Prenatal Genetic Screening and Diagnostic Testing: Assessing Patients' Knowledge, Clinical Experiences, and Utilized Resources in Comparison to Provider's Perceptions.

Objective This survey study aimed to assess patient knowledge, clinical resources, and utilized resources about genetic screening and diagnostic testing. Study Design A one-time anonymous paper survey was distributed to 500 patients at a major urban obstetrics and gynecology department, and an online survey was sent to 229 providers. Descriptive statistics and chi-squared analyses were performed. Results In all, 466 of 500 patient surveys were completed, and 441 analyzed (88.2% response rate). Among providers, 66 of 229 (29.0% response rate) responded. Patients were on average 32 years old, 27 weeks pregnant, and most often reported a graduate degree level of education (47.4%). Over 75% of patients reported accurate knowledge of basic genetic statements. Patients reported that discussing screening and diagnostic testing with their provider was significantly associated with properly defining screening and diagnostic testing ( p < 0.001). Less than 10% of patients reported providers distributing web/video links, books, or any other resource; however, patients most often independently accessed web links (40.1%). Conclusion Our findings suggest a positive impact from patient and provider discussions in office on patient knowledge and understanding. Discrepancies between educational resources distributed in the clinic and individually accessed resources highlight possible areas of change. Future work should evaluate and implement differing resources to increase patient knowledge.

Differentially Regulated miRNAs and Their Related Molecular Pathways in Lichen Sclerosus.

Lichen sclerosus (LS) is a chronic inflammatory skin disorder with unknown pathogenesis. The aberrant expression of microRNAs (miRNAs) is considered to exert a crucial role in LS. We used the next-generation sequencing technology (RNASeq) for miRNA profiling and Ingenuity Pathway Analysis (IPA) for molecular network analysis. We performed qRT-PCR, miRNA transfection and Matrigel assays for functional studies. We identified a total of 170 differentially expressed miRNAs between female LS and matched adjacent normal tissue using RNASeq, with 119 upregulated and 51 downregulated. Bioinformatics analysis revealed molecular networks that may shed light on the pathogenesis of LS. We verified the expression of a set of miRNAs that are related to autoimmunity, such as upregulated miR-326, miR-142-5p, miR-155 and downregulated miR-664a-3p and miR-181a-3p in LS tissue compared to the matched adjacent normal tissue. The differentially expressed miRNAs were also verified in blood samples from LS patients compared to healthy female volunteers. Functional studies demonstrated that a forced expression of miR-142-5p in human dermal fibroblast PCS-201-010 cells resulted in decreased cell proliferation and migration. These findings suggest that differentially expressed miRNAs may play an important role in LS pathogenesis; therefore, they could serve as biomarkers for LS management.

Dynamically decreased miR-671-5p expression is associated with oncogenic transformation and radiochemoresistance in breast cancer.

BACKGROUND: Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment. METHODS: The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed. RESULTS: Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability. CONCLUSIONS: miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management.

Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets.

Lichen sclerosus (LS) is an inflammatory dermatosis with a predilection for anogenital skin. Developing lesions lead to vulvar pain and sexual dysfunction, with a significant loss of structural anatomical architecture, sclerosis, and increased risk of malignancy. Onset may occur at any age in both sexes, but typically affects more females than males, presenting in a bimodal fashion among pre-pubertal children and middle-aged adults. A definitive cure remains elusive as the exact pathogenesis of LS remains unknown. A general review of LS, histologic challenges, along with amounting support for LS as an autoimmune disease with preference for a Th1 immune response against a genetic background is summarized. In addition to the classically referenced ECM1 (extracellular matrix protein 1), a following discussion of other immune and genetic targets more recently implicated as causative or accelerant agents of disease, particularly miR-155, downstream targets of ECM1, galectin-7, p53, and epigenetic modifications to CDKN2A, are addressed from the viewpoint of their involvement in three different, but interconnected aspects of LS pathology. Collectively, these emerging targets serve not only as inherently potential therapeutic targets for treatment, but may also provide further insight into this debilitating and cryptic disease.

Provider and Patient Knowledge and Views of Office Practices on Weight Gain and Exercise during Pregnancy.

