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Proper action of the female sex steroids, 17ß-estradiol (E2) and progesterone (P4) on endometrium is essential for fertility. Beyond its role in regulating the cell cycle, cyclin A2 (CCNA2) also mediates E2 and P4 signaling in vitro, but a potential role in modulating steroid action for proper endometrial tissue development and function is unknown. To fill this gap in our knowledge, we examined human endometrial tissue from fertile and infertile women for CCNA2 expression and correlated this with pregnancy outcome. Functional assessment of CCNA2 was validated in vivo using a conditional Ccna2 uterine deficient mouse model while in vitro function was assessed using human cell culture models. We found that CCNA2 expression was significantly reduced in endometrial tissue, specifically the stromal cells, from women undergoing in vitro fertilization who failed to achieve pregnancy. Conditional deletion of Ccna2 from mouse uterine tissue resulted in an inability to achieve pregnancy which appears to be due to alterations in the process of decidualization, which was confirmed using in vitro models. From these studies, we conclude that CCNA2 expression during the proliferative/regenerative stage of the menstrual cycle acts as a safeguard allowing for proper steroid responsiveness, decidualization and pregnancy. When CCNA2 expression levels are insufficient there is impaired endometrial responsiveness, aberrant decidualization and loss of pregnancy.
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Methyltransferase-like 3 (METTL3), the catalytic enzyme of methyltransferase complex for m6A methylation of RNA, is essential for mammalian development. However, the importance of METTL3 in human placentation remains largely unexplored. Here, we show that a fine balance of METTL3 function in trophoblast cells is essential for successful human placentation. Both loss-of and gain-in METTL3 functions are associated with adverse human pregnancies. A subset of recurrent pregnancy losses and preterm pregnancies are often associated with loss of METTL3 expression in trophoblast progenitors. In contrast, METTL3 is induced in pregnancies associated with fetal growth restriction (FGR). Our loss of function analyses showed that METTL3 is essential for the maintenance of human TSC self-renewal and their differentiation to extravillous trophoblast cells (EVTs). In contrast, loss of METTL3 in human TSCs promotes syncytiotrophoblast (STB) development. Global analyses of RNA m6A modification and METTL3-RNA interaction in human TSCs showed that METTL3 regulates m6A modifications on the mRNA molecules of critical trophoblast regulators, including GATA2, GATA3, TEAD1, TEAD4, WWTR1, YAP1, TFAP2C and ASCL2, and loss of METTL3 leads to depletion of mRNA molecules of these critical regulators. Importantly, conditional deletion of Mettl3 in trophoblast progenitors of an early post-implantation mouse embryo also leads to arrested self-renewal. Hence, our findings indicate that METLL3 is a conserved epitranscriptomic governor in trophoblast progenitors and ensures successful placentation by regulating their self-renewal and dictating their differentiation fate.
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Increased activation of ovarian primordial follicles in Erß knockout (ErßKO) rats becomes evident as early as postnatal day 8.5. To identify the ERß-regulated genes that may control ovarian primordial follicle activation, we analyzed the transcriptome profiles of ErßKO rat ovaries collected on postnatal days 4.5, 6.5, and 8.5. Compared to wildtype ovaries, ErßKO ovaries displayed dramatic downregulation of Indian hedgehog (Ihh) expression. IHH-regulated genes, including Hhip, Gli1, and Ptch1, were also downregulated in ErßKO ovaries. This was associated with a downregulation of steroidogenic enzymes Cyp11a1, Cyp19a1, and Hsd17b1. The expression of Ihh remained very low in ErßKO ovaries despite the high levels of Gdf9 and Bmp15, which are known upregulators of Ihh expression in the granulosa cells of activated ovarian follicles. Strikingly, the downregulation of the Ihh gene in ErßKO ovaries began to disappear on postnatal day 16.5 and recovered on postnatal day 21.5. In rat ovaries, the first wave of primordial follicles is rapidly activated after their formation, whereas the second wave of primordial follicles remains dormant in the ovarian cortex and slowly starts activating after postnatal day 12.5. We localized the expression of Ihh mRNA in postnatal day 8.5 wildtype rat ovaries but not in the age-matched ErßKO ovaries. In postnatal day 21.5 ErßKO rat ovaries, we detected Ihh mRNA mainly in the activated follicles in the ovaries' peripheral regions. Our findings indicate that the expression of Ihh in the granulosa cells of the activated first wave of ovarian follicles depends on ERß.
