IUD self-removal: A randomized controlled trial of a self-removal guide in clinical and nonclinical settings.

OBJECTIVES: Intrauterine device (IUD) users often encounter barriers to desired removal. Self-removal, while previously found to be successful only 19% of the time, may mitigate these obstacles. Our primary objective was to evaluate the effectiveness of our previously developed IUD self-removal guide. Our secondary objectives were to evaluate the acceptability of the guide and characterize the self-removal process. STUDY DESIGN: This was a randomized controlled trial comparing IUD self-removal success rates with and without a guide. Participants selected a clinical or nonclinical setting for self-removal. The primary outcome was the rate of successful IUD self-removal. Covariates of interest included demographic characteristics, parity, body mass index, and attempted removal setting. RESULTS: Of the 116 participants, 35 (30%) successfully removed their IUDs, 20 (32%) randomized to the guide, and 15 (28%) randomized to no guide (p = 0.7). While our guide was not associated with increased successful self-removal, the majority (97%) of those randomized to it reported it to be helpful. Those who selected a nonclinical setting (80%) were more successful at self-removal (35% vs 9%, p = 0.01). Most participants would recommend IUD self-removal to a friend (68%) and attempt again with a future IUD (80%). CONCLUSIONS: The proportion of participants who successfully removed their IUDs was higher than previously shown, with or without the use of our guide. Our inclusion of a nonclinical setting was novel, in which the proportion of successful self-removal was significantly higher. Providers should consider discussion of IUD self-removal, with a reasonable expectation about the likelihood of success, as a means of increasing reproductive autonomy. IMPLICATIONS: IUD self-removal was feasible and acceptable.

Scholarly activity following National Institutes of Health Women's Reproductive Health Research K12 training-a cohort study.

BACKGROUND: National Institutes of Health funding to address basic reproductive health for common female conditions remains disproportionately low, in part because of low success rates of grant applications by obstetrician-gynecologists. OBJECTIVE: This study aimed to evaluate the scholarly productivity of individuals supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Women's Reproductive Health Research K12 career development award, created to advance careers of obstetrician-gynecologist physician-scientists. STUDY DESIGN: We performed a cohort study of individuals who completed at least 2 years of Women's Reproductive Health Research training by June 30, 2015, and had at least 5-year follow-up. Earliest training start date was December 1, 1998. Primary outcomes from public data sources (National Institutes of Health RePORTER, PubMed, iCite) were (1) number of total and R01 National Institutes of Health grants as principal investigator; (2) numbers of total and first and last author publications; and (3) median and highest publication impact factor measured by the relative citation ratio. Secondary outcomes from an email survey subcohort were total number of research grants, federally funded grants, and number of National Institutes of Health grants as coinvestigator; institutional promotions and academic appointments, national and National Institutes of Health leadership roles; and career and mentorship satisfaction. Outcomes were recorded at 5, 10, and 15 years postgraduation, and aggregate anonymized data were divided into 3 groups using Women's Reproductive Health Research completion dates: June 30 of 2005, 2010, and 2015. Temporal trends were assessed. Results were stratified by gender, number of awarded grant cycles (1-2 vs 3-4), and specialty type. Analyses used Fisher exact or Pearson chi-square tests, and Mantel-Haenszel tests of trend. RESULTS: The distribution of the cohort (N=178) by graduation completion date was: on or before June 30, 2005 (57 [32%]); July 1, 2005 to June 30, 2010 (60 [34%]); and July 1, 2010 to June 30, 2015 (61 [34%]). Most participants were female (112 [64%]) and maternal-fetal medicine trained (53 [30%]), followed by no fellowship (50 [28%]). Of the 178 participants, 72 (40%) received additional National Institutes of Health funding as a principal investigator, 45 (25%) received at least 1 R01, and 23 (13%) received 2 to 5 R01s. There were 52 (31%) scholars with >10 first author publications, 66 (39%) with >10 last author publications, and 108 (63%) with ≥25 publications. The highest relative citation ratio was a median of 8.07 (interquartile range, 4.20-15.16). There were 121 (71%) scholars with relative citation ratio ≥5, indicating >5-fold greater publication impact than that of other National Institutes of Health-funded scientists in similar areas of research. No differences by gender, institution, or temporal trends were observed. Of the full cohort, 69 (45.7%) responded to the survey; most self-identified as women (50 [73%]) and White (51 [74%]). CONCLUSION: Our findings suggest that the infrastructure provided by an institutional K award is an advantageous career development award mechanism for obstetrician-gynecologists, a group of predominantly women surgeons. It may serve as a corrective for the known inequities in National Institutes of Health funding by gender.

