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Purpose Finance is a male-dominated field of work. This study aims to understand if learning in finance follows the same pattern. Furthermore, the authors want to understand if foreign female students are subject to the same cultural norms and sorting mechanisms as their counterparts from the USA or Finland. Design/methodology/approach In the context of a capstone course, students of two well-known international business programs (one in the USA, the other in Finland) participate in a business simulation. The authors surveyed the students on their learning experience across different business functions. The authors collected 440 responses over five years. Findings A gender gap exists in learning finance. Females surveyed reported learning less (9%–15%) than males. However, foreign females reported learning more (11%–17%). Additionally, the authors find no gender gap in learning of other business functions (i.e. marketing and strategy). Foreign females seem to bypass traditional roles and sorting mechanisms. Originality/value To the best of the authors’ knowledge, this study is the first to document the moderating effect of foreignness on the gender gap in learning.

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we describe the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. A pan-cancer tissue microarray analysis indicates that the target is commonly detected (> 50% of cases) in breast, prostate, liver and lung cancer. Citation Format: Kristopher Lofgren, Sreeja Sreekumar, Nicolette Reker, Kyle Ernzen, Paraic A. Kenny. Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-02.

Expedited partner therapy (EPT) refers to the practice of having patients diagnosed with chlamydia or gonorrhea deliver medication directly to their partner(s) to treat them presumptively for infection. Although EPT facilitates timely treatment and prevents reinfection, it remains underused. We used findings from key informant interviews to design and implement a statewide survey to estimate knowledge and utilization of EPT and to identify barriers and facilitators to EPT among Minnesota providers.From November to December 2020, we carried out 15 interviews with health providers who currently provide EPT and coded interviews by recurring themes. We then conducted a statewide online survey on sexually transmitted infection treatment and barriers to EPT, from December 2020 to March 2021. We disseminated the survey to all licensed Minnesota health providers, and those who reported treating bacterial sexually transmitted infections in the past year were included in the study.Interview themes included the importance of direct provision of partner medication, administrative/pharmacy barriers to treatment, inclusive EPT eligibility, and patient counseling. Of the 623 health providers who completed the online survey, only 70% thought EPT was legal and only 37% currently offer EPT. Of those who did not provide EPT, 78% said they would under certain circumstances. Barriers included concerns about safety/liability of prescribing without a medical examination, administrative concerns about prescriptions, and patient acceptance.Given that over a quarter of respondents did not know expedited partner therapy (EPT)'s legal status, improving provider education may increase EPT provision. More research is needed on system-level barriers and patient acceptance of solutions identified in this study.

Amphiregulin (AREG) is a transmembrane protein which, following TACE/ADAM17-dependent cleavage, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. Expression of Amphiregulin has been described by immunohistochemistry in several tumor types, including lung, prostate, head and neck, gastric, pancreatic and breast cancers but evidence for a functional requirement for Amphiregulin in these malignancies is more limited. We have previously described the development of a monoclonal antibody, GMF-1A3, that selectively recognizes the Amphiregulin epitope that is revealed following cleavage by TACE/ADAM17 and demonstrated that drug conjugates of this antibody have anti-tumor activity in mouse models. By directly evaluating Amphiregulin cleavage, immunohistochemistry on tissue specimens using this antibody can be used to evaluate the extent to which Amphiregulin is being proteolytically processed in cancer, which is a more direct measure of Amphiregulin activity. As a potential companion diagnostic for this antibody-drug conjugate, this immunohistochemistry assay allows identification of tumors with high levels of the cleaved Amphiregulin target. Here we evaluate levels of cleaved Amphiregulin in 370 specimens from 10 tumor types and demonstrate that it is widely expressed in solid tumors and is especially common (more than 50% of cases) in breast, prostate, liver and lung cancer.

COVID-19 is challenging many societal institutions, including our criminal justice systems. Some have proposed or enacted (e.g., the State of New Jersey) reductions in the jail and/or prison populations. We present a mathematical model to explore the epidemiologic impact of such interventions in jails and contrast them with the consequences of maintaining unaltered practices. We consider infection risk and likely in-custody deaths, and estimate how within-jail dynamics lead to spill-over risks, not only affecting incarcerated people but increasing exposure, infection, and death rates for both corrections officers and the broader community beyond the justice system. We show that, given a typical jail-community dynamic, operating in a business-as-usual way results in substantial, rapid, and ongoing loss of life. Our results are consistent with the hypothesis that large-scale reductions in arrest and speeding of releases are likely to save the lives of incarcerated people, jail staff, and the wider community.

