Publications by authors named "Ellen Fox"

40 Publications

Ethics Consultation in United States Hospitals: Assessment of Training Needs.

J Clin Ethics 2021 ;32(3):1-9

Altarum Institute, Ann Arbor, Michigan USA.

Background: To help inform the development of more accessible, acceptable, and effective ethics consultation (EC) training programs, we conducted an EC training needs assessment, exploring ethics practitioners' opinions on: the relative importance of various EC practitioner competencies; the potential market for EC training (that is, how many individuals would benefit and how much individuals and hospitals would be willing to pay); and the preferred content, format, and characteristics of EC training.

Methods: As part of a multipart study, we surveyed "best informants" who self-identified as the person most actively involved in EC or healthcare ethics in a random sample of 600 U.S. general hospitals, stratified for bed size.

Results: The competency that was ranked most important for a lead or solo ethics consultant was knowledge of ethics, while common sense was ranked least important. The median estimated number of individuals at each hospital who would benefit from EC training was six at the basic level, three at the advanced level, and two for EC management training. In 19.1 percent of hospitals, respondents thought their hospital would not be willing to pay anything for EC training within the next two years. Respondents thought potential trainees would be likely to participate in EC training on multiple different topics. Opinions varied widely on preferred formats. Most respondents thought it very important to be able to interact with instructors and with other trainees, practice EC skills, receive a certificate for completing EC training, and complete EC training during work hours.

Conclusions: These findings provide U.S. population data that may be useful to healthcare educators and bioethics leaders in their efforts to develop EC training programs and products that match trainees' preferences and needs.
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August 2021

Health care ethics programs in U.S. Hospitals: results from a National Survey.

BMC Med Ethics 2021 07 29;22(1):107. Epub 2021 Jul 29.

Altarum Institute, 3520 Green Ct., Suite 300, Ann Arbor, MI, 48105, USA.

Background: As hospitals have grown more complex, the ethical concerns they confront have grown correspondingly complicated. Many hospitals have consequently developed health care ethics programs (HCEPs) that include far more than ethics consultation services alone. Yet systematic research on these programs is lacking.

Methods: Based on a national, cross-sectional survey of a stratified sample of 600 US hospitals, we report on the prevalence, scope, activities, staffing, workload, financial compensation, and greatest challenges facing HCEPs.

Results: Among 372 hospitals whose informants responded to an online survey, 97% of hospitals have HCEPs. Their scope includes clinical ethics functions in virtually all hospitals, but includes other functions in far fewer hospitals: ethical leadership (35.7%), regulatory compliance (29.0%), business ethics (26.2%), and research ethics (12.6%). HCEPs are responsible for providing ongoing ethics education to various target audiences including all staff (77.0%), nurses (59.9%), staff physicians (49.0%), hospital leadership (44.2%), medical residents (20.3%) and the community/general public (18.4%). HCEPs staff are most commonly involved in policy work through review of existing policies but are less often involved in development of new policies. HCEPs have an ethics representative in executive leadership in 80.5% of hospitals, have representation on other hospital committees in 40.7%, are actively engaged in community outreach in 22.6%, and lead large-scale ethics quality improvement initiatives in 17.7%. In general, major teaching hospitals and urban hospitals have the most highly integrated ethics programs with the broadest scope and greatest number of activities. Larger hospitals, academically affiliated hospitals, and urban hospitals have significantly more individuals performing HCEP work and significantly more individuals receiving financial compensation specifically for that work. Overall, the most common greatest challenge facing HCEPs is resource shortages, whereas underutilization is the most common greatest challenge for hospitals with fewer than 100 beds. Respondents' strategies for managing challenges include staff training and additional funds.

Conclusions: While this study must be cautiously interpreted due to its limitations, the findings may be useful for understanding the characteristics of HCEPs in US hospitals and the factors associated with these characteristics. This information may contribute to exploring ways to strengthen HCEPs.
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http://dx.doi.org/10.1186/s12910-021-00673-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320092PMC
July 2021

Ethics Consultation in U.S. Hospitals: Determinants of Consultation Volume.

Am J Bioeth 2021 Mar 26:1-7. Epub 2021 Mar 26.

Altarum Institute.

