Managing offshore multi-use settings: Use of conceptual mapping to reduce uncertainty of co-locating seaweed aquaculture and wind farms.

The offshore Multi-use Setting (MUS) is a concept that aims to co-locate marine industrial activities, including wind farms and aquaculture. MUS is considered an innovative approach to promoting efficiency in space and resource use whilst contributing global policy priorities. However, the impacts of MUS development across social, economic, and environmental domains are uncertain, hindering the commercialisation of the concept. In this study, we initially demonstrate the potential consequences of co-locating seaweed aquaculture and a wind farm as a step towards MUS. Using a hypothetical case study and modified Delphi methodology, 14 subject matter experts predicted potential outcomes across social and environmental objectives. Five Cognitive maps and impact tables of 58 potential consequences were generated based on experts' perspective on co-locating seaweed aquaculture and a wind farm. The findings highlight the potential to exasperate pressures in the area, including those already attributed to wind farm operations, such as species mortality and stakeholder conflict. However, it may also enhance social-ecological conditions, such as resource provisioning and promoting habitat functionality in the region, through the addition of seaweed aquaculture. The cognitive maps demonstrate the complexity of managing MUS implementation, where high degree of variability and uncertainty about the outcomes is present. The findings of this study provide the vital entry point to performing further integrative assessment and modelling approaches, such as probabilistic analysis and simulations, in support of MUS decision-making. The research also strongly recommends alternative strategies in the pursuit of combining seaweed production and wind farms to avoid significant financial (among many other) trade-offs and risks. More broadly, we have found that our approach's ability to visually represent a complex situation while considering multiple objectives could be immensely valuable for other bioeconomy innovations or nature-based solutions. It helps mitigate the potential for expensive investments without a comprehensive evaluation of the associated risks and negative impacts, as necessitated by the principles of sustainability in decision-making.

Demystifying Breast Disease Markers.

Breast imaging radiologists regularly perform image-guided biopsies of suspicious breast lesions based on features that are associated with a likelihood of malignancy ranging from 2% to greater than 95% (Breast Imaging Reporting and Data System categories 4 and 5). As diagnostic partners, pathologists perform histopathologic assessment of these tissue samples to confirm a diagnosis. Correlating the imaging findings with the histopathologic results is an integral aspect of multidisciplinary breast care. Assessment of radiologic-pathologic concordance is vital in guiding appropriate management, as it enables identification of discordant results, minimizing the chance of misdiagnosis. Undersampling can lead to false-negative results, with the frequencies of false-negative diagnoses varying on the basis of multiple factors, including biopsy type (eg, core needle, vacuum-assisted needle), needle gauge, and type of lesion sampled at biopsy (ie, mass, calcifications, asymmetry, architectural distortion). Improving a radiologist's knowledge of macroscopic and microscopic breast anatomy and more common breast diseases and their expected imaging findings ensures more accurate radiologic-pathologic correlation and management recommendations. The histopathologic and molecular characteristics of biopsy-sampled breast lesions aid in making an accurate diagnosis. Hematoxylin-eosin staining provides critical morphologic details, whereas immunohistochemical staining enables molecular characterization of many benign and malignant lesions, which is critical for tailored treatment. The authors review commonly encountered benign and malignant breast diseases, their corresponding histopathologic phenotypes, and the histopathologic markers that are essential to clinching the diagnosis of these entities. As part of a multidisciplinary team that provides optimal patient care, radiologists should be knowledgeable of the foundations of histopathologic diagnosis and the implications for patient management to ensure appropriate radiologic-pathologic concordance. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.

Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)-derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently, Crebbp-deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss of Crebbp was insufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.Significance: Loss-of-function mutations of CREBBP are common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation. Cancer Discov; 7(3); 322-37. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.

The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program.

The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.

Detailed protocol for administration of intralesional IL-2 for the treatment of Stage IIIc and IV M1a metastatic melanoma based on current NCCN guidelines.