OBJECTIVE: This study sought to assess provider and patient knowledge and beliefs on gestational weight gain (GWG) and exercise during pregnancy, outline current clinical practices and the perceived value of educational tools. STUDY DESIGN: Providers and patients at the George Washington Medical Faculty Associates Obstetricians and Gynecologists clinic were recruited for a voluntary survey. Descriptive statistics of responses were compared and chi-square analysis tested for significant associations. RESULTS: A total of 461 patient and 36 provider questionnaires were analyzed. Providers recommended GWG consistent with the Institute of Medicine guidelines for a "normal" body mass index (82.9%); however, a majority (52.8%) recommended GWG below guidelines for obese women. All providers reported counseling patients on GWG, but only 53.4% of patients reported discussing personal recommendations. About half of providers reported distributing educational materials for GWG (60.0%); however, only 30.6% of patients reported receiving them. African American patients self-reported receiving the highest rates of counseling and educational materials, though a lower rate of recommendations to exercise. Patients perceived educational tools to be more useful than did providers. CONCLUSION: Our findings suggest a gap between provider-patient perceptions regarding counseling and provision of informational materials. Future research should study whether implementing various educational tools might increase the efficacy of current practices.

In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.

Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 µg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 µg/dL prior to treatment to 45 µg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 µg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient's ATP7A mutation (Q724H), which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

Assessment of genetics knowledge and skills in medical students: insight for a clinical neurogenetics curriculum.

The pace of discovery in biochemistry and genetics and its effect on clinical medicine places new curricular challenges in medical school education. We sought to evaluate students' understanding of neurogenetics and its clinical applications to design a pilot curriculum into the clinical neurology clerkship. We utilized a needs assessment and a written examination to evaluate the genetics knowledge of 81 third- and fourth-year medical students. The needs assessment surveyed students' self-perceptions of their own understanding of basic and clinically related genetic principles and clinical skills, as well as the most effective educational methods. Medical students reported more competence with basic science learned during the preclinical years than clinical concepts, and they demonstrated relatively low knowledge levels in clinical neurogenetics concepts on the examination, with an average of 29% correct on questions pertaining to genetic counseling compared with 82% correct with regard to inheritance patterns. Common, cross-specialty clinical skills were attained (e.g. internet search, family histories), while at least half of students reported minimal understanding or awareness of key genetics websites (e.g. OMIM) and indications for support group recommendations and genetics referrals. Teaching these more specific genetics skills and concepts needs to be emphasized in the clinical curriculum.

Maternal asthma, race and low birth weight deliveries.

BACKGROUND: Asthma during pregnancy may compromise the well-being of the fetus and potentially impact an infant's birth weight via different mechanisms. AIMS: 1) To assess the influence of asthma during pregnancy on the incidence of LBW outcomes in white non-Hispanic (WNH) and black non-Hispanic (BNH) women. 2) To identify other risk factors that affect low birth weight (LBW) (birth weight<2500g) outcomes among asthmatic women. DESIGN/SUBJECTS: We conducted a retrospective analysis of compiled perinatal data on 17,073 patients including 9348 WNH and 7725 BNH women delivering at the George Washington University Hospital between 1990 and 2003. Univariate and logistic regression analyses were used to examine associations. RESULTS: A total of 423 (2.5%) women had an asthma diagnosis, with a higher incidence in BNH women when compared to WNH women (3.4% vs. 1.7%, P<0.001). In the WNH population, asthmatic women had higher incidences of gravidity, thyroid disease, and illicit drug use, whereas in the BNH population, asthmatic women had higher incidences of increased body mass index (BMI), and use of alcohol, tobacco and illicit drugs. After controlling for confounders in multiple logistic regression analyses, there was an association between asthma and LBW outcomes in BNH women (OR: 1.7, CI: 1.1-2.6, p=0.01), but not in WNH women (OR=0.99, CI=0.5-2.2, p=0.97). CONCLUSIONS: Asthma during pregnancy is a risk factor for LBW outcomes in BNH but not WNH women. The increased alcohol and illicit drug use in BNH women with asthma is an unexpected finding that deserves further study.

Development of a culturally specific assessment tool for pelvic organ prolapse in a Mayan population.

INTRODUCTION: Pelvic organ prolapse is a common condition that can significantly affect a woman's life, including her sexual, urinary, and social functioning. In Guatemala, anecdotal evidence suggests that the daily activities of Mayan women contribute to and worsen the degree of pelvic organ prolapse. The objective of this research was to develop a culturally specific assessment tool to better evaluate how pelvic organ prolapse affects the daily activities of Mayan women in rural Guatemala. METHODS: A survey was created entitled a Culturally Specific Assessment Tool for Pelvic Organ Prolapse (CSAT-POP). The survey was administered to a 19 Mayan women with various degrees of pelvic organ prolapse in Montellano, Guatemala. Participants were asked using a Likert scale about how their pelvic organ prolapse affected their ability to perform 7 culturally specific activities of daily living. The survey was administered through an on-site interpreter who translated the CSAT-POP into Spanish and Quiché. RESULTS: Nineteen women were assessed using the CSAT-POP. Their mean age was 49.2 ± 28 years, and the median parity was 6.8 children (range 1-11). Three culturally specific activities: performing vigorous activities, gathering wood, and carrying water, were identified as the activities most impacted by pelvic organ prolapse. Of the participants, 15-20% were unable to perform these activities on a daily basis. However, preparing food, washing clothes, and caring for children were the activities reported by women with pelvic organ prolapse which required the least amount of assistance. CONCLUSIONS: The CSAT-POP identified several activities specific to the rural Mayan community in Guatemala which are difficult to perform with pelvic organ prolapse. By using culturally specific activities of daily living, the CSAT-POP allowed for more relevant assessment, identification, and treatment of women with pelvic organ prolapse in Guatemala.