The annual volume of ethics consultations (ECs) has been a topic of interest in the bioethics literature, in part because of its presumed relationship to quality. To better understand factors associated with EC volume, we used multiple linear regression to model the number of case consultations performed in the last year based on a national survey. We found that hospital bed size, academic affiliation, and urban/rural location were all associated with EC volume, but were the primary drivers. Instead, these variables affected EC volume three other variables, all of which relate to ethics staffing: the percentage of case consultations performed by a single individual; whether the survey respondent's main role at the hospital contained the word "ethics"; and especially, the number of full-time ethics program staff. We conclude that EC is an example of supply-sensitive care, and further research is needed to determine the optimal level of EC activity.
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http://dx.doi.org/10.1080/15265161.2021.1893548DOI Listing
March 2021

Ethics Consultation in U.S. Hospitals: Opinions of Ethics Practitioners.

Am J Bioeth 2021 Mar 26:1-19. Epub 2021 Mar 26.

Altarum Institute.

To design effective strategies to improve ethics consultation (EC) practices, it is important to understand the views of ethics practitioners. Previous U.S. studies of ethics practitioners have overrepresented the views of academic bioethicists. To help inform EC improvement efforts, we surveyed a random stratified sample of U.S. hospitals, examining ethics practitioners' opinions on EC in general, on their own EC service, on strategies to improve EC, and on ASBH practice standards. Respondents across all categories of hospitals had very positive perceptions of their own ethics consultation service (ECS) and few concerns about quality. Our findings suggest that the ethics-related needs of small, rural, non-teaching hospitals may be very different from those of academic medical centers, and therefore, different approaches to addressing ethical issues might be warranted.
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http://dx.doi.org/10.1080/15265161.2021.1893550DOI Listing
March 2021

Ethics Consultation in U.S. Hospitals: A National Follow-Up Study.

Am J Bioeth 2021 Mar 26:1-14. Epub 2021 Mar 26.

Altarum Institute.

A 1999-2000 national study of U.S. hospitals raised concerns about ethics consultation (EC) practices and catalyzed improvement efforts. To assess how practices have changed since 2000, we administered a 105-item survey to "best informants" in a stratified random sample of 600 U.S. general hospitals. This primary article details the methods for the entire study, then focuses on the 16 items from the prior study. Compared with 2000, the estimated number of case consultations performed annually rose by 94% to 68,000. The median number of consults per hospital was unchanged at 3, but more than doubled for hospitals with 400+ beds. The level of education of EC practitioners was unchanged, while the percentage of hospitals formally evaluating their ECS decreased from 28.0% to 19.1%. The gap between large, teaching hospitals and small, nonteaching hospitals widened since the prior study. We suggest targeting future improvement efforts to hospitals where needs are not being met by current approaches to EC.
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http://dx.doi.org/10.1080/15265161.2021.1893547DOI Listing
March 2021

Reopening Colleges During the Coronavirus Disease 2019 (COVID-19) Pandemic-One Size Does Not Fit All.

JAMA Netw Open 2020 07 1;3(7):e2017838. Epub 2020 Jul 1.

Fox Ethics Consulting, Arlington, Virginia.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.17838DOI Listing
July 2020

Unanswered Questions About Clinical Ethics Expertise.

Am J Bioeth 2019 11;19(11):91-94

University of Maryland, Baltimore.

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http://dx.doi.org/10.1080/15265161.2019.1669733DOI Listing
November 2019

A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response.

PLoS Negl Trop Dis 2019 01 17;13(1):e0007070. Epub 2019 Jan 17.

Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.

The natural history of schistosome infection in the mammalian host is determined by CD4+ T helper responses mounted against different parasite life cycle stages. A T helper 2 (TH2) response to schistosome eggs is required for host survival and establishment of chronic infection. However, a TH2 cell-derived cytokine also contributes to an immune milieu that is conducive to schistosome growth and development. Thus, the same responses that allow for host survival have been co-opted by schistosomes to facilitate parasite development and transmission, underscoring the significance of CD4+ T cell responses to both worms and eggs in the natural history of schistosome infection. Here we show that a cathepsin B1 cysteine protease secreted by schistosome worms not only induces TH2 responses, but also TH1 and TH17 responses, by a mechanism that is dependent on the proteolytic activity of the enzyme. Further investigation revealed that, in addition to the expected TH1 and TH2 responses, acute schistosome infection also induces a transient TH17 response that is rapidly down-regulated at the onset of oviposition. TH17 responses are implicated in the development of severe egg-induced pathology. The regulation of worm-induced TH17 responses during acute infection could therefore influence the expression of high and low pathology states as infection progresses.
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http://dx.doi.org/10.1371/journal.pntd.0007070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353221PMC
January 2019

A Comprehensive Approach to Eliciting, Documenting, and Honoring Patient Wishes for Care Near the End of Life: The Veterans Health Administration's Life-Sustaining Treatment Decisions Initiative.

