Monthly Progression of Emergency Medicine Resident Efficiency: What Can We Expect of Our Residents Throughout Training?

BACKGROUND: Developing the capacity for efficient patient care is essential during emergency medicine (EM) residency training. Previous studies have demonstrated that resident efficiency improves during each year of training. OBJECTIVES: This study assessed the progression of EM resident efficiency monthly and sought to develop a model that describes this progression in terms of patients per hour (pts/h) weighted by month of training. METHODS: We performed a retrospective review of EM resident efficiency as determined by pts/h using EM resident monthly patient logs from a postgraduate year (PGY) 1-3 EM training program. Mean pts/h and standard deviation (SDs) were calculated based on month of training. One-way analysis of variance compared year-to-year training. We formulated several linear regression models to describe this progression. RESULTS: We analyzed 51 consecutive months of patient logs from 110 residents. The mean pts/h for PGY1 was 1.201 (n = 85, SD = 0.241), for PGY2 was 1.497 (n = 82, SD = 0.218), and for PGY3 was 1.676 (n = 80, SD = 0.224). Linear regression was used to describe patients seen per hour by the month of training. A significant regression was found with an R2 of 0.437 and p < 0.000. Over 36 months of training, a resident's predicted pts/h is equal to 1.113 + (0.018 × month of training). CONCLUSIONS: EM resident efficiency increases monthly, with most improvement occurring in the PGY1 year. Understanding this improvement may aid in resident performance evaluation and the understanding of predicted resident workflow.

Factors Affecting Attendance at an Adapted Cardiac Rehabilitation Exercise Program for Individuals with Mobility Deficits Poststroke.

OBJECTIVE: The aim of this study was to determine the factors affecting attendance at an adapted cardiac rehabilitation program for individuals poststroke. METHODS: A convenience sample of ambulatory patients with hemiparetic gait rated 20 potential barriers to attendance on a 5-point Likert scale upon completion of a 6-month program of 24 prescheduled weekly sessions. Sociodemographic characteristics, depressive symptoms, cardiovascular fitness, and comorbidities were collected by questionnaire or medical chart. RESULTS: Sixty-one patients attended 77.3 ± 12% of the classes. The longer the elapsed time from stroke, the lower the attendance rate (r = -.34, P = .02). The 4 greatest barriers influencing attendance were severe weather, transportation problems, health problems, and traveling distance. Health problems included hospital readmissions (n = 6), influenza/colds (n = 6), diabetes and cardiac complications (n = 4), and musculoskeletal issues (n = 2). Of the top 4 barriers, people with lower compared to higher income had greater transportation issues (P = .004). Greater motor deficits of the stroke-affected leg were associated with greater barriers related to health issues (r = .7, P = .001). The only sociodemographic factor associated with a higher total mean barrier score was non-English as the primary language spoken at home (P = .002); this factor was specifically related to the barriers of cost (P = .007), family responsibilities (P = .018), and lack of social support (P = .001). No other associations were observed. CONCLUSION: Barriers to attendance were predominantly related to logistic/transportation and health issues. People who were more disadvantaged socioeconomically (language, finances), and physically (stroke-related deficits) were more affected by these barriers. Strategies to reduce these barriers, including timely referral to exercise programs, need to be investigated.

PROGNOSTIC VALUE OF THE MULTIPLE MINI-INTERVIEW FOR EMERGENCY MEDICINE RESIDENCY PERFORMANCE.

BACKGROUND: The Multiple Mini-Interview (MMI) uses short, structured contacts, and is known to predict medical school success better than traditional interviews and application materials. Its utility in Emergency Medicine residency selection is untested. OBJECTIVES: We investigate whether it provides additional information regarding future first-year resident performance that can be useful in resident selection. METHODS: From three Emergency Medicine residency programs, 71 interns in their first month completed an MMI developed to focus on desirable resident characteristics. Application data were reviewed. First-year resident performance assessments covering the American Council for Graduate Medical Education (ACGME) core competencies, along with professionalism and performance concerns, were obtained. Multiple logistic regressions were employed and MMI correlations were compared with program rank lists and typical selection factors. RESULTS: An individual's score on the MMI correlated with overall performance (p < 0.05) in single logistic regression. MMI correlated with ACGME individual competencies patient care and procedural skills at a less robust level (p < 0.1), but not with any other outcomes. Rank list position correlated with the diagnostic skill competency (p < 0.05), but no others. Traditional selection factors correlated with overall performance, disciplinary action, patient care, medical knowledge, and diagnostic skills (p < 0.05). MMI was not correlated significantly with the outcomes when included in multiple ordinal logistic regression with other selection factors. CONCLUSIONS: MMI scores correlate with overall performance, but are not statistically significant when other traditional selection factors were considered. The MMI process seems potentially superior to program rank list at correlating with first-year performance. The MMI may provide additional benefit when examined using a larger and more diverse sample.