Neurocognitive and mental health impact of adrenoleukodystrophy across the lifespan: Insights for the era of newborn screening.

X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.

Pancytopenia and Profound Neutropenia as a Sequela of Severe SARS-CoV-2 Infection (COVID-19) With Concern for Bone Marrow Involvement.

Pancytopenia and neutropenia due to coronavirus disease 2019 (COVID-19) are rare. Here we report a case of neutropenia as a sequela of COVID-19 with concern for bone marrow infiltration. The patient was successfully treated with granulocyte colony-stimulating factor.

A Qualitative Exploration of Somali Refugee Women's Experiences with Family Planning in the U.S.

The purpose of our study was to explore the knowledge, attitudes, and experiences of Somali refugee women with family planning in the U.S. We conducted focus groups of Somali refugee women and used grounded theory methodology to identify emergent themes. Fifty-three women, aged 18-49 years, participated. Somali refugee women's cultural and religious beliefs and social identities strongly influence their conceptualization of family planning. Participants agreed that a woman's fertility is ultimately decided by Allah and identified environmental changes after immigration and the desire to optimize maternal health as facilitators to modern contraceptive use. Misconceptions about and fear of side effects of modern contraceptive methods, including a fear of infertility, were identified as barriers to use. To deliver patient-centered family planning counseling to Somali refugee women, it is essential that healthcare providers approach these discussions with cultural humility and consider employing community partners or cultural brokers to help provide family planning education.

Perceptions of Anal Intercourse Among Heterosexual Women: A Pilot Qualitative Study.

INTRODUCTION: More than one-third of women in the U.S. have engaged in heterosexual anal intercourse (HAI), but little is known regarding women's perceptions of HAI and motivations for engaging in this sexual behavior. AIM: This study aimed to explore U.S. women's motivations for engaging in HAI and to investigate how they navigate HAI in the context of sexual relationships. METHODS: Semi-structured interviews were conducted with 20 women, ages 18-50 years old, who had engaged in anal intercourse with a male partner within the past 3 months. The interview guide was developed utilizing a conceptual framework based on the Theory of Planned Behavior. MAIN OUTCOME MEASURE: Thematic content analysis was performed, and salient themes were identified. RESULTS: Salient themes were identified in all key components of the construct, including attitudes toward the behavior, subjective norms, and perceived behavioral control. Women's intent to engage in HAI was influenced by their attitudes toward HAI and level of control and trust with their partners. Primary motivators were partner and personal pleasure and sexual curiosity and experimentation. CONCLUSION: The Theory of Planned Behavior construct was well suited to explore factors influencing women's intent to engage in HAI. Most women perceive negative societal norms toward HAI. Although this does not appear to affect intention to engage in HAI, it does affect disclosure of this sexual activity with friends and healthcare providers. It is important for healthcare providers to provide open, non-judgmental counseling regarding HAI to decrease stigma, enhance communication, and improve sexual health. Benson LS, Gilmore KC, Micks EA, et al. Perceptions of Anal Intercourse Among Heterosexual Women: A Pilot Qualitative Study. Sex Med 2019;7:198-206.

Engaging men in an mHealth approach to support postpartum family planning among couples in Kenya: a qualitative study.