Jt Comm J Qual Patient Saf 2019 01 17;45(1):47-56. Epub 2018 Aug 17.

Background: There is an emerging consensus that clinicians should initiate a proactive "goals of care conversation" (GoCC) with patients whose serious illness is likely to involve decisions about life-sustaining treatments (LSTs) such as artificial nutrition, ventilator support, or cardiopulmonary resuscitation. This conversation is intended to elicit the patient's values, goals, and preferences as a basis for shared decisions about treatment planning. LST decisions are often postponed until the patient is within days or even hours of death and no longer able to make his or her goals and preferences known. Decisions then fall to surrogates who may be uncertain about what the patient would have wanted.

Life-sustaining Treatment Decisions Initiative (lstdi): The Veterans Health Administration's Life-Sustaining Treatment Decisions Initiative (LSTDI) was designed to ensure that patients' goals, values, and preferences for LSTs are elicited, documented, and honored across the continuum of care. The LSTDI includes a coordinated set of evidence-based strategies that consists of enterprisewide practice standards for conducting, documenting, and supporting high-quality GoCCs; staff training to enhance proficiency in conducting, documenting, and supporting GoCCs; standardized, durable electronic health record tools for documenting GoCCs; monitoring and information technology tools to support implementation and improvement; a two-year multifacility demonstration project conducted to test and refine strategies and tools and to identify strong practices; and a program of study to evaluate the LSTDI and identify strategies critical to improving care for patients with serious illness.

Conclusion: The LSTDI moves beyond traditional advance care planning by addressing well-documented barriers to goal-concordant care for seriously ill patients.
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http://dx.doi.org/10.1016/j.jcjq.2018.04.007DOI Listing
January 2019

Strategies to Improve Health Care Ethics Consultation: Bridging the Knowledge Gap.

Authors:
Ellen Fox

AMA J Ethics 2016 May 1;18(5):528-33. Epub 2016 May 1.

Professor of bioethics at Clarkson University in Schenectady Potsdam, New York, the founder and CEO of Fox Ethics Consulting, and director of the Center for Ethics in Health Care at the Altarum Institute.

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http://dx.doi.org/10.1001/journalofethics.2016.18.5.pfor1-1605DOI Listing
May 2016

The Road to Certification for Clinical Ethics Consultants: Finding Our Bearings.

Authors:
Ellen Fox

Am J Bioeth 2016 ;16(3):33-5

a Fox Ethics Consulting, Altarum Institute, Clarkson University.

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http://dx.doi.org/10.1080/15265161.2015.1134713DOI Listing
August 2016

Ethics Consultation Quality Assessment Tool: A Novel Method for Assessing the Quality of Ethics Case Consultations Based on Written Records.

Am J Bioeth 2016 ;16(3):3-14

a National Center for Ethics in Health Care , Department of Veterans Affairs.

Although ethics consultation is offered as a clinical service in most hospitals in the United States, few valid and practical tools are available to evaluate, ensure, and improve ethics consultation quality. The quality of ethics consultation is important because poor quality ethics consultation can result in ethically inappropriate outcomes for patients, other stakeholders, or the health care system. To promote accountability for the quality of ethics consultation, we developed the Ethics Consultation Quality Assessment Tool (ECQAT). ECQAT enables raters to assess the quality of ethics consultations based on the written record. Through rigorous development and preliminary testing, we identified key elements of a quality ethics consultation (ethics question, consultation-specific information, ethical analysis, and conclusions and/or recommendations), established scoring criteria, developed training guidelines, and designed a holistic assessment process. This article describes the development of the ECQAT, the resulting product, and recommended future testing and potential uses for the tool.
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http://dx.doi.org/10.1080/15265161.2015.1134704DOI Listing
January 2017

How Do Healthcare Employees Rate the Ethics of Their Organization? An Analysis Based on VA [email protected] Staff Survey Data.