T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC®), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PDL1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1/PD-L1 axis and to deliver a CD28-mediated costimulatory signal. Here, we report that coexpression of the PD1-CD28 CSR in TRuC-T cells enhanced T cell receptor signaling, increased Th1 effector cytokines, decreased Th2/Th17 cytokines, and sustained effector function in the presence of PD-L1 when compared with TC-210. AntiMSLN TRuC-T cells engineered to coexpress PD1-CD28 CSRs comprising the ectodomain of PD-1 and the intracellular domain of CD28 linked by the transmembrane domain of PD-1 were selected for integration into an anti-MSLN TRuC-T cell therapy product called TC-510. In vitro, TC-510 showed significant improvements in persistence and resistance to exhaustion upon chronic stimulation by tumor cells expressing MSLN and PDL1 when compared with TC-210. In vivo, TC-510 showed a superior ability to provide durable protection following tumor rechallenge, versus TC-210. These data demonstrate that integration of a PD1-CD28 CSR into TRuC-T cells improves effector function, resistance to exhaustion, and prolongs persistence. Based on these findings, TC-510 is currently being evaluated in patients with MSLN-expressing solid tumors.

Acute kidney injury (AKI) is a common complication of cardiac surgery that is associated with increased hospital length of stay and mortality risk. The most common diagnostic criteria come from the Kidney Disease Improving Global Outcomes Guidelines. These criteria rely on detecting changes in serum creatinine relative to a baseline measurement and decreased urine output. These markers are meant to capture a decrease in the overall filtration rate. However, the filtration rate may or may not change depending on the baseline health of the individual patient and the type and severity of the injury. In addition, these markers are influenced by factors other than renal function or health, such as the administration of certain drugs or the volume status of the patient. Up to this point, research has primarily focused on the application of serum and urinary biomarkers that increase in response to renal injury or cell death. While these tests have advantages over current methods, the clinical utility of these tools is limited by high cost and a long wait time for results. Thus, there is a need for a noninvasive biomarker that is physiologically linked to the development of AKI and is easy to interpret. Studies have shown that renal hypoxia is a common factor in the development of most forms of AKI. In addition, early studies found there was a strong correlation between urine oxygen partial pressure (PuO2) and renal tissue oxygenation. Others have confirmed that low PuO2 is a risk factor for developing AKI in the setting of cardiac surgery. While we have developed a noninvasive PuO2 monitor, it is necessary to build an algorithm that can interpret this data and help the care team digest the information contained in the signal. Thus, the aim of this work was to test whether we could combine noninvasive PuO2 monitoring and machine learning to predict AKI with similar performance to injury-based biomarkers. The average area under the receiver operator characteristic curve for the machine learning algorithms was less than 0.7, which is the lower end of the predictive performance for injury-based biomarkers. However, we have identified several potential explanations and will work to address them in the future. Developing a noninvasive PuO2 monitor, and related algorithm could potentially improve outcomes in cardiac surgery and more generally in resource limited or austere settings such as during space travel.

