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Dual excitation wavelength system for combined fingerprint and high wavenumber Raman spectroscopy.
Masson LE, O'Brien CM, Pence IJ, Herington JL, Reese J, van Leeuwen TG, Mahadevan-Jansen A
(2018) Analyst 143: 6049-6060
MeSH Terms: Animals, Cervix Uteri, Collagen, Female, Gelatin, Mice, Phantoms, Imaging, Pregnancy, Spectrum Analysis, Raman, Water
Show Abstract · Added November 26, 2018
A fiber optic probe-based Raman spectroscopy system using a single laser module with two excitation wavelengths, at 680 and 785 nm, has been developed for measuring the fingerprint and high wavenumber regions using a single detector. This system is simpler and less expensive than previously reported configurations of combined fingerprint and high wavenumber Raman systems, and its probe-based implementation facilitates numerous in vivo applications. The high wavenumber region of the Raman spectrum ranges from 2800-3800 cm-1 and contains valuable information corresponding to the molecular vibrations of proteins, lipids, and water, which is complimentary to the biochemical signatures found in the fingerprint region (800-1800 cm-1), which probes DNA, lipids, and proteins. The efficacy of the system is demonstrated by tracking changes in water content in tissue-mimicking phantoms, where Voigtian decomposition of the high wavenumber water peak revealed a correlation between the water content and type of water-tissue interactions in the samples. This dual wavelength system was then used for in vivo assessment of cervical remodeling during mouse pregnancy, a physiologic process with known changes in tissue hydration. The system shows that Raman spectroscopy is sensitive to changes in collagen content in the fingerprint region and hydration state in the high wavenumber region, which was verified using an ex vivo comparison of wet and dry weight. Simultaneous fingerprint and high wavenumber Raman spectroscopy will allow precise in vivo quantification of tissue water content in the high wavenumber region, paired with the high biochemical specificity of the fingerprint region.
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10 MeSH Terms
Development of a visually guided Raman spectroscopy probe for cervical assessment during pregnancy.
O'Brien CM, Cochran KJ, Masson LE, Goldberg M, Marple E, Bennett KA, Reese J, Slaughter JC, Newton JM, Mahadevan-Jansen A
(2019) J Biophotonics 12: e201800138
MeSH Terms: Cervix Uteri, Equipment Design, Female, Humans, Pregnancy, Spectrum Analysis, Raman
Show Abstract · Added November 26, 2018
Preterm birth (PTB) is the leading cause of neonatal death, however, accurate prediction methods do not exist. Detection of early changes in the cervix, an organ that biochemically remodels to deliver the fetus, has potential to predict PTB risk. Researchers have employed light-based methods to monitor biochemical changes in the cervix during pregnancy, however, these approaches required patients to undergo a speculum examination which many patients find uncomfortable and is not standard practice during prenatal care. Herein, a visually guided optical probe is presented that measures the cervix via introduction by bimanual examination, a procedure that is commonly performed during prenatal visits and labor for tactile monitoring of the cervix. The device incorporates a Raman spectroscopy probe for biochemical monitoring and a camera for visualizing measurement location to ensure it is void of cervical mucus and blood. This probe was tested in 15 patients receiving obstetric and gynecological care, and results acquired with and without a speculum revealed similar spectra, demonstrating that the visually guided probe conserved data quality. Additionally, the majority of patients reported reduced discomfort from the device. In summary, the visual guidance probe successfully measured the cervix while integrating with standard prenatal care, reducing a barrier in clinical translation.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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6 MeSH Terms
Characteristic findings of cervical Papanicolaou tests from transgender patients on androgen therapy: Challenges in detecting dysplasia.
Adkins BD, Barlow AB, Jack A, Schultenover SJ, Desouki MM, Coogan AC, Weiss VL
(2018) Cytopathology 29: 281-287
MeSH Terms: Androgens, Atypical Squamous Cells of the Cervix, Cervical Intraepithelial Neoplasia, Cervix Uteri, Ectodermal Dysplasia, Female, Humans, Papanicolaou Test, Papillomavirus Infections, Retrospective Studies, Squamous Intraepithelial Lesions of the Cervix, Transgender Persons, Uterine Cervical Neoplasms, Vaginal Smears
Show Abstract · Added April 15, 2019
INTRODUCTION - The characteristic features of Papanicolaou (Pap) tests collected from female-to-male (FTM) transgender patients on androgen therapy have not been well defined in the literature. FTM transgender patients require cervical cancer screening with the same recommended frequency as cis-gender females. Dysplasia remains challenging to differentiate from atrophy. Without pertinent history, the atrophic findings in younger transgender patients can be misinterpreted as high-grade dysplasia.
