Advancing Salary Equity in Schools of Medicine in the United States.

Equity, in broad terms, is a critical issue and has been identified as an area that needs particular attention in academic medicine. Gender equity, as a subset of overall equity, has equally been shown to be lacking in academic medicine, and most medical schools and academic health systems are involved in substantive journeys to improve all dimensions of equity, diversity, and inclusion. This Invited Commentary calls for including gender-based salary equity as a foundational accomplishment for institutions seeking to achieve overall equity. In addition, the authors provide evidence and recommendations to guide institutions toward best practices in achieving salary equity. They propose 4 areas of consideration: (1) prioritization by leadership; (2) prioritization of resources to ensure success; (3) development of corrective action plans which are "automatic" and based on clear guidelines; and (4) transparency of methodology, data, and results.

Rationale and Models for Career Advancement Sponsorship in Academic Medicine: The Time Is Here; the Time Is Now.

The business community has honed the concept of sponsorship and promulgated its utility for harnessing the talent of high-performing women and minorities whose contributions often go unrecognized within organizations. In recent years, academic medicine has begun to do the same. Whereas mentorship often centers on personal and professional development (e.g., skill building and goal setting), sponsorship focuses on enhancing the visibility, credibility, and professional networks of talented individuals. For upward career mobility, mentorship is limited in scope. Sponsorship, on the other hand, directly targets career advancement and is anchored in the sponsor's awareness of organizational structures and critical professional opportunities for junior faculty. Men are more likely to garner sponsors informally, and these sponsors tend to be male. Existing disparities between male and female medical faculty in achievement of academic rank and leadership roles, compensation, and research support suggest that high-performing women have a visibility gap. Such systemic inequity reflects a suboptimal business model that limits organizational potential. Formal sponsorship programs that match women with senior leaders facilitate access to beneficial relationships and institutionalize the value of equal opportunity. In this Perspective, the authors describe two successful sponsorship models that exist within academic medicine, the Society of General Internal Medicine's Career Advising Program and MD Anderson Cancer Center's Leaders' Sponsorship Program. They issue a call to action for much broader implementation of sponsorship programming to cultivate the advancement of all talented medical faculty and provide recommendations for such endeavors.

Provider and Patient Gender Influence on Timing of Do-Not-Resuscitate Orders in Hospitalized Patients with Cancer.

BACKGROUND: End-of-life decisions and advance directives require timely physician-patient discussions but barriers exist to these discussions. OBJECTIVE: To evaluate the influence of physician and patient gender on the timing of inpatient do-not-resuscitate (DNR) orders. DESIGN: Retrospective cohort study. SETTING/SUBJECTS: All adult patients (≥18 years) with cancer who received inpatient DNR orders at The University of Texas MD Anderson Cancer Center between January 2011 and December 2013. MEASUREMENTS: Gender interaction between physicians and patients towards timing of the DNR order. RESULTS: We identified 4,157 unique patients with a cancer diagnosis. These patients were treated by 353 physicians, of whom 123 (34.8%) were females and 230 (65.2%) were males. Multivariate analysis showed female patients were 1.3 times more likely to have early DNR orders written during hospital admission than were male patients (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.07-1.50). When comparing gender interaction between physicians and patients, our results showed that female physicians were 1.5 times more likely to write early DNR orders with their female patients than for their male patients (OR, 1.48; 95% CI, 1.13-1.94). Same gender physician-patient dyads were not found between male physician and their patients (OR, 1.09; 95% CI, 0.91-1.31). Higher age, more comorbid conditions, and progression of diseases were also associated with early DNR orders (all p < 0.01). CONCLUSION: Female patients are more likely to receive early DNR orders from their female physicians. Gender and gender interaction between physician and patients may potentially influence the timing of receiving DNR order.

Accumulation of isolevuglandin-modified protein in normal and fibrotic lung.

Protein lysine modification by γ-ketoaldehyde isomers derived from arachidonic acid, termed isolevuglandins (IsoLGs), is emerging as a mechanistic link between pathogenic reactive oxygen species and disease progression. However, the questions of whether covalent modification of proteins by IsoLGs are subject to genetic regulation and the identity of IsoLG-modified proteins remain unclear. Herein we show that Nrf2 and Nox2 are key regulators of IsoLG modification in pulmonary tissue and report on the identity of proteins analyzed by LC-MS following immunoaffinity purification of IsoLG-modified proteins. Gene ontology analysis revealed that proteins in numerous cellular pathways are susceptible to IsoLG modification. Although cells tolerate basal levels of modification, exceeding them induces apoptosis. We found prominent modification in a murine model of radiation-induced pulmonary fibrosis and in idiopathic pulmonary fibrosis, two diseases considered to be promoted by gene-regulated oxidant stress. Based on these results we hypothesize that IsoLG modification is a hitherto unrecognized sequelae that contributes to radiation-induced pulmonary injury and IPF.