Post-exercise hypotension (PEH) is an immediate reduction in blood pressure (BP) after a single bout of exercise that forms the long-term hypertension amelioration by chronic exercise. The present study aims to explore a novel mechanism of PEH, with a focus of skeletal muscle-derived extracellular vesicles (SkM-EVs). We hypothesize that repetitively contracting-relaxing muscle releases antioxidant-enriched EVs that induce hypotension. Experiments were carried out in 48 male Sprague-Dawley rats. BP was recorded by a Millar catheter inserted into right carotid artery. EVs were isolated from SkM and plasma using ultracentrifugation, and then qualified and quantified using transmission electron microscopy and the ZetaView nanoparticle tracking analyzer. Results: First, in rats undergoing 1-hour of treadmill exercise (15/30/15 m/min for 10/40/10 min), we found an elevated BP during exercise (34.7 ± 5.2 mmHg, p < 0.001; n = 8), followed by a decrease in BP below baseline during the post exercise period (-7.3 ± 1.1 mmHg, p < 0.01). Pretreatment with the EV inhibitor GW4869 (1.5 mg/kg) had no effects on hypertension during exercise, but completely abolished the post-exercise hypotension (1.93 ± 0.64 mmHg, p < 0.001), suggesting a role for SkM-EVs in this response. Bolus i.v. injection of SkM-EVs from exercised rats (400 μg EV protein) induced a dramatic decrease in BP (-16.7 ± 4.4 mmHg; p < 0.01, n = 6/group) in non-exercised rats, which lasted for up to 40 min. Second, 1-hour sciatic nerve electrical stimulation (2.5V, 50Hz, 0.3s/3s)-evoked hindlimb muscle contraction in isoflurane-anesthetized rats induced a biphasic change in BP, with hypertension during the initial 20 min followed by hypotension in the last 40 min. Transection of the sciatic nerve or pretreatment with GW4869 abolished the stimulation-evoked hypertension and hypotension. Bolus i.v. injection of EVs from contracting-muscle significantly reduced BP with a maximal change of -14 ± 3.2 mmHg (p = 0.003; n = 5). Third, mass spectroscopic and western blotting analyses of these EVs identified 827 proteins, including Catalase, GSTMs, PRDXs, EPHX1, HSP90, and many others, which are involved in redox homeostasis and mitochondrial bioenergetics. Finally, using muscle-specific GFP reporter mice (MS-mG), we found increased SkM-EVs in both muscle and plasma following exercise by using flow cytometry. Confocal imaging identified GFP+-particles in the neurons of the rostral ventrolateral medulla (RVLM) of C57BL/6 mice that received an injection of SkM-EVs isolated from the exercised MS-mG mice, suggesting their active uptake across the blood-brain barrier. In summary, the major findings of this study include (1) SkM-EVs are essential for PEH; (2) i.v. administration of SkM-EVs reduced BP; (3) SkM-EVs contain enriched antioxidant enzymes and other cytoprotective proteins. These results suggest a novel mechanism underpinning PEH and provides a potential therapeutic strategy for hypertension. Supported by NIH grant R01HL160820. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SummaryLong-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. It has been proposed that high affinity cells are preferentially selected into this compartment, potentiating the immune response. Here we used single cell RNA-seq to track the development of Ighg2A10cells, specific for thePlasmodium falciparumcircumsporozoite protein (PfCSP) within the germinal center (GC). We identified cells differentiating into memory B cells (MBC) or PCs and estimated their affinity by V(D)J sequencing. While pre-memory cells were of lower affinity than GC B cells generally, the affinity of pre-PC cells was indistinguishable. Rather, a larger proportion of cells differentiated into PCs in waning GCs. These later emigrants replaced early arrivals in the bone marrow allowing the development of a high affinity PC compartment.

This critical literature review provides study details for 36 studies examining the effect of glossing for language acquisition among English language learners (ELLs). Useful tables include specificity of participants, gloss types, target vocabulary items and text information about all studies. An analysis of these studies reveals that glossing is an effective means to enhance reading comprehension among ELLs. However, gloss language—whether L1 or English, may depend on learner factors. Other findings include the importance of proximity of gloss to text and the need for glosses that do not require readers to leave the text to access meaning. Considerations such as text genre, text length, targeted items for glossing, number of items to gloss, and gloss presentation are also examined and discussed, including which gloss types may result in trade-offs when glossing is used as a means to promote incidental vocabulary acquisition through independent reading. Several recommendations for further research are offered.

Limited research exists regarding the diet quality and nutritional concerns of people with Parkinson's disease (PwPD) and their informal caregivers. The study's purpose was to assess diet quality via the Healthy Eating Index-2015 (HEI-2015) and self-reported nutrition concerns via semi-structured, dyadic interviews of 20 PwPD (69.7 ± 9.2 yrs) and their caregivers (66.7 ± 13.0 yrs). HEI-2015 scores were 58.3 ± 12.4 and 58.1 ± 10.6 for PwPD and caregivers, respectively. Reported dietary concerns related to PD included: change in appetite or amount eaten, gastrointestinal issues, food-medication management, chewing/swallowing issues, and change in taste/smell. The poor diet quality and nutrition concerns identified suggest nutrition professionals and caregivers are critical on the healthcare team to promote optimal health among PwPD. Future research should address overall and specific aspects of diet quality, and nutritional concerns identified by dyads in this study, such as gastrointestinal issues and food-medication management.