METHODS - A review of all cervical Pap tests of transgender patients receiving androgen therapy (2010-2017) was performed. Bethesda diagnosis, cytomorphological features, HPV testing and cervical biopsy results were reviewed.
RESULTS - Eleven transgender patients receiving androgen therapy were identified with 23 cervical Pap tests, 11 HPV tests and five cervical biopsies performed. A review of the Pap tests demonstrated: 57% negative for intraepithelial lesion; 13% unsatisfactory; 13% atypical squamous cells of undetermined significance; 13% atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion; and 4% high-grade squamous intraepithelial lesion. The rates of abnormal tests were higher than our age-matched cis-gender atrophic cohort rates of unsatisfactory (0.5%), atypical squamous cells of undetermined significance (7%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (0%) and high-grade squamous intraepithelial lesion (0.5%). The cytological findings from liquid-based preparations included dispersed and clustered parabasal-type cells, scattered degenerated cells, smooth evenly dispersed chromatin, and occasional mild nuclear enlargement and irregularity. Dysplastic cells had larger nuclei, hyperchromatic clumped chromatin, and more irregular nuclear contours.
CONCLUSIONS - The evaluation of dysplasia can be challenging on Pap tests from transgender patients on androgen therapy. The cohort evaluated had higher rates of unsatisfactory and abnormal Pap tests. Pathologists should be familiar with the distinctive cytomorphological changes in the Pap tests from patients on androgen therapy to evaluate them appropriately.
© 2018 John Wiley & Sons Ltd.
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14 MeSH Terms
In vivo Raman spectroscopy for biochemical monitoring of the human cervix throughout pregnancy.
O'Brien CM, Vargis E, Rudin A, Slaughter JC, Thomas G, Newton JM, Reese J, Bennett KA, Mahadevan-Jansen A
(2018) Am J Obstet Gynecol 218: 528.e1-528.e18
MeSH Terms: Adult, Cervix Uteri, Female, Healthy Volunteers, Humans, Parturition, Postpartum Period, Pregnancy, Pregnancy Trimester, First, Pregnancy Trimester, Second, Pregnancy Trimester, Third, Spectrum Analysis, Raman
Show Abstract · Added March 31, 2018
BACKGROUND - The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications.
OBJECTIVE - The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair.
STUDY DESIGN - In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6-week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses.
RESULTS - Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm) and cholesterol (1447 cm) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals.
CONCLUSION - Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth.
Copyright © 2018. Published by Elsevier Inc.
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12 MeSH Terms
Prostaglandin-Endoperoxide Synthase 1 Mediates the Timing of Parturition in Mice Despite Unhindered Uterine Contractility.
Herington JL, O'Brien C, Robuck MF, Lei W, Brown N, Slaughter JC, Paria BC, Mahadevan-Jansen A, Reese J
(2018) Endocrinology 159: 490-505
MeSH Terms: Abortifacient Agents, Steroidal, Animals, Cells, Cultured, Cervical Ripening, Cervix Uteri, Cyclooxygenase 1, Female, In Vitro Techniques, Luteolysis, Membrane Proteins, Mice, Inbred Strains, Mice, Knockout, Mifepristone, Myometrium, Ovariectomy, Oxytocics, Oxytocin, Pregnancy, Pregnancy, Prolonged, Progesterone, Uterine Contraction
Show Abstract · Added March 31, 2018
Cyclooxygenase (COX)-derived prostaglandins stimulate uterine contractions and prepare the cervix for parturition. Prior reports suggest Cox-1 knockout (KO) mice exhibit delayed parturition due to impaired luteolysis, yet the mechanism for late-onset delivery remains unclear. Here, we examined key factors for normal onset of parturition to determine whether any could account for the delayed parturition phenotype. Pregnant Cox-1KO mice did not display altered timing of embryo implantation or postimplantation growth. Although messenger RNAs of contraction-associated proteins (CAPs) were differentially expressed between Cox-1KO and wild-type (WT) myometrium, there were no differences in CAP agonist-induced intracellular calcium release, spontaneous or oxytocin (OT)-induced ex vivo uterine contractility, or in vivo uterine contractile pressure. Delayed parturition in Cox-1KO mice persisted despite exogenous OT treatment. Progesterone (P4) withdrawal, by ovariectomy or administration of the P4-antagonist RU486, diminished the delayed parturition phenotype of Cox-1KO mice. Because antepartum P4 levels do not decline in Cox-1KO females, P4-treated WT mice were examined for the effect of this hormone on in vivo uterine contractility and ex vivo cervical dilation. P4-treated WT mice had delayed parturition but normal uterine contractility. Cervical distensibility was decreased in Cox-1KO mice on the day of expected delivery and reduced in WT mice with long-term P4 treatment. Collectively, these findings show that delayed parturition in Cox-1KO mice is the result of impaired luteolysis and cervical dilation, despite the presence of strong uterine contractions.