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Receptor beta de Estrógeno , Proteínas Hedgehog , Animales , Femenino , Ratas , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Folículo Ovárico/metabolismo , Ovario/metabolismo , ARN Mensajero/metabolismoRESUMEN
Loss of ERß increases primordial follicle growth activation (PFGA), leading to premature ovarian follicle reserve depletion. We determined the expression and gene regulatory functions of ERß in dormant primordial follicles (PdFs) and activated primary follicles (PrFs) using mouse models. PdFs and PrFs were isolated from 3-week-old Erß knockout (Erßnull) mouse ovaries, and their transcriptomes were compared with those of control Erßfl/fl mice. We observed a significant (≥2-fold change; FDR p-value ≤ 0.05) deregulation of approximately 5% of genes (866 out of 16,940 genes, TPM ≥ 5) in Erßnull PdFs; ~60% (521 out of 866) of the differentially expressed genes (DEGs) were upregulated, and 40% were downregulated, indicating that ERß has both transcriptional enhancing as well as repressing roles in dormant PdFs. Such deregulation of genes may make the Erßnull PdFs more susceptible to increased PFGA. When the PdFs undergo PFGA and form PrFs, many new genes are activated. During PFGA of Erßfl/fl follicles, we detected a differential expression of ~24% genes (4909 out of 20,743; ≥2-fold change; FDR p-value ≤ 0.05; TPM ≥ 5); 56% upregulated and 44% downregulated, indicating the gene enhancing and repressing roles of Erß-activated PrFs. In contrast, we detected a differential expression of only 824 genes in Erßnull follicles during PFGA (≥2-fold change; FDR p-value ≤ 0.05; TPM ≥ 5). Moreover, most (~93%; 770 out of 824) of these DEGs in activated Erßnull PrFs were downregulated. Such deregulation of genes in Erßnull activated follicles may impair their inhibitory role on PFGA. Notably, in both Erßnull PdFs and PrFs, we detected a significant number of epigenetic regulators and transcription factors to be differentially expressed, which suggests that lack of ERß either directly or indirectly deregulates the gene expression in PdFs and PrFs, leading to increased PFGA.
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Receptor beta de Estrógeno , Folículo Ovárico , Femenino , Ratones , Animales , Receptor beta de Estrógeno/metabolismo , Folículo Ovárico/metabolismo , Ovario/metabolismo , Regulación de la Expresión Génica , Transcriptoma , Ratones NoqueadosRESUMEN
The placenta establishes a maternal-fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors, and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of transcription factors GATA2 and GATA3 in labyrinth trophoblast progenitors (LaTPs) have underdeveloped placenta and die by ~embryonic day 9.5. Single-cell RNA sequencing analysis revealed excessive accumulation of multipotent LaTPs upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate into matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promotes trophoblast progenitor-to-SynT commitment, ensuring establishment of the maternal-fetal exchange interface.
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Regulación del Desarrollo de la Expresión Génica , Intercambio Materno-Fetal , Embarazo , Femenino , Humanos , Animales , Ratones , Placenta , Trofoblastos , Diferenciación Celular/fisiología , Desarrollo Fetal , Factores de Transcripción GATARESUMEN
The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.