Additional representative examples of Amphiregulin immunostaining in breast cancer specimens

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERα)-positive breast cancer. Many ERα target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERα-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Furthermore, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the therapeutic response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERα-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response. Cancer Res; 75(22); 4830–8. ©2015 AACR.

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PDF file, 3449K, ChIP data showing recruitment of HIF-1a, HIF-2a, and RNA pol II to HREs 2-5 in the Brk promoter.

PDF file, 4524K, Regulation of Brk protein and mRNA expression in MCF7 cells.

PDF file, 5252K, Table detailing patient information from HCI tumor samples used.

PDF file, 2022K, Western and mRNA data downing retroviral transduction of Brk gene and subsequent over expression, as well as maintenance of HIF1a/2a knockdown.

When estimating an effect of an action with a randomized or observational study, that study is often not a random sample of the desired target population. Instead, estimates from that study can be transported to the target population. However, transportability methods generally rely on a positivity assumption, such that all relevant covariate patterns in the target population are also observed in the study sample. Strict eligibility criteria, particularly in the context of randomized trials, may lead to violations of this assumption. Two common approaches to address positivity violations are restricting the target population and restricting the relevant covariate set. As neither of these restrictions are ideal, we instead propose a synthesis of statistical and simulation models to address positivity violations. We propose corresponding g-computation and inverse probability weighting estimators. The restriction and synthesis approaches to addressing positivity violations are contrasted with a simulation experiment and an illustrative example in the context of sexually transmitted infection testing uptake. In both cases, the proposed synthesis approach accurately addressed the original research question when paired with a thoughtfully selected simulation model. Neither of the restriction approaches were able to accurately address the motivating question. As public health decisions must often be made with imperfect target population information, model synthesis is a viable approach given a combination of empirical data and external information based on the best available knowledge.

At a time when antibiotic resistance is seemingly ubiquitous worldwide, understanding the mechanisms responsible for successful emergence of new resistance genes may provide insights into the persistence and pathways of dissemination for antibiotic-resistant organisms in general. For example, Escherichia coli strains harboring a class A β-lactamase-encoding gene (bla(CTX-M-15)) appear to be displacing strains that harbor a class C β-lactamase gene (bla(CMY-2)) in Washington State dairy cattle. We cloned these genes with native promoters into low-copy-number plasmids that were then transformed into isogenic strains of E. coli, and growth curves were generated for two commonly administered antibiotics (ampicillin and ceftiofur). Both strains met the definition of resistance for ampicillin (≥32 μg/mL) and ceftiofur (≥16 μg/mL). Growth of the CMY-2-producing strain was compromised at 1,000 μg/mL ampicillin, whereas the CTX-M-15-producing strain was not inhibited in the presence of 3,000 μg/mL ampicillin or with most concentrations of ceftiofur, although there were mixed outcomes with ceftiofur metabolites. Consequently, in the absence of competing genes, E. coli harboring either gene would experience a selective advantage if exposed to these antibiotics. Successful emergence of CTX-M-15-producing strains where CMY-2-producing strains are already established, however, requires high concentrations of antibiotics that can only be found in the urine of treated animals (e.g., >2,000 μg/mL for ampicillin, based on literature). This ex vivo selection pressure may be important for the emergence of new and more efficient antibiotic resistance genes and likely for persistence of antibiotic-resistant bacteria in food animal populations. IMPORTANCE We studied the relative fitness benefits of a cephalosporin resistance enzyme (CTX-M-15) that is displacing a similar enzyme (CMY-2), which is extant in E. coli from dairy cattle in Washington State. In vitro experiments demonstrated that CTX-M-15 provides a significant fitness advantage, but only in the presence of very high concentrations of antibiotic that are only found when the antibiotic ampicillin, and to a lesser extent ceftiofur, is excreted in urine from treated animals. As such, the increasing prevalence of bacteria with bla(CTX-M-15) is likely occurring ex vivo. Interventions should focus on controlling waste from treated animals and, when possible, selecting antibiotics that are less likely to impact the proximal environment of treated animals.

