The American Board of Obstetrics and Gynecology's remote certifying examination: successes and challenges.

In response to the COVID-19 pandemic, the American Board of Obstetrics and Gynecology canceled the 2020 in-person subspecialty certifying examinations and developed remote administration of 4 subspecialty certifying examinations in 2021 for both examiners and candidates. Because of the continued risks of the COVID-19 pandemic, the 2021 specialty certifying examinations and the 2022 subspecialty certifying examinations were also administered remotely for candidates. For these examinations, examiners participated remotely in 2021 and were at the American Board of Obstetrics and Gynecology testing center in 2022. Overall, the American Board of Obstetrics and Gynecology remote certifying examinations have been well-received by candidates and examiners according to posttest survey data. Candidate performance has been comparable to that observed in the previous in-person examinations. In this review, we describe our implementation, process modifications, successes, and challenges with remote testing. During this process, the American Board of Medical Specialties approval was required, and the Standards for Educational and Psychological Testing served as our testing-industry guideline to ensure valid interpretation of scores and fairness to candidates.

Contraceptive Technology: Present and Future.

Many sexually active, reproductive-aged persons capable of becoming pregnant use some method of contraception. To expand options for those desiring birth control, new choices include a vaginal ring, transdermal patch, progestin-only pill, and spermicide. Compared with currently available methods, additional technologies that are highly effective, easy to use, cost efficient, and well-tolerated lay on the horizon. During contraceptive counseling, patient choice, and reproductive autonomy should remain paramount.

Health Benefits of Air Pollution Reduction.

Air pollution is a grave risk to human health that affects nearly everyone in the world and nearly every organ in the body. Fortunately, it is largely a preventable risk. Reducing pollution at its source can have a rapid and substantial impact on health. Within a few weeks, respiratory and irritation symptoms, such as shortness of breath, cough, phlegm, and sore throat, disappear; school absenteeism, clinic visits, hospitalizations, premature births, cardiovascular illness and death, and all-cause mortality decrease significantly. The interventions are cost-effective. Reducing factors causing air pollution and climate change have strong cobenefits. Although regions with high air pollution have the greatest potential for health benefits, health improvements continue to be associated with pollution decreases even below international standards. The large response to and short time needed for benefits of these interventions emphasize the urgency of improving global air quality and the importance of increasing efforts to reduce pollution at local levels.

Loss of Gadd45b accelerates BCR-ABL-driven CML.

Gadd45b is a member of Gadd45 stress sensor protein family that also includes Gadd45a & Gadd45g. To investigate the effect of Gadd45b in bcr-abl oncogene driven chronic myeloid leukemia (CML) development, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45b null myeloid progenitors transduced with a retroviral vector expressing BCR-ABL. Loss of Gadd45b was observed to accelerate BCR-ABL driven CML development with shortened median mouse survival time. BCR-ABL Gadd45b deficient CML progenitors exhibited increased proliferation and decreased apoptosis, associated with hyper-activation of c-Jun NH2-terminal kinase and Stat5. These results provide novel evidence that gadd45b, like gadd45a, functions as a suppressor of BCR-ABL driven leukemia, albeit via a different mechanism.

Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia.

There is substantial evidence that early growth response-1 (Egr1) gene, a zinc-finger transcription factor, behaves as a tumor suppressor in leukemia. This includes reports from this laboratory that constitutive Egr1 overrides leukemia conferred by deregulated c-Myc or E2F-1 in the M1 myeloid leukemic cell line by promoting differentiation. To investigate the effect of Egr1 on the initiation and progression of Chronic Myelogenous Leukemia (CML), lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr1 was observed to accelerate the development of BCR-ABL driven leukemia in recipient mice, resulting in the development of a more aggressive disease, a significantly shortened median survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin-cKit+Sca+). Egr1 deficient progenitors expressing BCR-ABL exhibited decreased apoptosis, and increased cell viability and proliferation relative to WT counterparts. Secondary BMT of BCR-ABL BM revealed that loss of Egr1 resulted in enrichment of LSCs, consistent with shorter survival time and more aggressive disease of these mice compared to WT counterparts. Furthermore, serial re-plating colony assays indicated that loss of Egr1 increased self-renewal ability of BCR-ABL expressing BM. These novel findings on the tumor suppressor role of Egr1 in CML provide the impetus to study the effect of altering Egr1 expression in AML, where the overall five year survival rate remains low. The effect of loss of Egr1 in CML could reflect its established functions in normal hematopoiesis, maintaining quiescence of HSCs and driving terminal differentiation to the monocyte/macrophage lineage. Gain of function studies should validate these conclusions and provide further rationale for increased Egr1 as a therapeutic target in AML.

