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Jennifer C. Sasaki Ashley Allemang Steven M. Bryce Laura Custer Kerry L. Dearfield Yasmin Dietz Azeddine Elhajouji Patricia A. Escobar Albert J. Fornace Jr Roland Froetschl Sheila Galloway Ulrike Hemmann Giel Hendriks Heng-Hong Li Mirjam Luijten Gladys Ouedraogo Lauren Peel Stefan Pfuhler Daniel J. Roberts Véronique Thybaud Jan van Benthem Carole L. Yauk Maik Schuler 《Environmental and molecular mutagenesis》2020,61(1):114-134
In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc. 相似文献
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Fiene Marie Kuijper Uma V. Mahajan Seul Ku Daniel A.N. Barbosa Sheila M. Alessi Sherman C. Stein Kyle M. Kampman Brandon S. Bentzley Casey H. Halpern 《Neuromodulation》2022,25(2):253-262
ObjectivesCocaine is the second most frequently used illicit drug worldwide (after cannabis), and cocaine use disorder (CUD)-related deaths increased globally by 80% from 1990 to 2013. There is yet to be a regulatory-approved treatment. Emerging preclinical evidence indicates that deep brain stimulation (DBS) of the nucleus accumbens may be a therapeutic option. Prior to expanding the costly investigation of DBS for treatment of CUD, it is important to ensure societal cost-effectiveness.AimsWe conducted a threshold and cost-effectiveness analysis to determine the success rate at which DBS would be equivalent to contingency management (CM), recently identified as the most efficacious therapy for treatments of CUDs.Materials and MethodsQuality of life, efficacy, and safety parameters for CM were obtained from previous literature. Costs were calculated from a societal perspective. Our model predicted the utility benefit based on quality-adjusted life-years (QALYs) and incremental-cost-effectiveness ratio resulting from two treatments on a one-, two-, and five-year timeline.ResultsOn a one-year timeline, DBS would need to impart a success rate (ie, cocaine free) of 70% for it to yield the same utility benefit (0.492 QALYs per year) as CM. At no success rate would DBS be more cost-effective (incremental-cost-effectiveness ratio <$50,000) than CM during the first year. Nevertheless, as DBS costs are front loaded, DBS would need to achieve success rates of 74% and 51% for its cost-effectiveness to exceed that of CM over a two- and five-year period, respectively.ConclusionsWe find DBS would not be cost-effective in the short term (one year) but may be cost-effective in longer timelines. Since DBS holds promise to potentially be a cost-effective treatment for CUDs, future randomized controlled trials should be performed to assess its efficacy. 相似文献
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Marie Warrer Petersen Tine Sylvest Meyhoff Marie Helleberg Maj-Brit Nørregaard Kjær Anders Granholm Carl Johan Steensen Hjortsø Thomas Steen Jensen Morten Hylander Møller Peter Buhl Hjortrup Mik Wetterslev Gitte Kingo Vesterlund Lene Russell Vibeke Lind Jørgensen Klaus Tjelle Thomas Benfield Charlotte Suppli Ulrik Anne Sofie Andreasen Thomas Mohr Morten H. Bestle Lone Musaeus Poulsen Mette Friberg Hitz Thomas Hildebrandt Lene Surland Knudsen Anders Møller Christoffer Grant Sølling Anne Craveiro Brøchner Bodil Steen Rasmussen Henrik Nielsen Steffen Christensen Thomas Strøm Maria Cronhjort Rebecka Rubenson Wahlin Stephan Jakob Luca Cioccari Balasubramanian Venkatesh Naomi Hammond Vivekanand Jha Sheila Nainan Myatra Christian Gluud Theis Lange Anders Perner 《Acta anaesthesiologica Scandinavica》2020,64(9):1365-1375
Introduction
Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.Methods
The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.Discussion
The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.6.