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Cromatina , Trofoblastos , Embarazo , Femenino , Humanos , Trofoblastos/metabolismo , Cromatina/genética , Cromatina/metabolismo , Placentación/genética , Diferenciación Celular/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Linaje de la Célula/genética , Placenta/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
Background: Obesity and visceral adiposity are associated with anovulation. The most common cause of anovulatory infertility in women of reproductive age is polycystic ovary syndrome (PCOS). We conducted this formative study to examine the effects of a remotely delivered, group-based lifestyle program for women with overweight/obesity and PCOS on ovulation, PCOS related quality of life (PCOSQ) and body composition. Methods: Women with anovulatory infertility caused by PCOS (N = 12) were enrolled in a 6-month high-intensity weight management intervention. Participants were asked to attend 45 min., group behavioral lifestyle sessions, delivered remotely by a registered dietitian weekly across the 6-mo. study and comply with a reduced energy diet, increased physical activity (225 min/wk.), and self-monitoring of weight, physical activity and diet. Diets consisted of five portion-controlled meals (three shakes + two entrees), at least five servings of fruits/vegetables, and ad libitum non-caloric beverages daily. Wilcoxon signed-rank tests were used to assess changes in outcomes across the intervention. Results: Twelve women received the weight loss intervention (mean age = 32.7 ± 4.2 yrs., BMI = 36.8 ± 4.5 kg/m2, 92% college educated), and 8 completed the intervention. Eight (67%) women reported ovulating during the intervention with an average time to ovulation of 57 ± 45 days. Women lost an average of 3.85 ± 5.94 kg (p = 0.02), decreased their BMI (-1.61 ± 1.09 kg/m2; p = 0.04), and waist circumference (-4.54 ± 3.03 cm; p = 0.04) over the 6-mo. intervention. Additionally, self-reported menstrual problems measured by PCOSQ significantly improved over the study (p = 0.03). Conclusion: A multicomponent group-based, remotely delivered, lifestyle intervention delivered remotely is a feasible and potentially scalable option to achieve clinically relevant (>3%) weight loss in women with PCOS. Clinical trial registration: www.clinicaltrials.gov, identifier: NCT03677362.
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OBJECTIVE: To examine the expression of uterine natural killer (uNK) cells and cytotoxic T lymphocytes (CTLs) in endometrial biopsies from reproductive-age women with and without nonstructural abnormal uterine bleeding (AUB) and evaluate the expression of granulysin within these cell populations and potential modulation of matrix metalloproteinase (MMP) expression. DESIGN: Experimental study, retrospective design. SETTING: Academic research laboratory. PATIENT(S): Patients with nonstructural AUB with no other gynecological pathologies and control patients without AUB. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Immunohistochemical analysis of granulysin, CD56 (uNK cell marker), and CD8 (CTL marker) expression as well as granulysin messenger ribonucleic acid (mRNA) expression levels in endometrial biopsy samples. Assessment of granulysin regulation of human endometrial stromal cell MMP-1 and MMP-3 mRNA expression. RESULT(S): The numbers of uNK cells and CTLs were significantly greater in endometrial biopsy tissue from women with AUB than those from controls. In accord with the increased expression of uNK cells and CTLs, granulysin expression was significantly greater in endometrial biopsies from patients with AUB than in from controls and colocalized to both cell types but not endometrial stromal or epithelial cells. The increased granulysin protein expression was associated with the increased granulysin mRNA expression in adjacent serial sections from these same samples. The treatment of the human endometrial stromal cell line t-HESC with granulysin resulted in a significant increase in MMP-1 and MMP-3 mRNA expression. CONCLUSION(S): In the current study, immunohistochemistry showed an increased expression of uNK cells, CTLs, and granulysin among subjects with AUB compared with that of subjects without AUB, leading to conclusions that disturbances in the balance of immune cells and an increase in granulysin expression may have implications in the pathophysiology of AUB and include enhanced MMP-1 and MMP-3 expression.