Sponsorship: a path to the academic medicine C-suite for women faculty?

Despite increases in the percentages of women medical school graduates and faculty over the past decade, women physicians and scientists remain underrepresented in academic medicine's highest-level executive positions, known as the "C-suite." The challenges of today and the future require novel approaches and solutions that depend on having diverse leaders. Such diversity has been widely shown to be critical to creating initiatives and solving complex problems such as those facing academic medicine and science. However, neither formal mentoring programs focused on individual career development nor executive coaching programs focused on individual job performance have led to substantial increases in the proportion of women in academic medicine's top leadership positions.Faced with a similar dilemma, the corporate world has initiated sponsorship programs designed to accelerate the careers of women as leaders. Sponsors differ from mentors and coaches in one key area: They have the position and power to advocate publicly for the advancement of nascent talent, including women, in the organization. Although academic medicine differs from the corporate world, the strong sponsorship programs that have advanced women into corporations' upper levels of leadership can serve as models for sponsorship programs to launch new leaders in academic medicine.

NRF2 deficiency reduces life span of mice administered thoracic irradiation.

Subsets of cancer survivors who have been subjected to thoracic irradiation face the prospect of developing pulmonary injury. Radiation-induced pulmonary fibrosis is an insidious injury that presents 6 to 24 months after irradiation and continues to progress over a period of years. TGF-ß and reactive oxygen species contribute significantly to the pathogenesis of this injury. The transcription factor NRF2 controls antioxidant gene expression and therefore regulates the cellular oxidant burden. This work demonstrates an additional paradigm for NRF2: suppression of TGF-ß-mediated signaling, assessed by measuring expression of a surrogate TGF-ß1 target gene (PAI-1) in lung fibroblasts. Thoracic irradiation of Nfe2l2(-/-) mice resulted in rapid expression of PAI-1 and FSP-1 compared to irradiated wild-type mice. Examination of lung tissue 16 weeks after thoracic irradiation of Nfe2l2(-/-) mice revealed the presence of distended alveoli and decreased numbers of alveoli compared to wild-type mice. Suppression of NRF2 expression shortened life span in mice administered 16 Gy to the thorax. Nfe2l2(+/-) and Nfe2l2(-/-) mice exhibited a mean life span of 176 days compared to wild-type mice, which lived an average of 212 days. These novel results identify NRF2 as a susceptibility factor for the development of late tissue injury.

Haemophilus influenzae lysate induces aspects of the chronic obstructive pulmonary disease phenotype.

Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the lower airways of patients with chronic obstructive pulmonary disease (COPD). Whether it contributes to COPD progression is unknown. Here, we determined which aspects of the COPD phenotype can be induced by repetitive exposure to NTHi products. Mice were exposed weekly to an aerosolized NTHi lysate, and inflammation was evaluated by measurement of cells and cytokines in bronchoalveolar lavage fluid (BALF) and immunohistochemical staining; structural changes were evaluated histochemically by periodic acid fluorescent Schiff's reagent, Masson's trichrome, and Picrosirius red staining; mucin gene expression was measured by quantitative RT-PCR; and the role of TNF-alpha was examined by transgenic airway overexpression and use of an inhibitory antibody. NTHi lysate induced rapid activation of NF-kappaB in airway cells and increases of inflammatory cytokines and neutrophils in BALF. Repetitive exposure induced infiltration of macrophages, CD8+ T cells, and B cells around airways and blood vessels, and collagen deposition in airway and alveolar walls, but airway mucin staining and gel-forming mucin transcripts were not increased. Transgenic overexpression of TNF-alpha caused BALF neutrophilia and inflammatory cell infiltration around airways, but not fibrosis, and TNF-alpha neutralization did not reduce BALF neutrophilia in response to NTHi lysate. In conclusion, NTHi products elicit airway inflammation in mice with a cellular and cytokine profile similar to that in COPD, and cause airway wall fibrosis but not mucous metaplasia. TNF-alpha is neither required for inflammatory cell recruitment nor sufficient for airway fibrosis. Colonization by NTHi may contribute to the pathogenesis of small airways disease in patients with COPD.

Reduction of bleomycin-induced pulmonary fibrosis by serum amyloid P.