BACKGROUND: Involving male partners in family planning (FP) education and counseling may improve FP utilization and help meet couples' reproductive health needs in the postpartum period. We aimed to explore Kenyan men's and women's perspectives on an interactive short message service (SMS) approach to support postpartum FP decision-making, and inform intervention content for a randomized controlled trial (RCT). METHODS: We conducted four focus group discussions (FGD) among men (n = 35) and two among pregnant/postpartum women (n = 15) in western Kenya. Female participants were recruited at antenatal clinics; male participants were referred by antenatal attendees. FGDs included participant critique of pilot theory-based SMS messages. FGD transcripts were coded by two investigators and analyzed using an iterative, modified grounded theory approach. These data informed the intervention and RCT design, in which women had the option to refer male partners for trial enrollment. RESULTS: Men strongly desired inclusion in FP programs, and frequently discussed negative relationship consequences of women's covert contraceptive use. Female and male participants voiced a variety of concerns about contraceptive side effects and potential harms, which were central to narratives of community influence on personal contraceptive choices. Most participants felt that receiving FP-focused SMS and including men would be beneficial. They perceived that SMS dialogue with a nurse about FP could reduce misperceptions and may stimulate communication within couples, thereby improving contraceptive access and continuation. Shared decision-making around FP within couple relationships, in consultation with clinicians, was highly valued. CONCLUSIONS: Health concerns about FP and limited couple communication are perceived contributors to postpartum unmet contraceptive need. With women's consent, the inclusion of male partners in FP services, and specifically in an mHealth SMS intervention, is acceptable and desired. Receiving SMS may trigger communication about postpartum FP within couples. SMS content should address contraceptive knowledge gaps, anticipated side effects and FP misperceptions, and allow for real-time method choice assistance.

Parenting and perinatal depression: meeting women's needs.

Introduction: Symptoms of depression during pregnancy and the postpartum period can negatively impact parenting. It is important to understand the parenting experiences of women with depression, and what parenting support they need. Methods: This is a mixed methods analysis of data (demographic data, depression outcomes, patient survey results, and transcripts of patient and care manager focus groups) from an open treatment trial of the feasibility of delivering perinatal depression treatment using collaborative care in a rural obstetric setting. Results: Patients who attended focus groups did not differ significantly from those who did not. Qualitative analysis of focus groups revealed the following themes: Maternal mood and parenting difficulties are interrelated; Access to depression treatment is complicated by expectations for the perinatal period and by factors related to parenting; Women want parenting support in the context of treatment for perinatal depression. Conclusion: Women receiving perinatal depression treatment experience unique parenting challenges and desire parenting support. Healthcare providers caring for these women should be mindful of their patients' parenting needs. Future research should explore ways to integrate parenting interventions with depression treatments. Mother-infant interaction is a key determinant of optimal infant development and integrating parenting support with perinatal depression treatments can have significant public health impact.

Use of the Levonorgestrel Intrauterine Device in Women With Type 2 Diabetes.

IN BRIEF Women with type 2 diabetes are less likely to receive prescriptions for contraceptives despite the fact that diabetes is associated with an increased risk of maternal and fetal complications. In the largest case series to date examining use of the levonorgestrel-releasing intrauterine device (LNG-IUD) in women with type 2 diabetes, we demonstrate that the LNG-IUD is safe and effective and does not affect glycemic control in women with type 2 diabetes. In this study of 115 women under the age of 55 years with type 2 diabetes who had an LNG-IUD placed between 2007 and 2012, we found low rates of pregnancies, expulsions, and other complications in every age category and disease stratification. Thirty-nine patients had A1C data before and up to 2 years after placement, and there was no significant change in A1C (mean A1C decrease of 0.17, 95% CI -0.76 to 0.43). This study will enable evidence-based contraceptive counseling for women with type 2 diabetes.

Post-transplant adaptive function in childhood cerebral adrenoleukodystrophy.

Objective: Hematopoietic stem cell transplantation (HSCT) is the only treatment known to slow or halt inflammatory demyelination among boys with the cerebral form of X-linked adrenoleukodystrophy (cALD), a devastating childhood condition affecting the central nervous system. HSCT can lead to a range of adverse outcomes including fatality. Previous studies have examined the potential predictors of post-HSCT survival and neurologic functioning. However, little is known about patients' daily-life adaptive functional outcomes (i.e., ability to communicate, maintain social relationships, and independently execute tasks of daily living). The purpose of this retrospective cohort study was to identify which patient characteristics and treatment-related variables predict long-term adaptive function among the survivors of HSCT for cALD. Methods: We obtained caregiver ratings of adaptive functioning of 65 transplant survivors at an average of 4.6 years (range: 1.0-24.1 years) post-HSCT. Using linear regression with penalized maximum likelihood estimation, we modeled the relative contribution of pre-transplant neurocognitive test performance, MRI severity, transplant regimen, and length of time since transplant on patient adaptive functioning outcomes. Results: Higher radiographic disease severity and poorer performance on baseline neurocognitive tests requiring fine motor skills and visual perception were associated with inferior adaptive functioning after HSCT. Use of radiation during the transplant preparative regimen also predicted poorer adaptive outcomes. Interpretation: In addition to radiological disease severity, baseline neurocognitive test performance is associated with post-transplant adaptive functional outcomes. Neurocognitive measures may play an important role in prognostic counseling and post-transplant treatment planning for patients considering HSCT for cALD.