Adolescent experiences of violence and relation to violence perpetration beyond young adulthood among an urban sample of Black and African American males.

The purpose of this study is to determine if experiences of physical violence during early and late adolescence (12-21 years) places urban Black males at increased risk for interpersonal violence perpetration beyond young adulthood (30 years and older). Participants of this cross-sectional study were Black and African American men (N = 455) between the ages of 30 and 65 years, recruited from four urban clinical sites in the Northeast. Multivariate logistic regression models were used to analyze the relation of adolescent experiences of violence to: (1) past 6 month street violence involvement and (2) past year intimate partner violence perpetration. Ten percent of the sample reported that they experienced adolescent victimization. Men reporting adolescent victimization were significantly more likely to report past 6-month street violence involvement (Adjusted Odds Ratio (AOR) = 3.2, 95 % CI = 1.7-6.3) and past 6 month intimate partner violence perpetration (AOR = 2.8, 95 % CI = 1.8-5.4) compared to men who did not report such victimization. Study findings suggest that in order to prevent adulthood perpetration of violence, more work is needed to address experiences of victimization among young Black males, particularly violence experienced during adolescence.

The multiple mini-interview for emergency medicine resident selection.

BACKGROUND: The Multiple Mini-Interview (MMI) uses multiple, short-structured contacts to evaluate communication and professionalism. It predicts medical school success better than the traditional interview and application. Its acceptability and utility in emergency medicine (EM) residency selection are unknown. OBJECTIVE: We theorized that participants would judge the MMI equal to a traditional unstructured interview and it would provide new information for candidate assessment. METHODS: Seventy-one interns from 3 programs in the first month of training completed an eight-station MMI focused on EM topics. Pre- and post-surveys assessed reactions. MMI scores were compared with application data. RESULTS: EM grades correlated with MMI performance (F[1, 66] = 4.18; p < 0.05) with honors students having higher scores. Higher third-year clerkship grades were associated with higher MMI performance, although this was not statistically significant. MMI performance did not correlate with match desirability and did not predict most other components of an application. There was a correlation between lower MMI scores and lower global ranking on the Standardized Letter of Recommendation. Participants preferred a traditional interview (mean difference = 1.36; p < 0.01). A mixed format (traditional interview and MMI) was preferred over a MMI alone (mean difference = 1.1; p < 0.01). MMI performance did not significantly correlate with preference for the MMI. CONCLUSIONS: Although the MMI alone was viewed less favorably than a traditional interview, participants were receptive to a mixed-methods interview. The MMI does correlate with performance on the EM clerkship and therefore can measure important abilities for EM success. Future work will determine whether MMI performance predicts residency performance.

Early Emergency Medicine Milestone Assessment for Predicting First-Year Resident Performance.

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) requires emergency medicine (EM) residency training programs to monitor residents' progress using standardized milestones. The first assessment of PGY 1 resident milestones occurs midway through the first year and could miss initial deficiencies. Early assessment of PGY 1 EM resident milestones has potential to identify at-risk residents prior to standard midyear evaluations. We developed an orientation syllabus for PGY 1 residents followed by a milestone assessment. Assessment scores helped predict future milestone scores and American Board of Emergency Medicine (ABEM) In-Training Examination (ITE) scores for PGY 1 residents. Methods: From 2013 to 2020, we developed and implemented Milestone Evaluation Day (MED), a simulation-based day and written exam assessing PGY 1 EM residents during their first month on the 23 ACGME 1.0 milestones. MED stations included a history and physical with verbal presentation, patient simulation, vascular access, wound management, and airway management. MED, Clinical Competency Committee-generated (CCC-generated) milestone, and ABEM ITE scores were averaged and compared utilizing Pearson's correlation coefficient. Results: Of 112 PGY 1 EM residents, 110 (98%) were analyzed over an 8-year period. We observed a moderate positive correlation of MED and CCC-generated milestone scores (r = .34, p < .001). There was a nonstatistically significant weak positive correlation of MED and ABEM ITE scores (r = .13, p = .17). Discussion: An early assessment of EM milestones in the PGY 1 year can assist in the prediction of CCC-generated milestone scores for PGY 1 residents.