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Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz , Endometrio , Femenino , Humanos , Células Asesinas Naturales , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , ARN Mensajero/genética , Estudios Retrospectivos , Linfocitos T Citotóxicos/metabolismo , Hemorragia Uterina/metabolismoRESUMEN
Transgender and gender non-conforming (TGNC) individuals face numerous barriers to healthcare, which contribute to many health disparities. TGNC persons may choose gender-affirming therapies with surgery and/or hormone replacement therapy (HRT) to manage gender incongruence. Despite the expanding use of HRT, the long-term outcomes on bone health and metabolism, are still relatively unknown in the TGNC population. In 2019, the International Society of Clinical Densitometry (ISCD) released an official position statement on the appropriate use of dual energy x-ray absorptiometry (DXA) to measure bone density in the TGNC population. In this study, we reviewed which "sex" is currently utilized among providers when performing DXA scans to calculate T- and Z-scores for TGNC persons and how this compares to the positions published by the ISCD. A retrospective analysis was performed utilizing HERON queries and subsequent chart review. HERON is a type of Informatics for Integrating Biology and the Bedside software that was utilized to find sets of patients of interest from electronic medical record data while preserving patient privacy through a query interface tool. Project specific sets including patient demographics, medications, gonadectomy, and DXA scan information was created in HERON to make this highly detailed data of specific patients available to the investigators on the platform, as reviewed and retrieved by the Institutional Review Board. The qualitative DXA data obtained from chart review was determined as "correct" or "incorrect" based on positions provided from the ISCD. 10 DXA scans that met inclusion criteria were obtained between 9 TGNC patients. In total, 18 T-scores and Z-scores of the 10 DXAs were reviewed and scored. Based on ISCD positions, 67% of the T-score and Z-scores were calculated incorrectly; using the erroneous "sex" based standard to compare scores. Like DXA scans, many current healthcare standards and protocols are based on a patient's sex or gender, which may cause confusion amongst healthcare personnel who have not received proper training regarding the TGNC population. In this study, 67% of T-scores and Z-scores were calculated incorrectly based on ISCD recommendations. An additional prospective research design is required to determine the consequences of incorrectly calculated DXA scans for TGNC patients. Furthermore, future research is needed to determine HRT's effects on bone mineral density in the TGNC population in the United States.
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Personas Transgénero , Humanos , Absorciometría de Fotón , Estudios Retrospectivos , Estudios Prospectivos , Densidad ÓseaRESUMEN
Kisspeptin (KP) and kisspeptin receptor (KPR) are essential for the onset of puberty, development of gonads, and maintenance of gonadal function in both males and females. Hypothalamic KPs and KPR display a high degree of sexual dimorphism in expression and function. KPs act on KPR in gonadotropin releasing hormone (GnRH) neurons and induce distinct patterns of GnRH secretion in males and females. GnRH acts on the anterior pituitary to secrete gonadotropins, which are required for steroidogenesis and gametogenesis in testes and ovaries. Gonadal steroid hormones in turn regulate the KP neurons. Gonadal hormones inhibit the KP neurons within the arcuate nucleus and generate pulsatile GnRH mediated gonadotropin (GPN) secretion in both sexes. However, the numbers of KP neurons in the anteroventral periventricular nucleus and preoptic area are greater in females, which release a large amount of KPs in response to a high estrogen level and induce the preovulatory GPN surge. In addition to the hypothalamus, KPs and KPR are also expressed in various extrahypothalamic tissues including the liver, pancreas, fat, and gonads. There is a remarkable difference in circulating KP levels between males and females. An increased level of KPs in females can be linked to increased numbers of KP neurons in female hypothalamus and more KP production in the ovaries and adipose tissues. Although the sexually dimorphic features are well characterized for hypothalamic KPs, very little is known about the extrahypothalamic KPs. This review article summarizes current knowledge regarding the sexual dimorphism in hypothalamic as well as extrahypothalamic KP and KPR system in primates and rodents.