Sheila A M Rauch Knashawn H Morales Cynthia Zubritsky Kathryn Knott David Oslin 《The American journal of geriatric psychiatry》2006,14(4):316-324
OBJECTIVE: The authors examined 1) rates of trauma and posttraumatic stress (PTS) in older adults in primary care; 2) factors related to more posttraumatic stress symptoms; and 3) the influence of posttraumatic stress and depression on health perceptions and negative health behaviors (i.e., suicidal ideation, smoking, and at-risk drinking). METHODS: As part of participation in a study at the Philadelphia VAMC and the University of Pennsylvania, a random subset (N = 2,718) of older adults (age > or = 65 years) with scheduled primary care visits were screened concerning demographics, the General Health Questionnaire-12, suicidal thoughts, alcohol consumption, cigarette smoking, perceived health status, PTS, and cognitive impairment. RESULTS: The rate of trauma in older adult primary care patients was high in both the VA (37%) and university-based clinics (24%). Many older adults reported interference from at least one of the three posttraumatic stress items assessed (VA, 18%; university-based primary care, 8%). In a model including demographic factors, higher PTS and depression were uniquely related to more negative health perceptions. In a model including demographic factors, both higher PTS and depression were uniquely related to higher likelihood of suicidal ideation. In contrast, PTS no longer contributed to a model of smoking once depression was included. Neither PTS nor depression significantly contributed to a model of at-risk drinking. CONCLUSIONS: Trauma and posttraumatic stress are frequent and significant problems for older adults in primary care. Both posttraumatic stress and depression are related to more negative health perceptions and higher likelihood of suicidal ideation. 相似文献
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Caroline A. Harrison BMedSci MRCS ; Martin J. Heaton MD FRCS ; Christopher M. Layton PhD ; Sheila Mac Neil PhD 《Wound repair and regeneration》2006,14(2):203-209
To produce a stable epidermis, keratinocytes need to be firmly attached to the basement membrane. However, following wounding, keratinocytes are required to develop a migratory phenotype in order to reepithelialize the wound. To investigate some of the issues underlying reepithelialization, we have developed a three-dimensional in vitro model of tissue-engineered skin, comprising sterilized human dermis seeded with human keratinocytes and dermal fibroblasts. Using this model, we have shown that the inclusion of fibroblasts within the model increases the stability of keratinocyte attachment. We have also demonstrated that keratinocyte migration occurs most effectively in the absence of a basement membrane and following the inclusion of fibroblasts in the model. In addition, subjecting the keratinocyte layer to mechanical trauma induces a migratory phenotype. We conclude that this three-dimensional in vitro wound model can be used to increase our understanding of the factors that enhance keratinocyte migration and hence wound healing in vivo. 相似文献
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This article reviews the anatomical and functional evidence for ascending pathways from specific brain regions to the PVN and SON which could influence AVP release. The majority of evidence favours the main projection being from a region in the caudal VLM which may coincide with the noradrenergic neurons of the A1 cell group. However, the transmitter(s) involved have yet to be identified, and whether the pathway is excitatory and/or inhibitory remains to be fully resolved.Anatomical and functional evidence is reviewed for descending projections from the SON and PVN to specific brain regions involved in cardiovascular control, and their possible involvement in baroreflex mechanisms is discussed. However, there is little unequivocal evidence that AVP is the main neurotransmitter utilized by descending projections from PVN to NTS and DMX. While, in some situations, circulating endogenous AVP exerts cardiovascular effects, details of its putative influences on baroreflex mechanisms are lacking. 相似文献
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Joyce J. Fitzpatrick Sheila Ryan DeWitt Baldwin Roger Bulger Jean Johnson-Pawlson Christopher McLaughlin Maureen Kelley Leopold Selketr Bernardine Lacey Charlene Hanson Robin Harvan Patricia Hinton Walker David Sluyter Mary Joan Ladden Neal Vanselow 《Journal of Midwifery & Women's Health》1998,43(1):61-65
In 1995, the National League for Nursing commissioned a Panel on Interdisciplinary/Transdisciplinary Education. The focus of the Panel's work was to examine educational issues that transcend the health professions and to make recommendations for future implementation of an interdisciplinary approach to addressing them. This article is being simultaneously published by several professional journals. The goal is to seek as much feedback as possible. 相似文献