Managing Subarachnoid Hemorrhage Precipitated by Anesthesia-assisted Rapid Opioid Detoxification: A Case Report.

INTRODUCTION: Anesthesia-assisted rapid opioid detoxification (AAROD) is a controversial method of treating opioid dependence that involves sedating patients during a period of provoked withdrawal. Reported adverse outcomes of the procedure demonstrate the importance of recognizing the potential complications of AAROD. CASE PRESENTATION: We present a case of a 41-year-old male presenting with a subarachnoid hemorrhage following an AAROD procedure. CONCLUSION: This case report and discussion reviews the pathophysiology of opioid withdrawal syndrome, potential complications following AAROD, and important management considerations.

Attenuated cold sensitivity in TRPM8 null mice.

Thermosensation is an essential sensory function that is subserved by a variety of transducer molecules, including those from the Transient Receptor Potential (TRP) ion channel superfamily. One of its members, TRPM8 (CMR1), a ligand-gated, nonselective cation channel, is activated by both cold and chemical stimuli in vitro. However, its roles in cold thermosensation and pain in vivo have not been fully elucidated. Here, we show that sensory neurons derived from TRPM8 null mice lack detectable levels of TRPM8 mRNA and protein and that the number of these neurons responding to cold (18 degrees C) and menthol (100 microM) is greatly decreased. Furthermore, compared with WT mice, TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury-induced responsiveness to acetone cooling. These results suggest that TRPM8 may play an important role in certain types of cold-induced pain in humans.

A prospective study to validate pulmonary blood mass changes on non-contrast 4DCT in pulmonary embolism patients.

PURPOSE: Limited diagnostic options exist for patients with suspected pulmonary embolism (PE) who cannot undergo CT-angiogram (CTA). CT-ventilation methods recover respiratory motion-induced lung volume changes as a surrogate for ventilation. We recently demonstrated that pulmonary blood mass change, induced by tidal respiratory motion, is a potential surrogate for pulmonary perfusion. In this study, we examine blood mass and volume change in patients with PE and parenchymal lung abnormalities (PLA). METHODS: A cross-sectional analysis was conducted on a prospective, cohort-study with 129 consecutive PE suspected patients. Patients received 4DCT within 48 h of CTA and were classified as having PLA and/or PE. Global volume change (VC) and percent global pulmonary blood mass change (PBM) were calculated for each patient. Associations with disease type were evaluated using quantile regression. RESULTS: 68 of 129 patients were PE positive on CTA. Median change in PBM for PE-positive patients (0.056; 95% CI: 0.045, 0.068; IQR: 0.051) was smaller than that of PE-negative patients (0.077; 95% CI: 0.064, 0.089; IQR: 0.056), with an estimated difference of 0.021 (95% CI: 0.003, 0.038; p = 0.0190). PLA was detected in 57 (44.2%) patients. Median VC for PLA-positive patients (1.26; 95% CI: 1.22, 1.30; IQR: 0.15) showed no significant difference from PLA-negative VC (1.25; 95% CI: 1.21, 1.28; IQR: 0.15). CONCLUSIONS: We demonstrate that pulmonary blood mass change is significantly lower in PE-positive patients compared to PE-negative patients, indicating that PBM derived from dynamic non-contrast CT is a potentially useful surrogate for pulmonary perfusion.

Quantifying pulmonary perfusion from noncontrast computed tomography.