Efficacy and Safety of Long-Acting Reversible Contraception in Women With Cardiovascular Conditions.

The physiological changes that occur during pregnancy can be deleterious to women with a cardiovascular condition. Evidence-based contraceptive counseling and provision is essential in this patient population. Although long-acting reversible contraception (LARCs), which include the intrauterine device (IUD) and the etonogestrel contraceptive implant, have been found to be safe and effective in healthy women, there are inadequate data regarding LARC use in patients with cardiovascular conditions. We conducted a retrospective chart review of women diagnosed with cardiovascular disease who had a copper IUD, levonorgestrel-releasing intrauterine system or contraceptive implant placed at the University of Washington Medical Center from 2007 to 2012. We abstracted and analyzed patient demographic characteristics, medical conditions, indications for LARC placement, and complications. The sample included 470 women with cardiovascular conditions. The mean age was 34.6 years. One hundred twenty-four patients (26.11%) were nulligravid and 169 patients (35.58%) were nulliparous. Four hundred ten chose the levonorgestrel-releasing intrauterine system (87.23%), 33 patients (7.02%) opted for the copper IUD, and 23 patients (4.89%) chose the etonogestrel implant. Eighteen patients (3.83%) had a confirmed IUD expulsion, 2 patients (0.43%) became pregnant, and there were 4 cases of pelvic inflammatory disease (0.85%). There were no cases of perforation. There were no confirmed cases of infective endocarditis associated with LARC insertion. In conclusion, LARC devices appear safe with few complications for women with cardiovascular conditions. Clinicians can be reassured that LARC may be offered as an appropriate option when counseling women with cardiovascular disease on safe contraceptive methods.

Immediate Postpartum Intrauterine Contraception Insertion.

The immediate postpartum period is a favorable time for initiating contraception because women who have recently given birth are often highly motivated to use contraception, pregnancy is excluded, and the hospital setting offers convenience for patients and providers. This article addresses immediate postpartum intrauterine contraception (IUC) insertion for copper and levonorgestrel IUC. Immediate postpartum IUC is safe and effective, with a majority of IUC devices retained at 6 and 12 months. There are increased rates of expulsion, compared with delayed postpartum insertion and interval insertion, which need to be weighed against the risk of patients not returning for postpartum follow-up.

Fluid genetic analyses predict the biological behavior of pancreatic cysts: three-year experience.

CONTEXT: EUS with fine-needle aspiration and cyst fluid analysis is routinely used to evaluate pancreatic cysts; however, the clinical course of these lesions is often not well defined. OBJECTIVE: Our study evaluated whether EUS imaging, cyst fluid CEA, and cytology combined with cyst fluid genetic analyses for allelic imbalance and genetic mutations can be used to better predict the malignant potential of pancreatic cysts. PATIENTS: Seventy-two patients underwent EUS-FNA for evaluation of pancreatic cysts from 2010 to 2013. DESIGN: In addition to routine cytology and fluid CEA, the aspirated cyst fluid was analyzed for the presence of KRAS mutations, GNAS mutations, and allelic imbalance (loss of heterozygosity). Patients were followed up to 3 years. SETTING: Tertiary care center. RESULTS: EUS revealed 39 IPMNs, 17 mucinous cystic neoplasms, and 16 serous cystadenomas. Twenty two of 56 patients with IPMNs or mucinous cystic neoplasms had pancreatic cysts with abnormal genetic fluid analysis. Of those 22 patients, 18 contained a non-benign clinical diagnosis. This is consistent with cyst fluid genetic analysis carrying a sensitivity and specificity of 75% and 88%, respectively, and a positive predictive value of 82%.There was also a significant negative predictive value of 81%. For mucinous cystic neoplasms the negative predictive value was 100%. CONCLUSION: Genetic mutations and allelic imbalance detected in pancreatic mucinous cysts are associated with progression to malignancy and could be helpful as predictors of biological behavior of pancreatic cysts. In our experience, genetic analyses when used in combination with EUS imaging, cytology, and fluid CEA could serve as a guide to clinical decisions regarding cyst surgical resection and follow up.