Copyright © 2018 Endocrine Society.
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MeSH Terms
In vivo Raman spectral analysis of impaired cervical remodeling in a mouse model of delayed parturition.
O'Brien CM, Herington JL, Brown N, Pence IJ, Paria BC, Slaughter JC, Reese J, Mahadevan-Jansen A
(2017) Sci Rep 7: 6835
MeSH Terms: Animals, Cervix Uteri, Cyclooxygenase 1, Extracellular Matrix Proteins, Female, Lipid Metabolism, Membrane Proteins, Mice, Nucleic Acids, Spectrum Analysis, Raman, Term Birth, Uterine Contraction
Show Abstract · Added October 11, 2017
Monitoring cervical structure and composition during pregnancy has high potential for prediction of preterm birth (PTB), a problem affecting 15 million newborns annually. We use in vivo Raman spectroscopy, a label-free, light-based method that provides a molecular fingerprint to non-invasively investigate normal and impaired cervical remodeling. Prostaglandins stimulate uterine contractions and are clinically used for cervical ripening during pregnancy. Deletion of cyclooxygenase-1 (Cox-1), an enzyme involved in production of these prostaglandins, results in delayed parturition in mice. Contrary to expectation, Cox-1 null mice displayed normal uterine contractility; therefore, this study sought to determine whether cervical changes could explain the parturition differences in Cox-1 null mice and gestation-matched wild type (WT) controls. Raman spectral changes related to extracellular matrix proteins, lipids, and nucleic acids were tracked over pregnancy and found to be significantly delayed in Cox-1 null mice at term. A cervical basis for the parturition delay was confirmed by other ex vivo tests including decreased tissue distensibility, hydration, and elevated progesterone levels in the Cox-1 null mice at term. In conclusion, in vivo Raman spectroscopy non-invasively detected abnormal remodeling in the Cox-1 null mouse, and clearly demonstrated that the cervix plays a key role in their delayed parturition.
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Neither vaginal nor buccal administration of 800 μg misoprostol alters mucosal and systemic immune activation or the cervicovaginal microbiome: a pilot study.
Kalams SA, Rogers LM, Smith RM, Barnett L, Crumbo K, Sumner S, Prashad N, Rybczyk K, Milne G, Dowd SE, Chong E, Winikoff B, Aronoff DM
(2016) Eur J Contracept Reprod Health Care 21: 436-442
MeSH Terms: Abortifacient Agents, Nonsteroidal, Administration, Buccal, Administration, Intravaginal, Cervix Uteri, Cross-Over Studies, Elafin, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immune System, Lymphocytes, Microbiota, Misoprostol, Pilot Projects, United States, Vagina
Show Abstract · Added June 2, 2017
OBJECTIVES - The aim of the study was to assess the extent to which misoprostol alters mucosal or systemic immune responses following either buccal or vaginal administration.
METHODS - This was a prospective, crossover pilot study of 15 healthy, reproductive-age women. Women first received 800 μg misoprostol either via buccal or vaginal administration and were crossed over 1 month later to receive the drug via the other route. Cervicovaginal lavage samples, cervical Cytobrush samples, cervicovaginal swabs, urine and blood were obtained immediately prior to drug administration and the following day. Parameters assessed included urine and cervicovaginal misoprostol levels, whole blood cytokine responses (by ELISA) to immune stimulation with lipopolysaccharide, peripheral blood and cervical lymphocyte phenotyping by flow cytometry, cervicovaginal antimicrobial peptide measurement by ELISA and vaginal microbial ecology assessment by 16S rRNA sequencing.
RESULTS - Neither buccal nor vaginal misoprostol significantly altered local or systemic immune and microbiological parameters.