Fibrotic diseases such as scleroderma, severe chronic asthma, pulmonary fibrosis, and cardiac fibrosis kill tens of thousands of people each year in the U.S. alone. Growing evidence suggests that in fibrotic lesions, a subset of blood monocytes enters the tissue and differentiates into fibroblast-like cells called fibrocytes, causing tissue dysfunction. We previously found that a plasma protein called serum amyloid P (SAP) inhibits fibrocyte differentiation in vitro. Bleomycin treatment is a standard model for pulmonary fibrosis, and causes an increase in collagen, fibrocytes, and leukocytes in the lungs, and a decrease in peripheral blood hemoglobin oxygen saturation. We find that injections of rat SAP in rats reduce all of the above bleomycin-induced changes, suggesting that the SAP injections reduced the bleomycin-induced pulmonary fibrosis. We repeated these studies in mice, and find that injections of murine SAP decrease bleomycin-induced pulmonary fibrosis. To confirm the efficacy of SAP treatment, we used a delayed treatment protocol using SAP from day 7 to 13 only, and then measured fibrosis at day 21. Delayed SAP injections also reduce the bleomycin-induced decrease in peripheral blood hemoglobin oxygen saturation, and an increase in lung collagen, leukocyte infiltration, and fibrosis. Our data suggest the possibility that SAP may be useful as a therapy for pulmonary fibrosis in humans.

Genetic susceptibility to late normal tissue injury.

The outcome of all cancer therapies, including radiation, has greatly improved in the last 25 years, resulting in a doubling of the number of long-term cancer survivors. However, a subset of these survivors incurs adverse chronic side effects in unavoidably irradiated normal tissues, persisting long after treatment and compromising the quality of life of these patients. Interpatient variability in normal tissue radiation response is well documented and suggested to be under genetic control. Fibrosis, a clinically significant late effect in many irradiated tissues that results in tissue remodeling and loss of function, is a complex genetic trait making identification of the underlying genes difficult. Current clinical and animal studies are providing information on the genetics and molecular basis of late normal tissue injury in the radiation therapy setting, bringing us closer to our dual goal of individualizing treatment by genetic profiling and improving the quality of life of long-term survivors.

Quantification of bleomycin-induced murine lung damage in vivo with micro-computed tomography.

RATIONALE AND OBJECTIVES: We explored noninvasive, in vivo cone-beam microcomputed tomography (micro-CT) to visualize and quantify fibrotic and inflammatory damage over the entire lung volume of mice. MATERIALS AND METHODS: We used bleomycin to induce pulmonary damage in vivo and compared the results from micro-CT with histologic measurements. Ten C57BL/6 mice were given 5 U/kg bleomycin intratracheally. Seven surviving mice were scanned with micro-CT before administration of bleomycin, and again before sacrifice. The resulting images were analyzed for lung volume measurements. After the final scan, all lungs were examined histologically and pulmonary damage was quantified. Damaged lung tissue regions were matched between micro-CT images and histologic sections for each mouse. RESULTS: The percent lung damage calculated from micro-CT and histology were correlated (r(2) = 0.49, r = 0.64 with P = 0.12), and the means of their respective distributions were not different (P > 0.05). CONCLUSION: This study shows that micro-CT is a promising alternative to predicting lung damage caused by bleomycin. CT image volumes of the thorax allow for global tissue sampling, which may be useful when following nonuniform lung damage that can occur from intratracheal administration of bleomycin.

Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003.

To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.

Joint tests for quantitative trait loci in experimental crosses.

Selective genotyping is common because it can increase the expected correlation between QTL genotype and phenotype and thus increase the statistical power of linkage tests (i.e., regression-based tests). Linkage can also be tested by assessing whether the marginal genotypic distribution conforms to its expectation, a marginal-based test. We developed a class of joint tests that, by constraining intercepts in regression-based analyses, capitalize on the information available in both regression-based and marginal-based tests. We simulated data corresponding to the null hypothesis of no QTL effect and the alternative of some QTL effect at the locus for a backcross and an F2 intercross between inbred strains. Regression-based and marginal-based tests were compared to corresponding joint tests. We studied the effects of random sampling, selective sampling from a single tail of the phenotypic distribution, and selective sampling from both tails of the phenotypic distribution. Joint tests were nearly as powerful as all competing alternatives for random sampling and two-tailed selection under both backcross and F2 intercross situations. Joint tests were generally more powerful for one-tailed selection under both backcross and F2 intercross situations. However, joint tests cannot be recommended for one-tailed selective genotyping if segregation distortion is suspected.

H2-Ea deficiency is a risk factor for bleomycin-induced lung fibrosis in mice.

Pulmonary fibrosis is a significant complication in cancer patients when treated by radiation, e.g., thoracic malignant diseases, or chemotherapeutic agents. Bleomycin is one of the primary drugs used to treat testicular cancer, but the incidence of significant pulmonary fibrosis limits the dose. It is known that susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait controlled by multiple genes, none of which, however, are yet known. In this study, we used expression profiling and genetic analysis in mouse models of bleomycin-induced pulmonary fibrosis and identified MHC class II antigen Ealpha (H2-Ea) as a risk factor for this disease. We found that a loss-of-function deletion in the H2-Ea gene was linked to susceptibility. A functional test of H2-Ea in transgenic mice showed 100% survival in the transgenic mice compared with 53% in C57BL/10J mice and significantly decreased pulmonary fibrosis from 16.42% (C57BL/10J) to 5.76% (transgenic; P = 1.20e(-8)). These results show that H2-Ea expression protects mice from bleomycin-induced pulmonary fibrosis, which implicates H2-Ea as a candidate susceptibility gene for pulmonary fibrosis.