J Healthc Manag 2015 May-Jun;60(3):169-84

Healthcare organizations with an ethical culture experience higher levels of employee productivity, less staff turnover, better levels of patient safety, resource and cost savings, and higher levels of patient satisfaction. Employees' perceptions of the ethics of their organization are considered a good indicator of the ethics culture. How employees rate the ethics of their organization is not well understood. Previous research has identified a number of attributes that are salient to employees' perceptions in this area. However, little is known about how employees synthesize their perceptions of these attributes to rate the ethics of their organization. Without this knowledge, managers have little specific information to act on to improve practices that would in turn improve employees' perceptions of their organization's ethics. For this study, we used data from Department of Veterans Affairs' (VA) 2014 [email protected] Staff Survey administered to Veterans Health Administration (VHA) staff. We used multivariate regression analyses to investigate how VHA employees weigh their perceptions of eight attributes of an ethical organization to inform an overall rating of the ethics of their organization. We found that employee perceptions of fairness, clarity of expectations, accountability, and leadership's prioritization of ethics had the strongest associations with the overall rating. In addition, employees disproportionately weighed their positive perceptions in determining their overall rating. Therefore, a strategy to improve employees' perceptions of these attributes could potentially have the greatest marginal return on investment with respect to improving employees' perceptions of the ethics of an organization.
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December 2015

Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms.

PLoS Negl Trop Dis 2015 23;9(7):e0003932. Epub 2015 Jul 23.

Department of Microbiology and Immunology, Uniformed Services University, Bethesda, Maryland, United States of America.

Filariae are tissue-invasive nematodes that cause diseases such as elephantiasis and river blindness. The goal of this study was to characterize the role of histamine during Litomosoides sigmodontis infection of BALB/c mice, a murine model of filariasis. Time course studies demonstrated that while expression of histidine decarboxylase mRNA increases throughout 12 weeks of infection, serum levels of histamine exhibit two peaks-one 30 minutes after primary infection and one 8 weeks later. Interestingly, mice treated with fexofenadine, a histamine receptor 1 inhibitor, demonstrated significantly reduced worm burden in infected mice compared to untreated infected controls. Although fexofenadine-treated mice had decreased antigen-specific IgE levels as well as lower splenocyte IL-5 and IFNγ production, they exhibited a greater than fourfold rise in eosinophil numbers at the tissue site where adult L. sigmodontis worms reside. Fexofenadine-mediated clearance of L. sigmodontis worms was dependent on host eosinophils, as fexofenadine did not decrease worm burdens in eosinophil-deficient dblGATA mice. These findings suggest that histamine release induced by tissue invasive helminths may aid parasite survival by diminishing eosinophilic responses. Further, these results raise the possibility that combining H1 receptor inhibitors with current anthelmintics may improve treatment efficacy for filariae and other tissue-invasive helminths.
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http://dx.doi.org/10.1371/journal.pntd.0003932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512699PMC
April 2016

Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy.

J Allergy Clin Immunol 2015 May 3;135(5):1341-51.e1-7. Epub 2014 Oct 3.

Department of Microbiology and Immunology, Uniformed Services University, Bethesda, Md. Electronic address:

Background: Allergen-specific immunotherapy (ASIT) is used to treat the symptoms of immediate type I hypersensitivity. The mechanisms driving establishment of allergen tolerance are not yet fully understood.

Objective: The goal of this study was to develop and immunologically characterize 3 murine models of ASIT to simulate protocols currently used to treat patients with type I hypersensitivities.

Methods: Ovalbumin (OVA)-sensitized mice were desensitized to OVA by means of repeated injections of OVA with a rapid, intermediate, or gradual protocol. After desensitization, mice were assessed for clinical sensitivity to OVA, and immunologic parameters were assessed.

Results: Mice in all treatment protocols displayed decreased vascular permeability in response to OVA challenge after desensitization. Circulating OVA-specific IgE levels, as well as basophil activation in response to OVA stimulation and IgE cross-linking, were significantly decreased in all treatment groups. Intermediate and gradual protocols, but not rapid desensitization, suppressed splenocyte proliferation and production of IL-4, IL-5, and IFN-γ in response to OVA and polyclonal activation. Similarly, significant increases in IL-10 production, numbers of CD4(+)CD25(+) forkhead box protein 3-positive regulatory T cells, and OVA-specific IgG1 antibody levels were only observed in mice undergoing prolonged ASIT regimens.