First trimester noninvasive fetal RHD genotyping using maternal dried blood spots.

OBJECTIVE: This study was aimed to evaluate whether maternal dried blood spots could be a potential source for the noninvasive fetal RHD genotyping, serving as a combined one-step test for both the First Trimester Screen and the fetal RHD genotyping. METHOD: Both the maternal dried blood spots and the peripheral blood samples from 19 RhD-negative pregnant women were obtained during the First Trimester Screen. DNA was extracted and sequential real-time PCRs were performed to determine the fetal RHD genotypes. Fetal RhD serological types were obtained after delivery. This study was approved by the Institutional Review Board, and informed consents were obtained. RESULTS: A total of 19/19 fetal RHD genotyping with maternal DBS were consistent with the follow-up serological RhD test results after birth. Eleven were RhD positive, and eight were RhD negative (RHD deletion or RHD-CE-D = 6, RHD pseudogene = 1, RHDVI = 1). Sensitivity = 100%, specificity = 100%, positive predictive value = 100%, negative predictive value = 100%. A total of 18/19 fetal gender were determined correctly with maternal DBS. One female fetus was falsely determined as male. Sensitivity = 100%, specificity = 91.6%, positive predictive value = 87.5%, negative predictive value = 100%. CONCLUSION: Maternal dried blood spots, with the benefits of flexible sample transportation and processing, could be utilized for the noninvasive prenatal fetal RHD genotyping and potentially be incorporated into the routine First Trimester Screen. Larger scale study is in progress to implement fetal RHD genotyping in routine prenatal care. © 2017 John Wiley & Sons, Ltd.

Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia.

The Gadd45a stress sensor gene is a member in the Gadd45 family of genes that includes Gadd45b & Gadd45g. To investigate the effect of GADD45A in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45a null myeloid progenitors transduced with a retroviral vector expressing the 210-kD BCR-ABL fusion oncoprotein. Loss of Gadd45a was observed to accelerate BCR-ABL driven CML resulting in the development of a more aggressive disease, a significantly shortened median mice survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin- cKit+Sca+). GADD45A deficient progenitors expressing BCR-ABL exhibited increased proliferation and decreased apoptosis relative to WT counterparts, which was associated with enhanced PI3K-AKT-mTOR-4E-BP1 signaling, upregulation of p30C/EBPα expression, and hyper-activation of p38 and Stat5. Furthermore, Gadd45a expression in samples obtained from CML patients was upregulated in more indolent chronic phase CML samples and down regulated in aggressive accelerated phase CML and blast crisis CML. These results provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven leukemia and may provide a unique prognostic marker of CML progression.

Gadd45b deficiency promotes premature senescence and skin aging.

The GADD45 family of proteins functions as stress sensors in response to various physiological and environmental stressors. Here we show that primary mouse embryo fibroblasts (MEFs) from Gadd45b null mice proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. The impaired proliferation and increased senescence in Gadd45b null MEFs is partially reversed by culturing at physiological oxygen levels, indicating that Gadd45b deficiency leads to decreased ability to cope with oxidative stress. Interestingly, Gadd45b null MEFs arrest at the G2/M phase of cell cycle, in contrast to other senescent MEFs, which arrest at G1. FACS analysis of phospho-histone H3 staining showed that Gadd45b null MEFs are arrested in G2 phase rather than M phase. H2O2 and UV irradiation, known to increase oxidative stress, also triggered increased senescence in Gadd45b null MEFs compared to wild type MEFs. In vivo evidence for increased senescence in Gadd45b null mice includes the observation that embryos from Gadd45b null mice exhibit increased senescence staining compared to wild type embryos. Furthermore, it is shown that Gadd45b deficiency promotes senescence and aging phenotypes in mouse skin. Together, these results highlight a novel role for Gadd45b in stress-induced senescence and in tissue aging.