In vivo respiratory-gated micro-CT imaging in small-animal oncology models.

Micro-computed tomography(micro-CT) is becoming an accepted research tool for the noninvasive examination of laboratory animals such as mice and rats, but to date, in vivo scanning has largely been limited to the evaluation of skeletal tissues. We use a commercially available micro-CT device to perform respiratory gated in vivo acquisitions suitable for thoracic imaging. The instrument is described, along with the scan protocol and animal preparation techniques. Preliminary results confirm that lung tumors as small as 1 mm in diameter are visible in vivo with these methods. Radiation dose was evaluated using several approaches, and was found to be approximately 0.15 Gy for this respiratory-gated micro-CT imaging protocol. The combination of high-resolution CT imaging and respiratory-gated acquisitions appears well-suited to serial in vivo scanning.

Education and training for radiation scientists: radiation research program and American Society of Therapeutic Radiology and Oncology Workshop, Bethesda, Maryland, May 12-14, 2003.

Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.

Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice.

Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11(C3H), and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.

Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis.

Susceptibility to radiation-induced pulmonary fibrosis is a heritable trait in mice. In a prior study of C57BL/6J (susceptible), C3Hf/Kam (resistant), and F1 and F2 mice derived from these strains, we estimated that approximately 38% of the measured phenotypic variation could be attributed to effects from a few genetic factors. In addition, we identified one genetic factor on chromosome 17 in the MHC region. To identify any additional genetic loci that might influence interstrain variability, we conducted a genome-wide linkage scan using 214 markers and the phenotypically extreme 94 (of 268) F2 mice. In regions exceeding suggestive linkage (LOD = 2.8), we followed up with additional markers. This scan revealed evidence for quantitative trait locus (QTL) on chromosomes 17 (LOD = 4.2), 1 (LOD = 4.5), and 18 (LOD = 3.9), which influence susceptibility to radiation-induced pulmonary fibrosis. An additional region containing a QTL on chromosome 6, LOD = 4.6, showed linkage in female mice only. The evidence for linkage to chromosome 18 weakened when it was analyzed jointly with other markers. These four loci are estimated to account for 70% of the genetic contribution to this trait with chromosome 17 and 1 accounting for 28 and 24%, respectively. To confirm and better define the influence of the chromosome 17-linked QTL on radiation sensitivity, we conducted studies on congenic mice in which the linked region on chromosome 17 had been transferred onto a B6.AKR or a C3.SW background. The chromosome 17-linked QTL was confirmed to influence the phenotype as the fibrotic radiation response of B6.AKR-H2(k) mice was significantly less than that of B6 mice (P = 0.0001). The QTL on chromosome 17 for radiation-induced lung fibrosis is within the same region as QTLs identified for lung damage after other insults, including bleomycin, ozone, and particle exposure, as well as for asthma, suggesting that this region of chromosome 17 may harbor a "universal" lung injury gene.

Radiation protection

There are few books on radiation protection for radiologic technologists. Several recent issues make the appearance of this text timely: (1) the Committee on Bioeffects of Ionizing Radiation (BEIR) now estimates the risk of radiation injury to the population to be greater than they had previously estimated; (2) current studies are now concerned with the bioeffects of low-level radiation, which is characteristic of diagnostic radiology; (3) based on a close examination of the radiation data on the Hiroshima and Nagasaki atom bomb survivors, the International Commission of Radiological Protection (ICRP) recently revised its recommendations on radiation protection and lowered the annual dose limit to the whole body for radiation workers from 50 mSv to 20 mSv; (4) the introduction of new imaging techniques, such as magnetic resonance imaging (MRI), requires an understanding of the bioeffects of exposure to magnetic fields and radio waves, as well as a thorough knowledge of the safety issues surrounding the use of these techniques to image the human body; and (5) quality control is an effective dose reduction tool and is now considered an essential element of radiation protection programs. Keeping these recent developments in mind, the purpose of this book is to: 1) Provide a current and thorough overview of the bioeffects of radiation. 2) Provide comprehensive coverage of the physical principles and technical aspects of radiation protection in diagnostic radiology. 3) Explore the hazards and safety considerations of MRI. 4) Explain the role of quality assurance/quality control in radiation protection. 5) Describe the recent recommendations and new developments in radiation protection for patients undergoing diagnostic X-ray examinations. 6) Summarize the results of various dose studies in X-ray imaging, including computed tomography and mammography