Conclusion: Suppression of IgE-mediated activation is a common feature of all desensitization schedules. Induction of immunoregulatory networks requires prolonged desensitization schedules.
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http://dx.doi.org/10.1016/j.jaci.2014.07.052DOI Listing
May 2015

Pleomorphic xanthoastrocytoma: report of two cases with unconventional clinical presentations.

Clin Neuropathol 2014 Nov-Dec;33(6):380-7

Aims: Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm with a relative circumscribed architecture that typically arises superficially in the cerebral hemispheres of teenagers and young adults. Our aim is to highlight unconventional clinical presentations of this distinct neoplasm.

Materials And Methods: We report two cases of PXA with unconventional clinical features, including clinical, pathologic, and immunohistochemical features.

Results: The first case developed in the left frontal lobe of a 20-year-old female with neurofibromatosis type 1 (NF1). Focal anaplastic features were present. The neoplastic cells were immunoreactive for GFAP, S-100 protein and focally for synaptophysin, with a MIB-1/Ki-67 proliferative labelling index of 16%. The second case developed in a 39-year-old female as a suprasellar neoplasm. The neoplastic cells expressed GFAP, S-100 protein and focally CD34. The adenohypophysis was positive for synaptophysin and pituicytes for TTF1. Molecular studies were negative for BRAF (V600E) mutation in both cases.

Conclusion: PXA is a distinct circumscribed neoplasm that may present in unexpected locations or clinical backgrounds. Neuropathologists must be aware of these unconventional presentations in order to provide a precise diagnosis leading to appropriate treatment.
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http://dx.doi.org/10.5414/NP300766DOI Listing
August 2016

Developing a certifying examination for health care ethics consultants: bioethicists need help.

Authors:
Ellen Fox

Am J Bioeth 2014 ;14(1):1-4

a National Center for Ethics in Health Care , U.S. Department of Veterans Affairs.

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http://dx.doi.org/10.1080/15265161.2014.873243DOI Listing
May 2014

Basophils help establish protective immunity induced by irradiated larval vaccination for filariasis.

Vaccine 2013 Aug 15;31(36):3675-82. Epub 2013 Jun 15.

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Basophils are increasingly recognized as playing important roles in the immune response toward helminths. In this study, we evaluated the role of basophils in vaccine-mediated protection against filariae, tissue-invasive parasitic nematodes responsible for diseases such as elephantiasis and river blindness. Protective immunity and immunological responses were assessed in BALB/c mice vaccinated with irradiated L3 stage larvae and depleted of basophils with weekly injections of anti-CD200R3 antibody. Depletion of basophils after administration of the vaccination regimen but before challenge infection did not alter protective immunity. In contrast, basophil depletion initiated prior to vaccination and continued after challenge infection significantly attenuated the protective effect conferred by vaccination. Vaccine-induced cellular immune responses to parasite antigen were substantially decreased in basophil-depleted mice, with significant decreases in CD4(+) T-cell production of IL-4, IL-5, IL-10, and IFN-γ. Interestingly, skin mast cell numbers, which increased significantly after vaccination with irradiated L3 larvae, were unchanged after vaccination in basophil-depleted mice. These findings demonstrate that basophils help establish the immune responses responsible for irradiated L3 vaccine protection.
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http://dx.doi.org/10.1016/j.vaccine.2013.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733094PMC
August 2013

Preventive ethics: addressing ethics quality gaps on a systems level.

Jt Comm J Qual Patient Saf 2012 Mar;38(3):103-11

National Center for Ethics in Health Care, Veterans Health Administration, US Department of Veterans Affairs, Washington, DC, USA.

Background: Preventive ethics (PE) is a key component of IntegratedEthics (IE), an innovative model developed by the Veterans Health Administration (VA)'s National Center for Ethics in Health Care which establishes a comprehensive, systematic, integrated approach to ethics in health care organizations. Since early 2008, IE has been implemented throughout all 153 medical centers and 21 regional networks within the US Department of Veterans Affairs (VA) health care system.