PURPOSE: Computed tomography (CT)-derived ventilation methods compute respiratory induced volume changes as a surrogate for pulmonary ventilation. Currently, there are no known methods to derive perfusion information from noncontrast CT. We introduce a novel CT-Perfusion (CT-P) method for computing the magnitude mass changes apparent on dynamic noncontrast CT as a surrogate for pulmonary perfusion. METHODS: CT-Perfusion is based on a mass conservation model which describes the unknown mass change as a linear combination of spatially corresponding inhale and exhale HU estimated voxel densities. CT-P requires a deformable image registration (DIR) between the inhale/exhale lung CT pair, a preprocessing lung volume segmentation, and an estimate for the Jacobian of the DIR transformation. Given this information, the CT-P image, which provides the magnitude mass change for each voxel within the lung volume, is formulated as the solution to a constrained linear least squares problem defined by a series of subregional mean magnitude mass change measurements. Similar to previous robust CT-ventilation methods, the amount of uncertainty in a subregional sample mean measurement is related to measurement resolution and can be characterized with respect to a tolerance parameter τ . Spatial Spearman correlation between single photon emission CT perfusion (SPECT-P) and the proposed CT-P method was assessed in two patient cohorts via a parameter sweep of τ . The first cohort was comprised of 15 patients diagnosed with pulmonary embolism (PE) who had SPECT-P and 4DCT imaging acquired within 24 h of PE diagnosis. The second cohort was comprised of 15 nonsmall cell lung cancer patients who had SPECT-P and 4DCT images acquired prior to radiotherapy. For each test case, CT-P images were computed for 30 different uncertainty parameter values, uniformly sampled from the range [0.01, 0.125], and the Spearman correlation between the SPECT-P and the resulting CT-P images were computed. RESULTS: The median correlations between CT-P and SPECT-P taken over all 30 test cases ranged between 0.49 and 0.57 across the parameter sweep. For the optimal tolerance τ = 0.0385, the CT-P and SPECT-P correlations across all 30 test cases ranged between 0.02 and 0.82. A one-sample sign test was applied separately to the PE and lung cancer cohorts. A low Spearmen correlation of 15% was set as the null median value and two-sided alternative was tested. The PE patients showed a median correlation of 0.57 (IQR = 0.305). One-sample sign test was statistically significant with 96.5 % confidence interval: 0.20-0.63, P < 0.00001. Lung cancer patients had a median correlation of 0.57(IQR = 0.230). Again, a one-sample sign test for median was statistically significant with 96.5 percent confidence interval: 0.45-0.71, P < 0.00001. CONCLUSION: CT-Perfusion is the first mechanistic model designed to quantify magnitude blood mass changes on noncontrast dynamic CT as a surrogate for pulmonary perfusion. While the reported correlations with SPECT-P are promising, further investigation is required to determine the optimal CT acquisition protocol and numerical method implementation for CT-P imaging.

Clinical prediction rule for SARS-CoV-2 infection from 116 U.S. emergency departments 2-22-2021.

OBJECTIVES: Accurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care. METHODS: Data came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records of 19,850 emergency department (ED) patients tested for SARS-CoV-2. The criterion standard for diagnosis of SARS-CoV-2 required a positive molecular test from a swabbed sample or positive antibody testing within 30 days. The prediction score was derived from a 50% random sample (n = 9,925) using unadjusted analysis of 107 candidate variables as a screening step, followed by stepwise forward logistic regression on 72 variables. RESULTS: Multivariable regression yielded a 13-variable score, which was simplified to a 13-point score: +1 point each for age>50 years, measured temperature>37.5°C, oxygen saturation<95%, Black race, Hispanic or Latino ethnicity, household contact with known or suspected COVID-19, patient reported history of dry cough, anosmia/dysgeusia, myalgias or fever; and -1 point each for White race, no direct contact with infected person, or smoking. In the validation sample (n = 9,975), the probability from logistic regression score produced an area under the receiver operating characteristic curve of 0.80 (95% CI: 0.79-0.81), and this level of accuracy was retained across patients enrolled from the early spring to summer of 2020. In the simplified score, a score of zero produced a sensitivity of 95.6% (94.8-96.3%), specificity of 20.0% (19.0-21.0%), negative likelihood ratio of 0.22 (0.19-0.26). Increasing points on the simplified score predicted higher probability of infection (e.g., >75% probability with +5 or more points). CONCLUSION: Criteria that are available at the point of care can accurately predict the probability of SARS-CoV-2 infection. These criteria could assist with decisions about isolation and testing at high throughput checkpoints.

SPRINT Through Tasks: A Novel Curriculum for Improving Resident Task Management in the Emergency Department.