GATA3 is somatically mutated in approximately 15% of estrogen receptor positive human breast tumors, however the mechanism(s) by which these alterations contribute to tumorigenesis are unclear. The observed patterns of mutations suggest a strong selective pressure to mutate a single allele of GATA3 in a manner favoring retention of the first of two zinc finger domains. The non-mutated GATA3 allele is maintained and expressed. We and others have hypothesized that expression of the mutant GATA3 protein may actively contribute to breast tumorigenesis, however the aging of several independently generated mouse models with mammary-specific mutant GATA3 expression did not result in tumorigenesis. In this study, we evaluated whether a mammary tumor-promoting dose of medroxyprogesterone acetate could synergize with mammary specific mutant GATA3 (G335fs) expression and accelerate the kinetics of tumor formation. We report that the tumor incidence rate in these animals did not differ from that observed in wild-type littermate controls.

A review of Abigail Favale, The Genesis of Gender: A Christian Theory.

Supplemental material, sj-docx-1-mpp-10.1177_23814683221150446 for Evaluation of Strategies to Improve Uptake of Expedited Partner Therapy for Chlamydia trachomatis Treatment in Minnesota: A Decision Analytic Model by Emily A. Groene, Christy M. Boraas, M. Kumi Smith, Sarah M. Lofgren, Meghan K. Rothenberger and Eva A. Enns in MDM Policy & Practice

Supplemental material, sj-docx-1-mpp-10.1177_23814683221150446 for Evaluation of Strategies to Improve Uptake of Expedited Partner Therapy for Chlamydia trachomatis Treatment in Minnesota: A Decision Analytic Model by Emily A. Groene, Christy M. Boraas, M. Kumi Smith, Sarah M. Lofgren, Meghan K. Rothenberger and Eva A. Enns in MDM Policy & Practice

Es tracta d'un erratum de l'article publicat a Journal of Communication Disorders. 2022 May-Jun;97:106214. DOI: 10.1016/j.jcomdis.2022.106214

Informed by entrenchment and usage-based theories, this mixed methods study, modeled after Riazi's mixed methods fully integrated design, examined how reading and writing may be used to facilitate lexical sequence acquisition for high school bilingual learners. The study compared the efficacy of two interventions on increasing the depth of knowledge of lexical sequences: a reading intervention requiring the reading of short informational texts embedded with eight target lexical sequences and a writing intervention requiring participants to follow the readings with the intentional use of target sequences in writing. A repeated measures factorial ANOVA found no impact of gender or first language on results; both groups made statistically significant gains on depth of knowledge during both interventions with large effect sizes, and they retained gains three to four weeks later. However, reading was found to be more impactful for one group, whereas reading and writing was found to be more impactful for the second group. Subsequent analyses of written responses by participants coupled with a repeated measures ANOVA measuring the acquisition of individual sequences demonstrated that participants were more likely to acquire and use some lexical sequences than others. Data from semi-structured interviews from 12 participants were analyzed through the lens of Anthias’ multilevel model of intersectionality to determine factors influencing intervention results as well as English learning generally. Results of this qualitative strand revealed that the requirement to read twice weekly led reading to become a habit for some participants, that text interest impacted some participants’ motivation to comprehend the text, and that interlinear glossing (providing synonyms above target sequences) was helpful for reading comprehension. Gender and L1 were found to influence learning through the long-lasting impact of bullying, which often led females and those with perceived accents to refrain from speaking English even years after bullying occurred. Other salient findings suggest that the employment of high school students may be underreported and that implicit teacher bias may impact the schooling of some bilingual learners. One LGBTQ bilingual learner narrative provided a positive example of empowerment despite the bullying of others. Several recommendations for research, policy, and teaching practices are discussed.

In this article, we explore several uses of zombie epidemics to make mathematical modeling and infectious disease epidemiology more accessible to public health professionals, students, and the general public.