Melanoma claims approximately 9,000 lives in the United States annually. Patients who present with satellite, in-transit, or distant cutaneous metastases have limited treatment options and the prognosis for patients with metastatic disease remains poor. Surgical excision remains the most common treatment modality for cutaneous metastases, but may not address concurrent subclinical in-transit metastases. Other palliative treatment options include Bacillus Calmette-Guérin (BCG) and isolated limb perfusion (ILP). Although intravenous IL-2 has been used for treatment of metastatic melanoma since 1998, intralesional IL-2 has only now been included in the most recent National Comprehensive Cancer Network (NCCN) guidelines after case series and phase I/II clinical trials have shown promising results against Stage IIIc and IV M1a melanoma. Intralesional IL-2 protocols have varied markedly from study to study and there are no consensus guidelines available to help direct treatment. Herein, we present a detailed protocol for the administration of intralesional IL-2 that has been successfully used at two different institutions for treatment of cutaneous melanoma metastases.

The colour of pain: can patients use colour to describe osteoarthritis pain?

OBJECTIVE: The aim of the present study was to explore patients' views on the acceptability and feasibility of using colour to describe osteoarthritis (OA) pain, and whether colour could be used to communicate pain to healthcare professionals. METHODS: Six group interviews were conducted with 17 patients with knee OA. Discussion topics included first impressions about using colour to describe pain, whether participants could associate their pain with colour, how colours related to changes to intensity and different pain qualities, and whether they could envisage using colour to describe pain to healthcare professionals. RESULTS: The group interviews indicated that, although the idea of using colour was generally acceptable, it did not suit all participants as a way of describing their pain. The majority of participants chose red to describe high-intensity pain; the reasons given were because red symbolized inflammation, fire, anger and the stop signal in a traffic light system. Colours used to describe the absence of pain were chosen because of their association with positive emotional feelings, such as purity, calmness and happiness. A range of colours was chosen to represent changes in pain intensity. Aching pain was consistently identified as being associated with colours such as grey or black, whereas sharp pain was described using a wider selection of colours. The majority of participants thought that they would be able to use colour to describe their pain to healthcare professionals, although issues around the interpretability and standardization of colour were raised. CONCLUSIONS: For some patients, using colour to describe their pain experience may be a useful tool to improve doctor-patient communication.

An exploratory investigation of barriers and enablers affecting investment in renewable companies and technologies in the UK.

The last few years have seen considerable research expenditure on renewable fuel technologies. However, in many cases, the necessary sustained and long-term funding from the investment community has not been realized at a level needed to allow technologies to become reality. According to global consulting firm Deloitte's recent renewable energy report (http://www.deloitte.com/energypredictions2012), many renewable energy projects stalled or were not completed because of issues including the global economy, the state of government finances, difficulties in funding and regulatory uncertainty. This investigation concentrates on the funding aspect and explores the perceived barriers and enablers to renewable technologies within the investment and renewables community. Thematic analysis of 14 in-depth interviews with representatives from renewable energy producers, banks and investment companies identified key factors affecting the psychology of investor behaviour in renewables. Eight key issues are highlighted, including a range of barriers and enablers, the role of the government, balance between cost/risk, value/return on investment, investment time scales, personality/individual differences of investors and the level of innovation in the renewable technology. It was particularly notable that in the findings the role of the government was discussed more than other themes and generally in quite critical terms, highlighting the need to ensure consistency in government funding and policy and a greater understanding of how government decision-making happens. Specific findings such as these illustrate the value of crossing disciplinary boundaries and highlight potential further research. Behavioural science and economic psychology in particular have much to offer at the interface of other disciplines such as political science and financial economics.

A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis.

Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.

Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.

Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.

Analysis of the coding genome of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.

BRAF mutations in hairy-cell leukemia.

BACKGROUND: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. METHODS: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. RESULTS: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

A behavioral-economic analysis of the essential value of brands.