Introduction: The emergency department (ED) presents a challenging task-management environment to emergency medicine (EM) trainees. However, equipping residents with a tool to improve task switching (generically known as multitasking) could have positive impacts on patient care and physician emotional state. We designed a task-management tool and educational curriculum with the goal of improving emergency medicine resident task-switching ability. Methods: The task-management tool uses the acronym SPRINT: (1) stabilize critical patients, (2) perform procedures, (3) rack (see new patients in the chart rack), (4) in or out (reassess and disposition), (5) type it up (chart completion). These tasks and their order were decided on by two seasoned clinicians based on their years of experience in the ED. The SPRINT tool was taught to EM residents through a 1-hour curriculum consisting of an introductory video, a classroom-based workshop with multimedia didactics, and team learning with a card game simulating the use of the SPRINT tool on a shift. Residents were surveyed to evaluate their task-management confidence and perceived effectiveness of the curriculum. Results: A total of 34 EM residents participated in this training on the SPRINT tool. There was an improvement in resident confidence in task management, and residents reporting having a strategy for task prioritization 8 weeks after the workshop. Discussion: The SPRINT curriculum provides EM residents with a tool to manage the complex task-management environment of the ED. Further research in task-management education should focus on patient-oriented outcomes among physicians who have received this training.

Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases.

OBJECTIVE: To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment. METHODS: We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002-October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria. FINDINGS: For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4-21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6-36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23-498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents. CONCLUSION: Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored.

A feasibility study of the sensitivity of emergency physician Dysphagia screening in acute stroke patients.

STUDY OBJECTIVE: To determine the sensitivity of dysphagia screening by emergency physicians on acute stroke patients. METHODS: To develop a 2-tiered dysphagia screen and performed it on a convenience sample of acute stroke patients. Tier 1 examined voice quality, swallowing complaints, facial asymmetry, and aphasia. Tier 2 involved a water swallow test, with evaluation for swallowing difficulty, voice quality compromise, and pulse oximetry desaturation (>or=2%). We classified patients passing both tiers as "low risk" and compared the screen's sensitivity to a formal assessment by speech language pathologists. To assess reproducibility, we performed 2 consecutive, blinded ED screens on a convenience sample of 32 patients. RESULTS: During 16 months, we enrolled a convenience sample of 103 patients, excluding 19 patients from data analysis for lack of a stroke discharge diagnosis (n=11), an incomplete speech language pathologist evaluation within 24 hours (n=7), or pneumonia on emergency department (ED) chest radiography (n=1). Of the 84 remaining patients, speech language pathologists identified dysphagia in 48. The sensitivity of the ED dysphagia screen was 96% (95% confidence interval [CI] 85% to 99%), with a negative likelihood ratio of 0.08 (95% CI 0.02 to 0.3). Reproducibility testing yielded a kappa for the overall screen result of 0.9 (95% CI 0.9-1.0) and a simple agreement of 97%. CONCLUSION: Preliminary data on the sensitivity and reliability of our ED dysphagia screening tool are promising. The simple screen provides an easy way for emergency physicians to identify acute stroke patients eligible for early oral medications and nutrition. Further validation and refinement of our screen are needed before its widespread adoption.

An Emergency Medicine Milestone-Based Simulation Curriculum: Acute Ischemic Stroke.

Introduction: The emergency medicine (EM) resident's ability to make independent decisions in the setting of acute ischemic stroke has been reduced as a result of the involvement of multidisciplinary teams. This simulation was created to give EM residents the opportunity to independently manage the early stages of ischemic stroke and its complications. Methods: A solo learner was presented with a 55-year-old male with complaints consistent with an acute stroke. The resident had to calculate stroke severity; coordinate hospital resources; discuss risks, benefits, and alternatives to thrombolysis; and deal with subsequent complications. The learner had to keep a broad differential for sudden change in mental status and consider alternative interventions. Strategies to decrease intracranial pressure needed to be implemented while obtaining neurosurgical consultation. Debriefing included discussion of expected actions in the context of the Accreditation Council for Graduate Medical Education (ACGME) milestones. Residents' review of their video performance added additional self-reflection. Results: A total of 69 PGY 3 EM residents independently participated in this simulation over a 5-year period. Thirty-two completed a postsimulation evaluation. Nearly all learners felt that this case reflected an actual patient encounter and increased their confidence in managing stroke. The milestone-based feedback tool was completed with all learners. Anticipated actions linked to Level 1 and 2 milestones were regularly achieved while acquisition of Level 3 and 4 actions varied. Discussion: Case actions were uniquely characterized by the ACGME milestones, which helped to delineate learners' knowledge gaps and provided concrete areas for improvement.