Background Molecular analyses have shown that tumours diagnosed as supratentorial primitive neuro-ectodermal tumours of the central nervous system (CNS-PNETs) in the past represent a heterogenous group of rare childhood tumours including high-grade gliomas (HGG), ependymomas, atypical teratoid/rhabdoid tumours (AT/RT), CNS neuroblastoma with forkhead box R2 (FOXR2) activation and embryonal tumour with multi-layered rosettes (ETMR). All these tumour types are rare and long-term clinical follow-up data are sparse. We retrospectively re-evaluated all children (0–18 years old) diagnosed with a CNS-PNET in Sweden during 1984–2015 and collected clinical data. Methods In total, 88 supratentorial CNS-PNETs were identified in the Swedish Childhood Cancer Registry and from these formalin-fixed paraffin-embedded tumour material was available for 71 patients. These tumours were histopathologically re-evaluated and, in addition, analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. Results The most frequent tumour types, after histopathological re-evaluation, were HGG (35%) followed by AT/RT (11%), CNS NB-FOXR2 (10%) and ETMR (8%). DNA methylation profiling could further divide the tumours into specific subtypes and with a high accuracy classify these rare embryonal tumours. The 5 and 10-year overall survival (OS) for the whole CNS-PNET cohort was 45% ± 12% and 42% ± 12%, respectively. However, the different groups of tumour types identified after re-evaluation displayed very variable survival patterns, with a poor outcome for HGG and ETMR patients with 5-year OS 20% ± 16% and 33% ± 35%, respectively. On the contrary, high PFS and OS was observed for patients with CNS NB-FOXR2 (5-year 100% for both). Survival rates remained stable even after 15-years of follow-up. Conclusions Our findings demonstrate, in a national based setting, the molecular heterogeneity of these tumours and show that DNA methylation profiling of these tumours provides an indispensable tool in distinguishing these rare tumours. Long-term follow-up data confirms previous findings with a favourable outcome for CNS NB-FOXR2 tumours and poor chances of survival for ETMR and HGG.

Nobel laureate Wolfgang Paul showed, back in the 1950s, that charged particles can be trapped using alternating electric fields. This technique is commonly referred to as Paul traps or radiofrequency traps (RF-traps) and is used in various areas of modern physics. This paper presents a 3D-printed mechanical Paul trap, a na\"ive simulation of the system in Python, and student investigations. The files for the 3D-printed trap are available for download and print, and the code for the simulation is available to run and tinker with., Comment: 4 pages, 4 figures

BACKGROUND: Persons with dementia encounter time-related problems and significant others often need to provide support in daily time management and use of time assistive technology (AT). Further research has been requested on how time AT for persons with dementia affects the situation of significant others. Moreover, there are a few previous qualitative studies on the experiences of time AT by persons with dementia. This study explores the experiences of persons with dementia and significant others in daily time management and their perceptions on how time AT affects everyday life. METHOD: Semi-structured interviews with persons with mild to moderate dementia (n = 6) and significant others (n = 9) were conducted three months after receiving prescribed time AT. Interviews were analysed using qualitative content analysis. RESULTS: A main category "Support by significant others is always part of daily time management", and three categories "Facing new challenges", "Using strategies to handle changes", and "Time assistive technology in daily life" illustrated that significant others provided support for daily time management in all phases of dementia. This support was often embedded in other kinds of support for emerging challenges. Support in time management was needed from an early stage in dementia, and responsibility for time management was gradually transferred to significant others. Time AT could support time orientation and were important for sharing the time management conducted by others but did not enable independent time management. CONCLUSIONS: Time-related assessments and interventions should be offered at an early stage of dementia to increase the possibility of maintaining daily time management skills. Using time AT to communicate time might increase agency and participation in daily occupations for persons with dementia. Given the central role of significant others for daily time management, the society needs to adequately support persons with dementia lacking support from significant others.

There has been an upsurge in more participatory, interactive and citizen-oriented governance practices all around the world since the 1990s. What they all have in common is an emphasis on mobilising citizens and stakeholders affected, strengthening local communities, ensuring efficient planning solutions, and securing enhanced legitimacy for existing governing institutions. Conversely, we have witnessed a growing interest in designing frameworks for evaluating the democratic quality of these innovations, asking questions such as the extent to which they actually are enhancing the quality of democracy? This article juxtaposes seven recent evaluative frameworks developed by academics, which address the question of the democratic quality of these new democratic innovations. The article concludes that there are many overlaps between the different frameworks in terms of criteria with a mix of traditional and more participatory democratic norms at play. Furthermore, it also concludes these evaluative practices in many ways reflect the managerial search for accountability mechanisms in the public sector.