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Kisspeptinas , Caracteres Sexuales , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Femenino , Hormona Liberadora de Gonadotropina , Kisspeptinas/metabolismo , Masculino , Maduración SexualRESUMEN
Autoimmune polyglandular syndrome type 1 (APS1) is a progressive life-threatening illness with no known cure. Current treatments involve replacement of the hormone deficiencies that result from autoimmune destruction of multiple endocrine organs. We report on a girl whose disease was progressing rapidly until she began on immunosuppressive agents. A healthy 6-year-old girl with no remarkable medical history presented with new onset hypocalcemic seizures and primary hypoparathyroidism. Howell-Jolly bodies consistent with autoimmune hyposplenism were also noted. Genetic testing revealed compound heterozygosity for 2 disease-associated variants in the autoimmune regulator (AIRE) gene. She later developed elevated liver enzymes, primary adrenal insufficiency, and alopecia totalis. Serologic testing revealed antibodies to 21-hydroxylase, intrinsic factor, and smooth muscle. Hydrocortisone was initiated for adrenal insufficiency. Shortly afterwards, her liver enzymes normalized, and her smooth muscle antibody levels began to decline. Serologic testing performed at age 11 revealed seropositivity for glutamic acid decarboxylase (GAD) antibodies, antinuclear antibodies, and Sjögren syndrome A (SSA) antibodies. At age 12, she was given 2 doses of rituximab. Hair loss rapidly progressed to alopecia totalis and then to alopecia universalis, at which time oral methotrexate treatment was initiated. For the past 7 years while on glucocorticoid and methotrexate treatment, our patient has displayed normalization of 2 antibodies, a lack of progression to additional autoimmune diseases, and experienced reversal of alopecia universalis.
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INTRODUCTION: Studies of anti-vaccine attitudes in the perinatal time period previously have not paid special attention to the MMR and varicella vaccines. Because both contain live attenuated virus, a contraindication during pregnancy, it is important to assess barriers to vaccination clinically during preconception to avoid the known fetal morbidity associated with congenital rubella or varicella infection. METHODS: The primary outcome of this study was to determine prevalence of patients with nonimmune status for rubella and varicella in the setting of advanced reproductive care. Secondary outcomes of interest included further understanding nonimmune reproductive-aged women's attitudes toward MMR and varicella vaccination during preconception. Patient records with laboratory orders for rubella or varicella immunoglobulin titers, placed at the KU Advanced Reproductive Care clinic between January 2017 and June 2020, were reviewed (n = 2,217). A cross-sectional survey was administered to patients with a laboratory reported negative titer result. RESULTS: Prevalence of nonimmunity to either rubella or varicella represented 6.0% (n = 134) and 3.8% (n = 85) of records, respectively; nineteen records (0.6%) demonstrated nonimmunity to both. The women who did not receive recommended vaccines following a non-immune titer result (n = 19) most commonly cited their rationale was to not delay fertility treatment further (n = 8), a requirement when receiving live attenuated virus vaccines. CONCLUSIONS: The prevalence of nonimmune persons in the study population fell within the range recognized to be sufficient for herd immunity. The majority of survey respondents indicated that CDC recommended vaccinations were of high personal importance, with strong congruence of thought among those who answered in favor of vaccines when posed with several true or false statements about personal beliefs and vaccine efficacy. The risk/benefit analysis of postponing fertility treatment to achieve adequate levels of immunity should be a focused discussion when establishing fertility treatment goals with patients in the setting of advanced reproductive care.