Interleukin-3 plays dual roles in osteoclastogenesis by promoting the development of osteoclast progenitors but inhibiting the osteoclastogenic process.

Interleukin (IL)-3, a multilineage hematopoietic growth factor, is implicated in the regulation of osteoclastogenesis. However, the role of IL-3 in osteoclastogenesis remains controversial; whereas early studies showed that IL-3 stimulates osteoclastogenesis, recent investigations demonstrated that IL-3 inhibits osteoclast formation. The objective of this work is to further address the role of IL-3 in osteoclastogenesis. We found that IL-3 treatment of bone marrow cells generated a population of cells capable of differentiating into osteoclasts in tissue culture dishes in response to the stimulation of the monocyte/macrophage-colony stimulating factor (M-CSF) and the receptor activator of nuclear factor kappa B ligand (RANKL). The IL-3-dependent hematopoietic cells were able to further proliferate and differentiate in response to M-CSF stimulation and the resulting cells were also capable of forming osteoclasts with M-CSF and RANKL treatment. Interestingly, IL-3 inhibits M-CSF-/RANKL-induced differentiation of the IL-3-dependent hematopoietic cells into osteoclasts. The flow cytometry analysis indicates that while IL-3 treatment of bone marrow cells slightly affected the percentage of osteoclast precursors in the surviving populations, it considerably increased the percentage of osteoclast precursors in the populations after subsequent M-CSF treatment. Moreover, osteoclasts derived from IL-3-dependent hematopoietic cells were fully functional. Thus, we conclude that IL-3 plays dual roles in osteoclastogenesis by promoting the development of osteoclast progenitors but inhibiting the osteoclastogenic process. These findings provide a better understanding of the role of IL-3 in osteoclastogenesis.

IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells.

BACKGROUND: Interleukin (IL)-11, a cytokine produced by breast cancer, has been implicated in breast cancer-induced osteolysis (bone destruction) but the mechanism(s) of action remain controversial. Some studies show that IL-11 is able to promote osteoclast formation independent of the receptor activator of NF-κB ligand (RANKL), while others demonstrate IL-11 can induce osteoclast formation by inducing osteoblasts to secrete RANKL. This work aims to further investigate the role of IL-11 in metastasis-induced osteolysis by addressing a new hypothesis that IL-11 exerts effects on osteoclast progenitor cells. METHODS: To address the precise role of breast cancer-derived IL-11 in osteoclastogenesis, we determined the effect of breast cancer conditioned media on osteoclast progenitor cells with or without an IL-11 neutralizing antibody. We next investigated whether recombinant IL-11 exerts effects on osteoclast progenitor cells and survival of mature osteoclasts. Finally, we examined the ability of IL-11 to mediate osteoclast formation in tissue culture dishes and on bone slices in the absence of RANKL, with suboptimal levels of RANKL, or from RANKL-pretreated murine bone marrow macrophages (BMMs). RESULTS: We found that freshly isolated murine bone marrow cells cultured in the presence of breast cancer conditioned media for 6 days gave rise to a population of cells which were able to form osteoclasts upon treatment with RANKL and M-CSF. Moreover, a neutralizing anti-IL-11 antibody significantly inhibited the ability of breast cancer conditioned media to promote the development and/or survival of osteoclast progenitor cells. Similarly, recombinant IL-11 was able to sustain a population of osteoclast progenitor cells. However, IL-11 was unable to exert any effect on osteoclast survival, induce osteoclastogenesis independent of RANKL, or promote osteoclastogenesis in suboptimal RANKL conditions. CONCLUSIONS: Our data indicate that a) IL-11 plays an important role in osteoclastogenesis by stimulating the development and/or survival of osteoclast progenitor cells and b) breast cancer may promote osteolysis in part by increasing the pool of osteoclast progenitor cells via tumor cell-derived IL-11. However, given the heterogeneous nature of the bone marrow cells, the precise mechanism by which IL-11 treatment gives rise to a population of osteoclast progenitor cells warrants further investigation.

Vinyl glove ingestion in children: a word of caution.