Background Significant growth in advanced practice registered nurse (APRN) student placements for clinical practicums have forced APRN preceptors, hospitals, and clinics to restrict the volume of APRN students they can accommodate. Purpose Describe the experiences and opinions of APRNs regarding their precepting experiences of APRN students in three main areas; placement antecedents, placement postcedents, and preceptor incentives. Methods Quality improvement study conducted via electronic survey that contained quantitative short answer and a qualitative open-ended question of APRNs licensed in the State of REDACTED in June, 2019. Findings A total of 757 surveys were quantitatively analyzed. Qualitative thematic analysis resulted in identifying one overarching theme, the need for shared responsibility and accountability, and six unique primary themes. Discussion Our findings indicate that APRN preceptors recognize their critical role but lack support and preparation to fully execute academic and profession strategic goals and objectives. There is the need for academic and professional ownership of APRN education at every level.

Background The Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG), is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. AREG is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Methods Using phage display, we identified antibodies that selectively recognize the residual transmembrane stalk of cleaved AREG. Conjugation with fluorescence labels and monomethyl auristatin E (MMAE) was used to study their intracellular trafficking and anti-cancer effects, respectively. Results We report the development of an antibody-drug conjugate (ADC), GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved AREG, providing a novel means of targeting cells with high rates of AREG shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved AREG. Antibodies conjugated with MMAE were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the AREG neo-epitope in formalin-fixed, paraffin-embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. Conclusions This ADC targeting AREG has potential utility in the treatment of breast and other tumors in which proteolytic AREG shedding is a frequent event.

Fungi have successfully established themselves across seemingly every possible niche, substrate, and biome. They are fundamental to biogeochemical cycling, interspecies interactions, food production, and drug bioprocessing, as well as playing less heroic roles as difficult to treat human infections and devastating plant pathogens. Despite community efforts to estimate and catalog fungal diversity, we have only named and described a minute fraction of the fungal world. The identification, characterization, and conservation of fungal diversity is paramount to preserving fungal bioresources, and to understanding and predicting ecosystem cycling and the evolution and epidemiology of fungal disease. Although species and ecosystem conservation are necessarily the foundation of preserving this diversity, there is value in expanding our definition of conservation to include the protection of biological collections, ecological metadata, genetic and genomic data, and the methods and code used for our analyses. These definitions of conservation are interdependent. For example, we need metadata on host specificity and biogeography to understand rarity and set priorities for conservation. To aid in these efforts, we need to draw expertise from diverse fields to tie traditional taxonomic knowledge to data obtained from modern -omics-based approaches, and support the advancement of diverse research perspectives. We also need new tools, including an updated framework for describing and tracking species known only from DNA, and the continued integration of functional predictions to link genetic diversity to functional and ecological diversity. Here, we review the state of fungal diversity research as shaped by recent technological advancements, and how changing viewpoints in taxonomy, -omics, and systematics can be integrated to advance mycological research and preserve fungal biodiversity.

Shin Gojira released five years after the devastating triple disaster of earthquake, tsunami and nuclear meltdown at the Fukushima Daiichi Nuclear Power Plant of March 2011, is an unabashed metaphorical censuring of the Japanese government response to that disaster under Prime Minister Kan Naoto, as well as a warning of the dangers of continued reliance on nuclear power. In this respect, it diverges from the message of nuclear disarmament effected by its 1954 progenitor, Gojira, but it still hews true to Godzilla’s roots as the concretized fear of a particular historical moment with the atom at its heart. This new iteration of Japan’s favourite kaijū, however, offers a trenchant condemnation of Japan’s pursuit of energy autonomy by relying on nuclear power generation. An oblique evocation of Auguste Rodin’s The Gates of Hell at the end of the film and the tip of Godzilla’s tail drive this point home. Through the metaphor of the gate, Godzilla becomes a liminal marker of an alternative possibility. Ultimately, however, although Godzilla is positioned as both a destructive force and a source of hope – as was the atom – the current reality in Japan suggests that the safe path forward has already been closed to the Japanese population.

To respond to the climate crisis, we need to accelerate system transformations at a pace, scale, and breadth not seen before. This means that it is urgent to shift development pathways towards net zero greenhouse gas emissions, even while progressing towards other sustainable development objectives. This paper argues that accelerated mitigation can not only benefit from policies that are outside the domain of conventional emission-focused mitigation policies but require such policies. We refer to this process as shifting development pathways towards sustainability. Here, we explore what enabling conditions make such shifts possible. We develop a framework to select examples of shifts — in realms such as educational access, housing access, fiscal arrangements, and institutional reform. We analyse them against key enablers. Our findings suggest that countries could learn from what has worked elsewhere, though context matters. Some enablers are more widely applicable, including finance, long-term vision, and focus on sustainable development objectives. Multiple enablers, integrated policy packages, and involvement of a broad range of actors help achieve multiple objectives. Some enablers may yield results in the near term, while others take time to yield results. Based on our analysis, we suggest that climate mitigation requires an “all of economy, all of society” approach. Graphical Abstract