CONCLUSION - In this pilot study, we did not observe significant alteration of mucosal or systemic immunology or vaginal microbial ecology 1 day after drug administration following either the buccal or vaginal route.
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16 MeSH Terms
Reduced prevalence of vulvar HPV16/18 infection among women who received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Rica Vaccine Trial.
Lang Kuhs KA, Gonzalez P, Rodriguez AC, van Doorn LJ, Schiffman M, Struijk L, Chen S, Quint W, Lowy DR, Porras C, DelVecchio C, Jimenez S, Safaeian M, Schiller JT, Wacholder S, Herrero R, Hildesheim A, Kreimer AR, Costa Rica Vaccine Trial Group
(2014) J Infect Dis 210: 1890-9
MeSH Terms: Adolescent, Adult, Cervix Uteri, Costa Rica, DNA, Viral, Female, Human papillomavirus 16, Human papillomavirus 18, Humans, Papillomavirus Infections, Papillomavirus Vaccines, Prevalence, Risk Factors, Vulva, Vulvar Diseases, Young Adult
Show Abstract · Added August 15, 2017
BACKGROUND - Vaccine efficacy (VE) against vulvar human papillomavirus (HPV) infection has not been reported and data regarding its epidemiology are sparse.
METHODS - Women (n = 5404) age 22-29 present at the 4-year study visit of the Costa Rica Vaccine Trial provided vulvar and cervical samples. A subset (n = 1044) was tested for HPV DNA (SPF10/LiPA25 version 1). VE against 1-time detection of vulvar HPV16/18 among HPV vaccinated versus unvaccinated women was calculated and compared to the cervix. Prevalence of and risk factors for HPV were evaluated in the control arm (n = 536).
RESULTS - Vulvar HPV16/18 VE (54.1%; 95% confidence interval [CI], 4.9%-79.1%) was comparable to cervix (45.8%; 95% CI, 6.4%-69.4%). Vulvar and cervical HPV16 prevalence within the control arm was 3.0% and 4.7%, respectively. Independent risk factors for vulvar HPV were similar to cervix and included: age (adjusted odds ratio [aOR] 0.5 [95% CI, .3-.9] ≥28 vs 22-23]); marital status (aOR 2.3 [95% CI, 1.5-3.5] single vs married/living-as-married); and number of sexual partners (aOR 3.6 [95% CI, 1.9-7.0] ≥6 vs 1).
CONCLUSIONS - In this intention-to-treat analysis, VE against vulvar and cervical HPV16/18 were comparable 4 years following vaccination. Risk factors for HPV were similar by anatomic site.
CLINICAL TRIALS REGISTRATION - NCT00128661.
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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16 MeSH Terms
Raman spectroscopy provides a noninvasive approach for determining biochemical composition of the pregnant cervix in vivo.
O'Brien CM, Vargis E, Paria BC, Bennett KA, Mahadevan-Jansen A, Reese J
(2014) Acta Paediatr 103: 715-21
MeSH Terms: Animals, Cervical Ripening, Cervix Uteri, Female, Humans, Pregnancy, Spectrum Analysis, Raman, Uterine Cervical Diseases
Show Abstract · Added March 31, 2014
UNLABELLED - The molecular changes that occur with cervical remodelling during pregnancy are not completely understood. This study reviews Raman spectroscopy, an optical technique for detecting changes in the pregnant cervix, and reports preliminary studies on cervical remodelling in mice that suggest that the technique provides advantages over other methods.
CONCLUSION - Raman spectroscopy is sensitive to biochemical changes in the pregnant cervix and has high potential as a tool for detecting premature cervical remodelling in pregnant women.
©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
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8 MeSH Terms
Comparison of human papillomavirus detections in urine, vulvar, and cervical samples from women attending a colposcopy clinic.
Sahasrabuddhe VV, Gravitt PE, Dunn ST, Brown D, Allen RA, Eby YJ, Smith K, Zuna RE, Zhang RR, Gold MA, Schiffman M, Walker JL, Castle PE, Wentzensen N
(2014) J Clin Microbiol 52: 187-92
MeSH Terms: Adult, Cervix Uteri, Early Detection of Cancer, Female, Humans, Papillomaviridae, Papillomavirus Infections, Sensitivity and Specificity, Specimen Handling, Urine, Vulva, Young Adult
Show Abstract · Added March 5, 2014
While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.
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12 MeSH Terms