Recently, Hursh and Silberberg (2008) have advanced a behavior-economic approach to measure the value of reinforcers, in which demand elasticity is measured relative to the point at which price is zero, a technique that allows for comparisons across reinforcers that show different consumption patterns or across different dosages or magnitudes of the same reinforcer. The authors have proposed an exponential model in which the elasticity coefficient measures the essential value of reinforcers. The application of the exponential model in various experiments has shown that it provided a good fit to the data and supplied different theoretically consistent results. Considering that this previous research has either been experimentally based or has involved nonhuman participants, the present work examined the application of the model to the analysis of changes in consumption of brands with changes in prices, employing data from actual consumers buying brands of food products in grocery shopping, differing in the level of informational (i.e., socially mediated) and utilitarian (i.e., product mediated) reinforcement they offered. Purchase information concerning two products was obtained from a consumer panel, which included data related to purchases of more than 1600 consumers during 52 weeks. The model, calculated for different brands, fitted the data only moderately, but its parameters showed good reliability across stores. The essential value of brands showed significant increases with increases in brand informational reinforcement. The results indicate the reliability of the measure of essential value as its application is extended from the closed setting of the laboratory to the open settings of the marketplace and to symbolic secondary reinforcers.

Inter-organisational communication for patients being case managed by community matrons.

Background Poor communication between community matrons (CMs), in-hours and out-of-hours (OoH) general practitioners (GPs) causes uncertainty and inefficiencies. Setting A practice-based commissioning group in West London and the associated CMs who case manage high users of hospital services. Question What helps good communication between CMs, GPs and OoH services to ensure that the right patients are case managed and hospital admissions are avoided? Methods Whole system participatory action research, with four stages: 1) identify communication problems as perceived by a wide range of stakeholders; 2) draw a diagram of the existing communication system, and with stakeholders redraw this to overcome its weaknesses; 3) pilot the changes proposed; 4) gain consensus among stakeholders about policy. Results Stakeholders agreed that standards should be adopted to improve communication for the care of patients who are case managed by CMs. Routine passage of information between GP, CMs and the OoH services would achieve this, and is feasible. Specifically: routine information (termed Special Patient Notes) should be sent to the OoH service about vulnerable patients, including those who are case managed by CMsclear information about CM attachment to general practices and how to refer to them should be easily accessibleGPs and CMs should meet quarterly for mutual learning and to discuss patientsthe OoH service electronically should cascade information to GPs, CMs and others named in the Special Patient Notescommissioners should routinely gather data to compare clusters of general practices for i) referrals to CMs, ii) posting Special Patient Notes, iii) unscheduled consultations and hospital admissions of all patients including those being case managed. Discussion This project revealed system-wide communication problems for the care of patients being case managed by CMs, and ways to overcome these. Commissioners could insist that these are adopted locally, and gather data to prompt compliance and evaluate the consequential cost savings.

The effect of sports injury on insulin-like growth factor-I and type 3 procollagen: implications for detection of growth hormone abuse in athletes.

CONTEXT: A method to detect exogenously administered growth hormone (GH) based on the measurement of two GH-dependent markers, IGF-I and type 3 procollagen (P-III-P) has been proposed. Skeletal or soft tissue injury may alter these markers. Elevations in either of these proteins after injury might lead to a false accusation of doping with GH. OBJECTIVE: The objective of the study was to assess the effect of musculoskeletal or soft tissue injury on IGF-I and P-III-P concentrations in amateur and elite athletes and assess the effect of injury on the proposed GH detection method. DESIGN: This was a longitudinal observational study after sporting injury. SETTING: The study was conducted at Southampton General Hospital and British Olympic Medical Centre. SUBJECTS: Subjects included elite and amateur athletes after an injury. INTERVENTION: Interventions included measurement of IGF-I and P-III-P and application of the GH-2000 discriminant function score up to 84 d after an injury as well as classification of injury by type and severity. OUTCOME MEASURES: IGF-I and P-III-P concentration and ability to detect GH abuse in athletes without the risk of false accusation because of an injury were measured. RESULTS: There was no change in IGF-I concentration after an injury. By contrast, P-III-P concentrations rose by 41.1 +/- 16.6%, reaching a peak around 14 d after an injury. The rise in P-III-P varied according to injury type and severity. This rise had a trivial effect on the GH-2000 discriminant function score, and no subject reached the threshold needed for a doping offense. CONCLUSIONS: Although there was a rise in P-III-P after injury, this was insufficient to invalidate the GH-2000 detection method based on IGF-I and P-III-P concentrations.