Issues: A STEP-BY-STEP APPROACH TO ETHICS QUALITY IMPROVEMENT: PE employs a systematic, step-by-step process improvement approach called

Issues: Identify an issue, Study the issue, Select a strategy, Undertake a plan, Evaluate and adjust, and Sustain and spread. After the ethics quality gap is described, a measureable and achievable improvement goal based on the gap is developed. One of the most challenging aspects of describing an ethics quality gap is to establish an appropriate ethical standard on which to base the operational definition of best ethics practice. PRACTICAL STEPS TO DEVELOPING A PREVENTIVE ETHICS FUNCTION: Within the VA's IE model, PE is situated as a subcommittee of the IE council, which is chaired by the facility director (equivalent to a hospital chief executive officer) and oversees all aspects of the organization's ethics program, including ethical leadership, ethics consultation, and PE. Each VA medical center is required to have a PE team led and managed by a PE coordinator and may need to address ethics issues across the full range of health care ethics domains.

Conclusions: The VA's IE model establishes a robust conceptual framework, along with concrete tools and resources, to integrate PE concepts into the day-to-day operations of a health care organization and is directly transferrable to other health care organizations and systems.
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http://dx.doi.org/10.1016/s1553-7250(12)38014-8DOI Listing
March 2012

The cross-pathway control system regulates production of the secondary metabolite toxin, sirodesmin PL, in the ascomycete, Leptosphaeria maculans.

BMC Microbiol 2011 Jul 26;11:169. Epub 2011 Jul 26.

School of Botany, University of Melbourne, Victoria, (3010), Australia.

Background: Sirodesmin PL is a secondary metabolite toxin made by the ascomycetous plant pathogen, Leptosphaeria maculans. The sirodesmin biosynthetic genes are clustered in the genome. The key genes are a non-ribosomal peptide synthetase, sirP, and a pathway-specific transcription factor, sirZ. Little is known about regulation of sirodesmin production.

Results: Genes involved in regulation of sirodesmin PL in L. maculans have been identified. Two hundred random insertional T-DNA mutants were screened with an antibacterial assay for ones producing low levels of sirodesmin PL. Three such mutants were isolated and each transcribed sirZ at very low levels. One of the affected genes had high sequence similarity to Aspergillus fumigatus cpcA, which regulates the cross-pathway control system in response to amino acid availability. This gene was silenced in L. maculans and the resultant mutant characterised. When amino acid starvation was artificially-induced by addition of 3-aminotriazole for 5 h, transcript levels of sirP and sirZ did not change in the wild type. In contrast, levels of sirP and sirZ transcripts increased in the silenced cpcA mutant. After prolonged amino acid starvation the silenced cpcA mutant produced much higher amounts of sirodesmin PL than the wild type.

Conclusions: Production of sirodesmin PL in L. maculans is regulated by the cross pathway control gene, cpcA, either directly or indirectly via the pathway-specific transcription factor, sirZ.
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http://dx.doi.org/10.1186/1471-2180-11-169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199737PMC
July 2011

Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis.

J Am Chem Soc 2011 Jun 6;133(25):9678-81. Epub 2011 Jun 6.

Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.

Gliotoxin, a major product of the gli non-ribosomal peptide synthetase gene cluster, is strongly associated with virulence of the opportunistic human pathogen Aspergillus fumigatus. Despite identification of the gli cluster, the pathway of gliotoxin biosynthesis has remained elusive, in part because few potential intermediates have been identified. In addition, previous studies suggest that knowledge of gli-dependent metabolites is incomplete. Here we use differential analysis by 2D NMR spectroscopy (DANS) of metabolite extracts derived from gli knock-out and wild-type (WT) strains to obtain a detailed inventory of gli-dependent metabolites. DANS-based comparison of the WT metabolome with that of ΔgliZ, a knock-out strain devoid of the gene encoding the transcriptional regulator of the gli cluster, revealed nine novel gliZ-dependent metabolites including unexpected structural motifs. Their identification provides insight into gliotoxin biosynthesis and may benefit studies of the role of the gli cluster in A. fumigatus virulence. Our study demonstrates the utility of DANS for correlating gene expression and metabolite biosynthesis in microorganisms.
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http://dx.doi.org/10.1021/ja2029987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151163PMC
June 2011

Occurrence of antibiotic resistance genes in reclaimed water and river water in the Werribee Basin, Australia.

J Water Health 2010 Sep 9;8(3):521-31. Epub 2010 Mar 9.