Background Antibiotic therapy is a known risk factor for Clostridioides difficile infection (CDI) and evidence suggests the magnitude of risk varies by spectrum of antibiotic activity and days of therapy (DOT). We quantified the risk of hospital-associated (HA) CDI associated with antibiotic therapy considering spectrum of activity and DOT. Methods We performed a retrospective cohort study of adult (≥18 years) inpatient encounters at a 576-bed academic medical center in Portland, OR between January 2018 and February 2020. We excluded patients with hospital stays under 4 days and those known to have recurrent (CDI in the previous 12 weeks) or community-acquired (CDI diagnosis within first 3 days of hospitalization) CDI. The primary exposure of antibiotic utilization was measured using the Antibiotic Spectrum Index (ASI), where spectrum-based weights are applied to each agent and DOT over the time at risk, summed over the encounter, and divided by the number of antibiotic days. The primary outcome was HA-CDI. We estimated the independent association between aggregate ASI and HA-CDI using multivariable logistic regression. Results Among 37,629 inpatient encounters, 68% patients received at least one antibiotic. We identified 159 cases of non-recurrent HA-CDI, which corresponds to 4.8 cases per 10,000 patient-days. Compared to those without HA-CDI, those with HA-CDI had a greater median number of distinct antibiotics prescribed (4 vs 1), greater median days of antibiotic therapy (22 vs 2), a greater median time at-risk (9 vs 6 days), and greater median Elixhauser Comorbidity Index (9 vs 4) (Kruskal-Wallis p-value < 0.0001 for all comparisons). There were no significant differences by age or sex. Patients with HA-CDI had a greater mean ASI per antibiotic day than those without (5.2 vs 3.2, Student’s t-test p < 0.0001). After adjusting for time at-risk and Elixhauser Comorbidity Index, each one-unit of ASI per antibiotic day was associated with 1.29 times increased odds of developing HA-CDI (Odds Ratio = 1.29, 95% Confidence Interval: 1.21 to 1.37). Conclusion The Antibiotic Spectrum Index was strongly associated with HA-CDI. ASI may be a useful tool for quantifying the risk of CDI according to the specific antibiotic therapy received among hospitalized patients. Disclosures All Authors: No reported disclosures.

SARS-CoV-2 likely emerged from an animal reservoir. However, the frequency of and risk factors for interspecies transmission remain unclear. We conducted a community-based study in Idaho, USA, of pets in households that had1 confirmed SARS-CoV-2 infections in humans. Among 119 dogs and 57 cats, clinical signs consistent with SARS-CoV-2 were reported for 20 dogs (21%) and 19 cats (39%). Of 81 dogs and 32 cats sampled, 40% of dogs and 43% of cats were seropositive, and 5% of dogs and 8% of cats were PCR positive. This discordance might be caused by delays in sampling. Respondents commonly reported close human‒animal contact and willingness to take measures to prevent transmission to their pets. Reported preventive measures showed a slightly protective but nonsignificant trend for both illness and seropositivity in pets. Sharing of beds and bowls had slight harmful effects, reaching statistical significance for sharing bowls and seropositivity.

The purpose of this study was to examine demographic-specific relationships between direct abdominal fat measures and anthropometric indices. A cross-sectional study was conducted utilizing abdominal fat measures (visceral fat area, VFA; visceral to subcutaneous adipose area ratio, VSR) and anthropometrics (body mass index, BMI; waist circumference, WC) data from the 2011–2018 National Health and Nutrition Examination Survey. Linear or polynomial linear regression models were used to examine the relationships of abdominal fat measures to anthropometrics with adjustment for demographics. The results revealed that while VFA was linearly related to BMI and WC across all demographics (p < 0.001), the relationships between VSR and both BMI and WC were concave in men and convex in women. The relationships between VFA, VSR, and BMI, WC varied by sex and race/ethnicity. In conclusion, increasing BMI and WC were linearly associated with increased VFA, but their relationships with VSR were nonlinear and differed by sex.