Maternal healthcare needs assessment survey at Rabia Balkhi Hospital in Kabul, Afghanistan.

OBJECTIVE: Since the Department of Health and Human Services chose Rabia Balkhi Hospital (RBH) in Kabul, Afghanistan, as a site for intervention in 2002, the status of women's health there has been of interest. This study created a tool to assess accessibility and quality of care of women admitted from May to July, 2005. METHODS: A 39-item questionnaire was created in English and translated into Dari. Hospital staff administered the survey to 292 women admitted to RBH for obstetric and gynecological complaints. RESULTS: Approximately 40% of the women traveled between 1 and 5 hours to reach RBH. Only 54% (158/292) of women reported having their blood pressure monitored during their pregnancy. About one-third of women reported that they had never received an immunization. CONCLUSIONS: This survey tool ascertained that women who received care at RBH traveled great lengths to reach the facility. Preventative measures such as blood pressure checks and immunizations are areas that need improvement.

Improving teaching skills in obstetrics and gynecology residents: evaluation of a residents-as-teachers program.

OBJECTIVE: The purpose of this study was to determine if a residents-as-teachers program improves residents' teaching skills. STUDY DESIGN: Twenty-four residents (13 intervention, 11 controls) participated in a controlled trial of a residents-as-teachers program. The intervention group attended a 10.5-hour workshop-based program. Afterwards, both groups were tested with a 6-station Objective Structured Teaching Examination (OSTE), conducted by standardized students. Both groups also completed teaching skills self-assessment questionnaires. In addition, the intervention group completed evaluations of each workshop. RESULTS: On the OSTE, the intervention group outscored the control group overall (mean: 74 vs 63, P =.001, 95% CI: 6-7 points) and on 4 out of 6 stations. Intervention residents increased their teaching self-assessment mean ratings from 3.5 to 4.0; residents gave the 6 workshops a mean rating of 4.49 (1-5 scale, 5 = best). CONCLUSION: The residents-as-teachers program improved the teaching skills of residents. Their self-assessment of their teaching skills also improved. They rated the workshops highly.

Pregnancy in a woman with a continent appendicovesicostomy: a case report.

BACKGROUND: Few cases of pregnancy following the Mitrofanoff procedure (continent appendicovesicostomy) have been reported, but in those cases there was an increased rate of cesarean delivery with no long-term consequences to renal function or to the urinary diversion. CASE: A 15-year-old primagravida with a prior nephrectomy for a dysplastic kidney and prior continent appendicovesicostomy for urinary retention due to spina bifida occulta and neurogenic bladder had a pregnancy complicated by preterm premature rupture of membranes, preterm labor, breech presentation and cesarean delivery with the assistance of a urologist. The patient had a minimal decline in renal function, and she and the infant did well. CONCLUSION: Cesarean delivery should be reserved for obstetric indications. Surgical assistance by a urologist at the time of cesarean delivery may be helpful.

Arrhythmogenic right ventricular dysplasia in pregnancy: a case report.

BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by progressive fibrous or fibrofatty tissue replacement of the right ventricular myocardium. Interspersed adipocytes and fibrous tissue may provide foci for arrhythmias. The clinical spectrum of ARVD may include asymptomatic premature ventricular complexes to ventricular tachycardia and sudden death. There is currently little information about ARVD in pregnancy. CASE: A 29-year-old primigravida, diagnosed with ARVD 1 year prior to pregnancy, underwent a full-term, uncomplicated pregnancy and delivery while maintained on acebutolol and an implanted cardioverter defibrillator. Her infant was born without an apparent cardiac anomaly or heart rate abnormality. CONCLUSION: Successful management of pregnancy complicated by ARVD can be accomplished with an implanted cardioverter defibrillator and an antiarrhythmic agent. Such patients should be managed with close monitoring during pregnancy for signs and symptoms of arrhythmia and preventive obstetric care appropriate to their clinical profile to optimize normal deliveries.

