece).

Abstract Background The ability of blood-feeding arthropods to successfully acquire and transmit pathogens of medical and veterinary importance has been shown to be interfered with, or enhanced by, the arthropod’s native microbiome. Mosquitoes transmit viruses, protozoan and filarial nematodes, the majority of which contribute to the 17% of infectious disease cases worldwide. Dirofilaria immitis, a mosquito-transmitted filarial nematodes of dogs and cats, is vectored by several mosquito species including Aedes aegypti. Methods In this study, we investigated the impact of D. immitis colonization on the microbiome of laboratory reared female Ae. aegypti. Metagenomic analysis of the V3–V4 variable region of the microbial 16S RNA gene was used for identification of the microbial differences down to species level. Results We generated a total of 1068 OTUs representing 16 phyla, 181 genera and 271 bacterial species. Overall, in order of abundance, Proteobacteria, Bacteroidetes, Actinobacteria and Firmicutes were the most represented phylum with D. immitis-infected mosquitoes having more of Proteobacteria (71%) than uninfected mosquitoes (56.9%). An interesting finding in this study is the detection of Klebsiella oxytoca in relatively similar abundance in infected and uninfected mosquitoes, suggesting a possible endosymbiotic relationship, and has been previously shown to indirectly compete for nutrients with fungi on domestic housefly eggs and larvae. While D. immitis colonization has no effect on the overall species richness, we identified significant differences in the composition of selected bacterial genera and phyla between the two groups. We also reported distinct compositional and phylogenetic differences in the individual bacterial species when commonly identified bacteria were compared. Conclusions To the best of our knowledge, this is the first study to understand the impact of a filarial infection on the microbiome of its mosquito vector. Further studies are required to identify bacteria species that could play an important role in the mosquito biology. While the microbiome composition of Ae. aegypti mosquito have been previously reported, our study shows that in an effort to establish itself, a filarial nematode modifies and alters the overall microbial diversity within its mosquito host.

In this study, we considered a bridging strategy between qualitative and quantitative research with the aim of achieving complementarity. A pilot case study using the Sheffield Elicitation Framework “SHELF” to estimate appropriate inputs for a quantitative energy systems model (based on a qualitative energy future scenario) was used to gain insights. Of novelty are the ethnographic insights of an example translation procedure as well as the methodological approach of the translation procedure itself. This paper reports the findings from this exercise concerning the practicalities of applying such a technique and the observations from the expert elicitation process itself. Based on this pilot, we make two recommendations. The first is the importance of devising a strategy in projects, and research programmes, where bridging between qualitative and quantitative research activities would be most effective. The second is that observations of discussions during the expert elicitation process provide value in the provenance of the estimates for quantitative modelling purposes and provide considerations for further development of qualitative future scenarios.

Background: Persistent post-traumatic symptoms (PPS) after traumatic brain injury (TBI) can lead to significant chronic functional impairment. Pseudocontinuous arterial spin labeling (pCASL) has been used in multiple studies to explore changes in cerebral blood flow (CBF) that may result in acute and chronic TBI, and is a promising neuroimaging modality for assessing response to therapies.Methods: Twenty-four subjects with chronic mild-moderate TBI (mmTBI) were enrolled in a pilot study of 10 days of computerized executive function training combined with active or sham anodal transcranial direct current stimulation (tDCS) for treatment of cognitive PPS. Behavioral surveys, neuropsychological testing, and magnetic resonance imaging (MRI) with pCASL sequences to assess global and regional CBF were obtained before and after the training protocol.Results: Robust improvements in depression, anxiety, complex attention, and executive function were seen in both active and sham groups between the baseline and post-treatment visits. Global CBF decreased over time, with differences in regional CBF noted in the right inferior frontal gyrus (IFG). Active stimulation was associated with static or increased CBF in the right IFG, whereas sham was associated with reduced CBF. Neuropsychological performance and behavioral symptoms were not associated with changes in CBF.Discussion: The current study suggests a complex picture between mmTBI, cerebral perfusion, and recovery. Changes in CBF may result from physiologic effect of the intervention, compensatory neural mechanisms, or confounding factors. Limitations include a small sample size and heterogenous injury sample, but these findings suggest promising directions for future studies of cognitive training paradigms in mmTBI.

ObjectiveTo systematically review methods developed and employed to evaluate the diagnostic accuracy of medical test when there is a missing or no gold standard.Study design and settingsArticles that proposed or applied any methods to evaluate the diagnostic accuracy of medical test(s) in the absence of gold standard were reviewed. The protocol for this review was registered in PROSPERO (CRD42018089349).ResultsIdentified methods were classified into four main groups: methods employed when there is a missing gold standard; correction methods (which make adjustment for an imperfect reference standard with known diagnostic accuracy measures); methods employed to evaluate a medical test using multiple imperfect reference standards; and other methods, like agreement studies, and a mixed group of alternative study designs. Fifty-one statistical methods were identified from the review that were developed to evaluate medical test(s) when the true disease status of some participants is unverified with the gold standard. Seven correction methods were identified and four methods were identified to evaluate medical test(s) using multiple imperfect reference standards. Flow-diagrams were developed to guide the selection of appropriate methods.ConclusionVarious methods have been proposed to evaluate medical test(s) in the absence of a gold standard for some or all participants in a diagnostic accuracy study. These methods depend on the availability of the gold standard, its' application to the participants in the study and the availability of alternative reference standard(s). The clinical application of some of these methods, especially methods developed when there is missing gold standard is however limited. This may be due to the complexity of these methods and/or a disconnection between the fields of expertise of those who develop (e.g. mathematicians) and those who employ the methods (e.g. clinical researchers). This review aims to help close this gap with our classification and guidance tools.

The Thomsen-Friedenreich (TF) antigen is a tumor-associated antigen consistently expressed on the apical surface of epithelial-based cancer cells, including pancreatic cancer. In this work, we report the development of multimodal imaging probe, the tripolymer fluorescent nanospheres, whose surface was fabricated with peanut agglutinin (PNA) moieties as TF molecular recognition molecules. Here, we demonstrate that the probe is able to detect TF antigen in human pancreatic cancer tissues and differentiate from normal tissue. What is most noteworthy regarding the probe is its ability to visualize tumor margins defined by epithelial TF antigen expression. Further, in vivo preclinical studies using an orthotopic mouse model of pancreatic cancer suggest the potential use of the nanospheres for laparoscopic imaging of pancreatic cancer tumor margins to enhance surgical resection and improve clinical outcomes. [READ ARTICLE](https://precisionnanomedicine.com/article/6495)

The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial "pause" in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.

Due to its focus on business topics such as entrepreneurship and management, AEE has generally been focused on economic motivations and market-driven rationales (Beckman, 2007; Manjon & Guo, 2015). The same holds true for the community development field (Phillips, 2003). This article examines an interdisciplinary collaboration between courses in two disparate units of the university: music and community development. Creative placemaking activities are presented as pedagogical tools for connecting AEE and community development goals. At the heart of the experiences described was a desire to extend beyond the dominant paradigm of both AEE and community development in relation to economic development of the individual (AEE) and collective (community development). In so doing, it is suggested that these projects represent a soulful approach to learning and community building (Westoby, 2016; Westoby & Dowling, 2009) via creative placemaking.