Unruptured second-trimester ovarian pregnancy.

Ovarian ectopic pregnancies are rare, with the majority diagnosed in the first trimester and often treated due to symptoms related to ovarian rupture. We report our experience with the diagnosis, management, and histologic evaluation of an unruptured second-trimester ovarian ectopic pregnancy. A 37-year-old woman presented with vague abdominal discomfort and irregular menses. Ultrasound detected a 16-week 4-day gestation with cardiac motion in the right adnexa and no evidence of an intrauterine pregnancy. Laparotomy with right salpingo-oophorectomy was performed, with removal of an unruptured pregnancy from the ovary. Although intraoperative examination and postoperative histopathologic evaluation demonstrated the classic Speigelberg criteria, it did not assist in the preoperative diagnosis, nor impact the treatment of the ovarian ectopic pregnancy in this case.

Developing an academic and American Indian tribal partnership in education: a model of community health nursing clinical education.

American Indian tribes shoulder a heavy burden in health inequities and recognize the value of partnerships with academic institutions. This article describes a unique education model developed through a partnership between a school of nursing and 2 Pacific Northwest tribes to provide clinical education for students. Over 3 years, students and faculty worked with 2 tribal communities to design research and implement education programs.

Gadd45 in modulation of solid tumors and leukemia.

The stress response gadd45 gene family participates in cell cycle control, cell survival, apoptosis, maintenance of genomic stability, DNA repair, and active DNA demethylation, in response to environmental and physiological stress including oncogenic stress. Given these diverse functions, it is anticipated that gadd45 genes can influence the initiation and progression of malignancy and the response to different treatments. This chapter will provide an overview of how the different members of the gadd45 gene family are expressed in different tumors and leukemia, how this may impact on progression of disease, and what happens when expression is manipulated. Studies from human tumor/leukemia samples, cell lines, and animal models are included in this review. An overriding theme is that each of the gadd45 genes has both tumor suppressor and tumor promoter functions, dependent on the tissue/cell type and transforming event.

Gadd45a levels in human breast cancer are hormone receptor dependent.

BACKGROUND: Gadd45a is a member of the Gadd45 family of genes that are known stress sensors. Gadd45a has been shown to serve as an effector in oncogenic stress in breast carcinogenesis in murine models. The present study was aimed at clarifying the expression of Gadd45a in human breast cancer and its correlation with clinicopathologic features. METHODS: The expression levels of Gadd45a in breast tissue samples of female breast surgery cases were examined by immunohistochemistry (IHC) using a Gadd45a antibody. Percent staining was determined and statistical analyses were applied to determine prognostic correlations. RESULTS: 56 female breast surgery cases were studied: Normal (11), Luminal A (9), Luminal B (11), HER2+ (10), Triple Negative (15). There was a highly significant difference in percent Gadd45a staining between groups [Mean]: Normal 16.3%; Luminal A 65.3%; Luminal B 80.7%; HER2+ 40.5%; TN 32%, P < 0.001, ANOVA. Gadd45a IHC levels for Normal cases found 82% negative/low. Luminal A breast cancer cases were found to be 67% high. Luminal B breast cancers were 100% high. Her2+ cases were 50% negative/low. Triple Negative cases were 67% negative/low. This difference in distribution of Gadd45a levels across breast cancer receptor subtypes was significant, P = 0.0009. CONCLUSIONS: Gadd45a levels are significantly associated with hormone receptor status in human breast cancer. Normal breast tissue displays low Gadd45a levels. High Gadd45a levels are associated with Luminal A and Luminal B subtypes. Absence of hormone receptors in Triple Negative subtype is associated with Negative/Low levels of Gadd45a. Further studies are indicated to elucidate the role of Gadd45a in breast cancer as a potential prognosticator or target for treatment.

Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants.