BACKGROUND: Vinyl gloves when ingested will harden and develop sharp edges producing gastric bezoars; bowel obstruction; and, ultimately, perforation. We report 4 children with complications secondary to vinyl glove ingestion who required surgical intervention. METHODS: A 3-year-old boy, a 13-year-old adolescent girl with Down syndrome, a 14-year-old adolescent girl, and a 15-year-old adolescent boy presented with bowel obstruction secondary to a bezoar caused by a vinyl glove. The adolescent girl with Down syndrome presented again at age 17 years with a large vinyl glove gastric bezoar. Three of the children had mental retardation, and 1 was a victim of child abuse. Three had laparoscopic-assisted removal of the vinyl glove bezoar, and 1 had laparotomy. RESULTS: The 4 children recovered uneventfully. Two of the patients had unsuspected intestinal perforation. The caretakers denied awareness of the vinyl glove ingestion. CONCLUSIONS: Vinyl glove ingestion can cause intestinal obstruction and perforation. Vinyl gloves should be removed from the immediate proximity of mentally retarded patients or patients with pica. Most of the time, the finding of vinyl gloves as etiology of the obstruction or perforation is incidental. If the event is known or witnessed, prompt surgical intervention is generally recommended.

Characteristic purpura of the ears, vasculitis, and neutropenia--a potential public health epidemic associated with levamisole-adulterated cocaine.

BACKGROUND: Dermatologists at the University of California, San Francisco recently reported two patients in the online Journal of the American Academy of Dermatology with purpura presumably induced by levamisole in contaminated cocaine. Levamisole-induced vasculitis and neutropenia has been reported elsewhere in the United States and Canada. Up to 70% of cocaine in the United States could be contaminated. OBJECTIVE: We sought to describe similar cases of vasculitis associated with cocaine use. METHODS: This is a retrospective case series. RESULTS: We report 6 remarkably similar patients seen over just the past few months with retiform purpura on the body and tender purpuric eruptions, necrosis, and eschars of the ears after cocaine use in New York and California. All of these patients had positive perinuclear antineutrophil cytoplasmic antibody values and 3 of the 6 also had an associated neutropenia. Direct immunofluorescence studies suggested an immune complex-mediated vasculitis. LIMITATIONS: This case series is descriptive in nature and, because testing is not easily performed, we did not test for levamisole in the serum or blood to prove this is the causative agent. CONCLUSION: It appears the use of cocaine is associated with the peculiar clinical findings of ear purpura, retiform purpura of the trunk, and neutropenia. We believe this case series may represent the tip of the iceberg as a looming public health problem caused by levamisole. Although the direct causal relationship may be difficult to establish, the astute dermatologist or primary care physician should be able to recognize the characteristic skin lesions and should be wary of the potential development of agranulocytosis.

Development of cell-based high-throughput assays for the identification of inhibitors of receptor activator of nuclear factor-kappa B signaling.

Bone loss due to metabolic or hormonal disorders and osteolytic tumor metastasis continues to be a costly health problem, but current therapeutics offer only modest efficacy. Unraveling of the critical role for the receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANK ligand (RANKL), in osteoclast biology provides an opportunity to develop more effective antiresorptive drugs. The in vivo effectiveness of RANKL inhibitors demonstrates the potency of the RANKL/RANK system as a drug target. Here, we report the development of cell-based assays for high-throughput screening to identify compounds that inhibit signaling from two RANK cytoplasmic motifs (PVQEET(559-564) and PVQEQG(604-609)), which play potent roles in osteoclast formation and function. Inhibitors of these motifs' signaling have the potential to be developed into new antiresorptive drugs that can complement current therapies. The cell-based assays consist of cell lines generated from RAW264.7 macrophages stably expressing a nuclear factor-kappa B-responsive luciferase reporter and a chimeric receptor containing the human Fas external domain linked to a murine RANK transmembrane and intracellular domain in which only one of the RANK motifs is functional. With these cells, specific RANK motif activation after chimeric receptor stimulation can be measured as an increase in luciferase activity. These assays demonstrated >300% increases in luciferase activity after RANK motif activation and Z '-factor values over 0.55. Our assays will be used to screen compound libraries for molecules that exhibit inhibitory activity. Follow-up assays will refine hits to a smaller group of more specific inhibitors of RANK signaling.