Department of Natural Resource Management and Geography, The University of Melbourne, Parkville, Victoria 3010, Australia.

The purpose of this study was to investigate the occurrence of antibiotic resistance genes (ARGs) in water used for irrigation in the Werribee River Basin, Australia, including river water and reclaimed effluent water (reclaimed water). Samples of reclaimed water, collected over a one-year period, were screened for the occurrence of ARGs using PCR detection assays. The presence of ARGs in the reclaimed water samples were contrasted with that of water samples taken from the Werribee River Basin, collected over the same time period, from five points selected for varying levels of urban and agricultural impact. Of the 54 river water samples collected, 2 (4%), 2 (4%), 0 and 0 were positive for methicillin, sulfonamide, gentamicin and vancomycin-resistant genes, respectively, while 6 of 11 reclaimed water samples were positive for methicillin (9%) and sulfonamide (45%). The presence/absence of ARGs did not appear to correlate with other measured water quality parameters. The low detection of ARGs in river water indicates that, regardless of its poor quality, the river has not yet been severely contaminated with ARGs. The greater prevalence of ARGs in reclaimed water indicates that this important agricultural water source will need to be monitored into the future.
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http://dx.doi.org/10.2166/wh.2010.102DOI Listing
September 2010

Ethical challenges within Veterans Administration healthcare facilities: perspectives of managers, clinicians, patients, and ethics committee chairpersons.

Am J Bioeth 2009 Apr;9(4):28-36

National Center for Ethics in Health Care, Veterans Health Administration, Seattle, WA 98108, USA.

To promote ethical practices, healthcare managers must understand the ethical challenges encountered by key stakeholders. To characterize ethical challenges in Veterans Administration (VA) facilities from the perspectives of managers, clinicians, patients, and ethics consultants. We conducted focus groups with patients (n = 32) and managers (n = 38); semi-structured interviews with managers (n = 31), clinicians (n = 55), and ethics committee chairpersons (n = 21). Data were analyzed using content analysis. Managers reported that the greatest ethical challenge was fairly distributing resources across programs and services, whereas clinicians identified the effect of resource constraints on patient care. Ethics committee chairpersons identified end-of-life care as the greatest ethical challenge, whereas patients identified obtaining fair, respectful, and caring treatment. Perspectives on ethical challenges varied depending on the respondent's role. Understanding these differences can help managers take practical steps to address these challenges. Further, ethics committees seemingly, are not addressing the range of ethical challenges within their institutions.
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http://dx.doi.org/10.1080/15265160802716795DOI Listing
April 2009

Secondary metabolism: regulation and role in fungal biology.

Curr Opin Microbiol 2008 Dec 3;11(6):481-7. Epub 2008 Nov 3.

School of Botany, The University of Melbourne, Victoria, 3010, Australia.

Filamentous fungi produce a diverse array of secondary metabolites--small molecules that are not necessary for normal growth or development. Secondary metabolites have a tremendous impact on society; some are exploited for their antibiotic and pharmaceutical activities, others are involved in disease interactions with plants or animals. The availability of fungal genome sequences has led to an enhanced effort at identifying biosynthetic genes for these molecules. Genes that regulate production of secondary metabolites have been identified and a link between secondary metabolism, light and sexual/asexual reproduction established. However, the role of secondary metabolites in the fungi that produce them remains a mystery. Many of these fungi live saprophytically in the soil and such molecules may provide protection against other inhabitants in this ecological niche.
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http://dx.doi.org/10.1016/j.mib.2008.10.007DOI Listing
December 2008

Priority setting and the ethics of resource allocation within VA healthcare facilities: results of a survey.

Organ Ethic 2008 Fall-Winter;4(2):83-96

National Center for Ethics in Health Care (VHA), Department of Veterans Affairs, Seattle, USA.

Background: Setting priorities and the subsequent allocation of resources is a major ethical issue facing healthcare facilities, including the Veterans Health Administration (VHA), the largest integrated healthcare delivery network in the United States. Yet despite the importance of priority setting and its impact on those who receive and those who provide care, we know relatively little about how clinicians and managers view allocation processes within their facilities.

Purpose: The purpose of this secondary analysis of survey data was to characterize staff members' perceptions regarding the fairness of healthcare ethics practices related to resource allocation in Veterans Administration (VA) facilities. The specific aim of the study was to compare the responses of clinicians, clinician managers, and non-clinician managers with respect to these survey items.