Accumulating evidence suggests that placental stresses during pregnancy can play an important role in the pathogenesis of preeclampsia. A common signal pathway that senses and converts placental stresses into intracellular stress response may be contributing to this pathology. Based on our previous findings, we extended our investigation to establish that Gadd45a stress signaling regulates sFlt-1 levels, particularly in placenta, when exposed to various preeclampsia-associated stresses including AT-1 receptor agonist (Angiotensin II), hypoxia, and inflammatory cytokines. Using a placental explant model, we found that Gadd45a was induced in response to all the preeclampsia stresses stated above. Although stress induced Gadd45a was associated with the activation of its downstream effectors phospho-p38 and phospho-JNK, the subsequent regulation of sFlt-1 levels occurred through either one of these effectors, but not both. These observations indicate that Gadd45a signaling may work as a hub connecting placental stresses and the pathogenesis of preeclampsia. It also provides evidence to justify testing the role of Gadd45 in the etiology of preeclampsia using in vivo mouse (i.e., Gadd45a null mice) models.

Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory.

Growth arrest and DNA damage-inducible ß (Gadd45b) has been shown to be involved in DNA demethylation and may be important for cognitive processes. Gadd45b is abnormally expressed in subjects with autism and psychosis, two disorders associated with cognitive deficits. Furthermore, several high-throughput screens have identified Gadd45b as a candidate plasticity-related gene. However, a direct demonstration of a link between Gadd45b and memory has not been established. The current studies first determined whether expression of the Gadd45 family of genes was affected by contextual fear conditioning. Gadd45b, and to a lesser extent Gadd45g, were up-regulated in the hippocampus following contextual fear conditioning, whereas Gadd45a was not. Next, Gadd45b knockout mice were tested for contextual and cued fear conditioning. Gadd45b knockout mice exhibited a significant deficit in long-term contextual fear conditioning; however, they displayed normal levels of short-term contextual fear conditioning. No differences between Gadd45b knockout and wild-type mice were observed in cued fear conditioning. Because cued fear conditioning is hippocampus independent, while contextual fear conditioning is hippocampus dependent, the current studies suggest that Gadd45b may be important for long-term hippocampus-dependent memory storage. Therefore, Gadd45b may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders.

Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling.

Gadd45 proteins function as stress sensors in response to various physiological and environmental stressors, interacting with other cellular proteins implicated in cellular stress responses, including p38 and JNK. This study shows that mice lacking either Gadd45a or Gadd45b are defective in the recruitment of granulocytes and macrophages to the intra-peritoneal cavity following intra-peritoneal administration of the bacterial cell wall pathogen-associated molecular pattern lipopolysaccharide (LPS). Bone marrow derived granulocytes and macrophages lacking either Gadd45a or Gadd45b are shown to be impaired in their chemotactic response to LPS, as well as other inflammatory stimuli such as N-formyl-methionine-leucine-phenylalanine and IL-8. Evidence was obtained also implicating Gadd45a and Gadd45b in other myeloid innate immune functions, including reactive oxygen species production, phagocytosis, and adhesion. Gadd45a and Gadd45b activation of p38 kinase was implicated in the response of granulocytes to LPS mediated chemotaxis, whereas Gadd45a and Gadd45b curtailment of JNK activation was linked to chemotaxis of macrophages in response to LPS. Collectively, these data highlight a novel role for both Gadd45a and Gadd45b in myeloid innate immune functions by differential modulation of p38 and JNK signaling in granulocytes compared to macrophages.

Gadd45 stress sensors in malignancy and leukemia.

Gadd45 proteins, including Gadd45a, Gadd45b, and Gadd45g, have been implicated in stress signaling in response to physiological and environmental stress, including oncogenic stress, which can result in cell cycle arrest, DNA repair, cell survival, senescence, and apoptosis. The function of Gadd45 as a stress sensor is mediated via a complex interplay of physical interactions with other cellular proteins implicated in cell cycle regulation and the response of cells to stress, notably PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Altered expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Using genetically engineered mouse models and bone-marrow transplantation, evidence has been obtained indicating that Gadd45 proteins can function to either promote or suppress tumor development and leukemia; this is dependent on the molecular nature of the activated oncogene and the cell type, via engagement of different signaling pathways.