Use of a doula for labor coaching in a patient with indolent systemic mastocytosis in pregnancy.

BACKGROUND: Few cases of pregnancy in women with systemic mastocytosis have been reported. The effects of this disease on pregnancy have not been well documented, nor have the benefits of doula services for labor been reported for mastocytosis. CASE: A 35-year-old woman with indolent systemic mastocytosis sought preconception counseling regarding the effects of her disease on pregnancy and the effects of drugs and anesthesia on her disease. She then had an uncomplicated pregnancy and delivery, with multidisciplinary coordination and assistance by doulas to reduce the need for medication in labor. CONCLUSION: Mastocytosis patients can achieve normal pregnancy outcomes. Predelivery planning can help prepare staff and patients for complications. Doulas can assist with labor preparation and delivery using nonmedical approaches to relief of pain and anxiety.

Implementation and evaluation of a genetics curriculum to improve obstetrician-gynecologist residents' knowledge and skills in genetic diagnosis and counseling.

OBJECTIVE: This study was undertaken to develop, implement, and evaluate a genetics curriculum for obstetrician-gynecologist residents. STUDY DESIGN: We prospectively evaluated the effect of a genetics curriculum on obstetrician-gynecologist residents' knowledge and skills. Residents completed a needs assessment and pretest. Educational intervention included 2 3-hour didactic sessions with 1 hour of lecture followed by case discussion and 1 3-hour session of experiential learning using standardized patients who evaluated residents' knowledge and skills in taking family history, drawing genetic pedigrees, and counseling patients. Posttest scores were compared with pretest scores. RESULTS: Needs assessment was completed by all 40 obstetrics and gynecology residents and identified limited and variable genetics education in medical school. Twenty-eight of 40 residents attended the entire educational intervention and completed the pretest and posttest, and 25 of 28 showed improved test scores. Residents stated that they were more confident in their ability to take a family history, record a 3-generation pedigree, and counsel patients about genetic conditions after completion of the genetics curriculum. CONCLUSION: This multifaceted genetics curriculum improved residents' knowledge of genetics as well as their confidence in applying genetic concepts as assessed by the pretest and posttest and by their comments in the debrief session.

Autosomal dominant polycystic kidney disease in pregnancy complicated by twin gestation and severe preeclampsia: a case report.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), an autosomal dominant genetic disorder with a reported prevalence of 1 in 1,000, may be associated with hypertensive disease in pregnancy. The evaluation of a pregnant woman with an adult-onset genetic disorder is complex and involves counseling about inheritance, prenatal diagnosis and management of the current pregnancy. CASE: A 33-year-old woman presented for obstetric care with a history of hypertension and ADPKD for 6 years. The patient had secondary infertility, which was treated by in vitro fertilization. The case was complicated by twin gestation and superimposed severe preeclampsia, leading to preterm cesarean delivery at 26 weeks' estimated gestational age. CONCLUSION: Because of the heritable nature of ADPKD and the long-term risk of end-stage renal disease requiring dialysis and/or renal transplantation, the evaluation and counseling of women with ADPKD who are pregnant or considering pregnancy should include a discussion of the modes of inheritance, natural history, available prenatal diagnostic options, and pregnancy risks and management options. Specific counseling issues in this case include the genetic concepts of variable expression and penetrance and the medical management of chronic hypertension and preeclampsia.

Erythropoietin use in a pregnant Jehovah's witness with anemia and beta-thalassemia: a case report.

BACKGROUND: Anemia in pregnancy is seen often because of iron deficiency and the "physiologic dilution" that occurs in the third trimester. Other causes include genetic conditions, such as sickle cell anemia and thalassemias. In cases not responding to iron therapy, patients occasionally require a blood transfusion to restore adequate circulating red blood cell mass. In patients belonging to the Jehovah's Witness sect, transfusion of blood products is not allowed, and treatment of anemia in pregnancy may require use of erythropoietin. CASE: A 26-year-old, African American woman belonging to the Jehovah's Witness sect presented with anemia associated with beta-thalassemia. Iron therapy and prenatal vitamins did not correct the anemia, and the patient became symptomatic, with fatigue and shortness of breath when walking. Therapy with synthetic erythropoietin corrected the anemia, and the patient had an otherwise-uncomplicated pregnancy and delivery. CONCLUSION: Synthetic erythropoietin has been used successfully in patients with renal failure and anemia. In pregnancy associated with renal failure and anemia, synthetic erythropoietin has been shown to be safe except for rare cases of hypertension. We treated anemia caused by beta-thalassemia in pregnancy with synthetic erythropoietin to avoid a transfusion in a Jehovah's Witness.