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Importance: Body image-related distress (BID) is common among head and neck cancer (HNC) survivors and associated with significant morbidity. Risk factors for HNC-related BID remain poorly characterized because prior research has used outcome measures that fail to fully capture BID as experienced by HNC survivors. Objective: To assess the association of demographic and oncologic characteristics with HNC-related BID using the Inventory to Measure and Assess imaGe disturbancE-Head & Neck (IMAGE-HN), a validated, multidomain, patient-reported outcome measure of HNC-related BID. Design, Setting, and Participants: This cross-sectional study assessed 301 adult survivors of surgically managed HNC at 4 academic medical centers. Main Outcomes and Measures: The primary outcome measure was IMAGE-HN scores, for which higher scores reflect more severe HNC-related BID. Multivariable linear regression analyses were performed to evaluate the association of patient characteristics with IMAGE-HN global and 4 subdomain (other-oriented appearance concerns, personal dissatisfaction with appearance, distress with functional impairments, and social avoidance) scores. Results: Of the 301 participants (212 [70.4%] male; mean [SD] age, 65.3 [11.7] years), 181 (60.1%) underwent free flap reconstruction. Graduation from college (ß = -9.6; 95% CI, -17.5 to -1.7) or graduate school (ß = -12.6; 95% CI, -21.2 to -3.8) was associated with lower IMAGE-HN social avoidance scores compared with less than a high school education. Compared with paid work, unemployment was associated with higher IMAGE-HN other-oriented appearance (ß = 10.7; 95% CI, 2.0-19.3), personal dissatisfaction with appearance (ß = 12.5; 95% CI, 1.2-23.7), and global (ß = 8.0; 95% CI, 0.6-15.4) scores. Compared with no reconstruction, free flap reconstruction was associated with higher IMAGE-HN global scores (ß = 11.5; 95% CI, 7.9-15.0) and all subdomain scores (other-oriented appearance: ß = 13.1; 95% CI, 8.6-17.6; personal dissatisfaction with appearance: ß = 15.4; 95% CI, 10.0-20.7; distress with functional impairment: ß = 12.8; 95% CI, 8.1-17.4; and social avoidance and isolation: ß = 10.2; 95% CI, 5.8-14.6). Higher IMAGE-HN distress with functional impairment scores were found in those who received surgery and adjuvant radiation (ß = 7.8; 95% CI, 2.9-12.7) or chemoradiotherapy (ß = 6.5; 95% CI, 1.8-11.3) compared with surgery alone. The multivariable regression model accounted for a modest proportion of variance in IMAGE-HN global (R2 = 0.18) and subdomain scores (R2 = 0.20 for other-oriented appearance, 0.14 for personal dissatisfaction with appearance, 0.21 for distress with functional impairment, and 0.13 for social avoidance and isolation). Conclusions and Relevance: In this cross-sectional study, factors associated with risk of HNC-related BID included free flap reconstruction, lower educational attainment, unemployment, and multiple treatment modalities. These characteristics explain a modest proportion of variance in IMAGE-HN scores, suggesting that other characteristics may be the major risk factors for HNC-related BID and should be explored in future studies.
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Insatisfacción Corporal/psicología , Supervivientes de Cáncer/psicología , Neoplasias de Cabeza y Cuello/psicología , Neoplasias de Cabeza y Cuello/terapia , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia Adyuvante , Estudios Transversales , Femenino , Colgajos Tisulares Libres , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Procedimientos de Cirugía Plástica/psicología , Factores de Riesgo , Autoinforme , Factores Socioeconómicos , Adulto JovenRESUMEN
The COVID-19 pandemic brought forward the challenge of dispersing accurate medical information to the public rapidly. Credible and non-credible sources may impact public reactions to the virus. The purpose of this study is to assess those reactions of women located in or near Kansas. A survey was conducted in July 2020 with questions on knowledge of COVID-19, attitudes and behaviors towards COVID-19, and primary sources of information. 305 survey respondents met criteria for further analysis, and descriptive statistical analyses were applied. Participants were generally knowledgeable of the pandemic, with a mean knowledge score of 11.40 out of 13 (SD 1.3). The attitude statement with the highest rate of agreement was that "social distancing is an effective way of controlling COVID-19 spread" (n = 265, 86.9%) and that with the highest rate of disagreement was, "I am not worried about my friends' and family members health" (n = 253, 83.0%). The most-implemented behaviors as indicated by participants were avoiding contact with sick individuals and washing hands with soap and water often (n = 294, 96.4%), and the least implemented was avoiding meat consumption (n = 257, 84.3%). Finally, most participants indicated that health officials were their primary source of information (n = 215, 70.5%). Participants of this survey had fairly good knowledge of the virus. Attitudes of participants as a whole may be described as cautious without being overly fearful. Reported behaviors also align well with current public health recommendations. These responses may be reflective of where participants are receiving their information, which, for the majority, is from public health officials.