Difficulty Breathing With a Rash: A Pediatric Simulation Case for Residents and Fellows.

INTRODUCTION: The purpose of the case is to teach health care professionals to recognize Henoch-Schönlein purpura (HSP), including rare and serious complications. The case includes a review of epidemiology, classification, clinical manifestations, and treatment of HSP. METHODS: Utilizing an adolescent simulation mannequin, we present the case of an 11-year-old female who presents to a pediatric emergency department with HSP and respiratory symptoms requiring intubation. This case reinforces the appearance of the characteristic rash and helps learners develop an algorithm for HSP management that includes the identification and management of abdominal pain associated with HSP, as well as the rare and serious complication of pulmonary vasculitis. We focus learners on managing severe respiratory distress in the HSP patient. Learners are assessed using standardized forms, and the learner outcome measurements include the recognition of HSP and successful management of abdominal pain and respiratory failure in this unique setting. RESULTS: This module has been used with pediatric residents, emergency medicine residents, pediatric emergency medicine fellows, and pediatric emergency medicine nurse practitioners. Approximately 30 learners have completed this module during seven separate sessions. All learners felt the case provided the opportunity to identify HSP as well as to manage a serious and rare complication of the disease. DISCUSSION: Overall, we have had positive feedback from the learners about this case, and it provides them the opportunity to see more rare complications during their training period. Learners leave the session with enhanced knowledge of HSP, as well as a review of respiratory failure and intubation.

The putative tumor suppressor deleted in malignant brain tumors 1 is an estrogen-regulated gene in rodent and primate endometrial epithelium.

Deleted in malignant brain tumors 1 (DMBT1) is a candidate suppressor of malignancies of the brain, lung, gut, and breast. We have been studying gene expression in the uterus in the presence of estrogens and their antagonists. Here, we show that DMBT1 RNA levels are robustly increased by estrogen treatment in the uteri of ovariectomized monkeys and rats. In monkeys, the progestin antagonist mifepristone inhibits estrogen-dependent uterine proliferation. As determined by a microarray experiment and quantitative analysis of RNA levels, mifepristone inhibited estrogenic induction of DMBT1. DMBT1 was not expressed in intact monkeys that were treated with a gonadotropin agonist to suppress steroidogenesis. An in vitro transfection study with human DMBT1 promoter constructs showed that an Alu site approximately 3000 nucleotides upstream of the gene mediates estrogenic regulation. Surprisingly, the estrogen antagonists tamoxifen, raloxifene, and ICI 182,780 also induced gene expression via this Alu site. Rodents represent a more convenient model system for studying uterine biology than monkeys. In rats, uterine DMBT1 RNA levels were dramatically up-regulated by estrogen. Consistent with the transfection study, tamoxifen and raloxifene increased DMBT1 RNA levels in vivo, but ICI 182,780 inhibited an estrogen-induced increase. Immunohistochemical studies showed that DMBT1 is specifically induced in glandular and luminal epithelia of the rat endometrium. Our experiments establish that DMBT1 is an estrogen-responsive gene with a possible role in endometrial proliferation or differentiation, and they have implications for the putative tumor suppressive and mucosal protective functions of DMBT1 in the uterus.

Association between adolescent marriage and marital violence among young adult women in India.

OBJECTIVE: To assess whether a history of adolescent marriage (<18 years) places women in young adulthood in India at increased risk of physical or sexual marital violence. METHODS: Cross-sectional analysis was performed on data from a nationally representative household study of 124385 Indian women aged 15-49 years collected in 2005-2006. The analyses were restricted to married women aged 20-24 years who participated in the marital violence (MV) survey module (n=10514). Simple regression models and models adjusted for participant demographics were constructed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between adolescent marriage and MV. RESULTS: Over half (58%) of the participants were married before 18 years of age; 35% of the women had experienced physical or sexual violence in their marriage; and 27% reported such abuse in the last year. Adjusted regression analyses revealed that women married as minors were significantly more likely than those married as adults to report ever experiencing MV (adjusted OR 1.77; 95% CI, 1.61-1.95) and in the last 12 months (adjusted OR 1.51; 95% CI, 1.36-1.67). CONCLUSIONS: Women who were married as adolescents remain at increased risk of MV into young adulthood.

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia.

There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.