Methods: We utilized a paper and web-based survey and a cross-sectional design of VHA clinicians and managers. Our sample consisted of a purposive stratified sample of 109 managers and a stratified random sample of 269 clinicians employed 20 or more hours per week in one of four VA medical centers. The four medical centers were participating as field sites selected to test the logistics of administering and reporting results of the Integrated Ethics Staff Survey, an assessment tool aimed at characterizing a broad range of ethical practices within a healthcare organization.

Results: In general, clinicians were more critical than clinician managers or non-clinician managers of the institutions' allocation processes and of the impact of resource decisions on patient care. Clinicians commonly reported that they did not (a) understand their facility's decision-making processes, (b) receive explanations from management regarding the reasons behind important allocation decisions, or (b) perceive that they were influential in allocation decisions. In addition, clinicians and managers both perceived that education related to the ethics of resource allocation was insufficient and that their facilities could increase their effectiveness in identifying and resolving ethical problems related to resource allocation.

Conclusion: How well a healthcare facility ensures fairness in the way it allocates its resources across programs and services depends on multiple factors, including awareness by decision makers that setting priorities and allocating resources is a moral enterprise (moral awareness), the availability of a consistent process that includes important stakeholder groups (procedural justice), and concurrence by stakeholders that decisions represent outcomes that fairly balance competing interests and have a positive net effect on the quality of care (distributive justice). In this study, clinicians and managers alike identified the need for improvement in healthcare ethics practices related to resource allocation.
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December 2008

Biosynthetic gene clusters for epipolythiodioxopiperazines in filamentous fungi.

Mycol Res 2008 Feb 1;112(Pt 2):162-9. Epub 2007 Sep 1.

School of Botany, The University of Melbourne, Vic 3010, Australia.

Epipolythiodioxopiperazines (ETPs) are toxic secondary metabolites made only by fungi. Recent research efforts have provided insight into the molecular mechanisms of the toxicity of these compounds. The availability of complete genome sequences for many fungi has also facilitated the identification of putative ETP biosynthetic gene clusters. Expression and mutational analyses have confirmed the role of such gene clusters in the biosynthesis of two ETPs, sirodesmin PL and gliotoxin. The creation of mutants unable to produce these ETPs has facilitated the assessment of these molecules as virulence factors in interactions between pathogenic fungi and their hosts.
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http://dx.doi.org/10.1016/j.mycres.2007.08.017DOI Listing
February 2008

A Zn(II)2Cys6 DNA binding protein regulates the sirodesmin PL biosynthetic gene cluster in Leptosphaeria maculans.

Fungal Genet Biol 2008 May 17;45(5):671-82. Epub 2007 Oct 17.

School of Botany, The University of Melbourne, Vic. 3010, Australia.

A gene, sirZ, encoding a Zn(II)(2)Cys(6) DNA binding protein is present in a cluster of genes responsible for the biosynthesis of the epipolythiodioxopiperazine (ETP) toxin, sirodesmin PL in the ascomycete plant pathogen, Leptosphaeria maculans. RNA-mediated silencing of sirZ gives rise to transformants that produce only residual amounts of sirodesmin PL and display a decrease in the transcription of several sirodesmin PL biosynthetic genes. This indicates that SirZ is a major regulator of this gene cluster. Proteins similar to SirZ are encoded in the gliotoxin biosynthetic gene cluster of Aspergillus fumigatus (gliZ) and in an ETP-like cluster in Penicillium lilacinoechinulatum (PlgliZ). Despite its high level of sequence similarity to gliZ, PlgliZ is unable to complement the gliotoxin-deficiency of a mutant of gliZ in A. fumigatus. Putative binding sites for these regulatory proteins in the promoters of genes in these clusters were predicted using bioinformatic analysis. These sites are similar to those commonly bound by other proteins with Zn(II)(2)Cys(6) DNA binding domains.
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http://dx.doi.org/10.1016/j.fgb.2007.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2399893PMC
May 2008

Ethics consultants' recommendations for life-prolonging treatment of patients in persistent vegetative state: a follow-up study.

J Clin Ethics 2007 ;18(1):64-71

National Center for Ethics in Health Care, U.S. Department of Veterans Affairs, Washington, DC, USA.

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July 2007
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