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COVID-19 , Pandemias , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Kansas/epidemiología , SARS-CoV-2RESUMEN
OBJECTIVE: To evaluate the use of a web-based application that assists in medication management during in vitro fertilization (IVF) treatment. DESIGN: Multicenter randomized controlled trial. SETTING: University hospitals. PATIENT(S): Women undergoing IVF. INTERVENTION(S): Subjects were recruited to assess quality of life during IVF and were randomly assigned to use either the OnTrack application to assist with medication management or conventional medication management. Surveys were administered at four time points. MAIN OUTCOME MEASURE(S): Medication surplus, incidence of medication errors, amount of patient-initiated communication, and patient satisfaction. RESULT(S): A total of 153 women participated. The average number of portal messages and telephone calls was similar between groups. Twelve patients in the control group (12/69, 17.4%) and 8 patients in the case group (8/72, 11.1%) made medication errors. There were similar amounts of medication surplus in the two groups. The estimated cost of medication waste was $2,578 ± $2,056 in the control group and $2,554 ± $1,855 in the case group. Patient satisfaction was similar between the two groups. CONCLUSION(S): Use of a web-based application did not decrease medication errors, medication surplus, or patient-initiated messages. Many patients had a medication surplus, which can be an area of cost reduction during IVF. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03383848.
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Quimioterapia Asistida por Computador , Fármacos para la Fertilidad Femenina/uso terapéutico , Fertilización In Vitro , Infertilidad/terapia , Intervención basada en la Internet , Administración del Tratamiento Farmacológico , Adulto , Ahorro de Costo , Análisis Costo-Beneficio , Costos de los Medicamentos , Quimioterapia Asistida por Computador/efectos adversos , Quimioterapia Asistida por Computador/economía , Fármacos para la Fertilidad Femenina/efectos adversos , Fármacos para la Fertilidad Femenina/economía , Fertilización In Vitro/efectos adversos , Fertilización In Vitro/economía , Humanos , Infertilidad/diagnóstico , Infertilidad/economía , Infertilidad/fisiopatología , Intervención basada en la Internet/economía , Cumplimiento de la Medicación , Errores de Medicación/prevención & control , Administración del Tratamiento Farmacológico/economía , Satisfacción del Paciente , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
PURPOSE: More than half of patients with head and neck squamous cell carcinoma (HNSCC) experience a delay initiating guideline-adherent postoperative radiation therapy (PORT), contributing to excess mortality and racial disparities in survival. However, interventions to improve the delivery of timely, equitable PORT among patients with HNSCC are lacking. This study (1) describes the development of NDURE (Navigation for Disparities and Untimely Radiation thErapy), a navigation-based multilevel intervention (MLI) to improve guideline-adherent PORT and (2) evaluates its feasibility, acceptability, and preliminary efficacy. METHODS: NDURE was developed using the six steps of intervention mapping (IM). Subsequently, NDURE was evaluated by enrolling consecutive patients with locally advanced HNSCC undergoing surgery and PORT (n = 15) into a single-arm clinical trial with a mixed-methods approach to process evaluation. RESULTS: NDURE is a navigation-based MLI targeting barriers to timely, guideline-adherent PORT at the patient, healthcare team, and organizational levels. NDURE is delivered via three in-person navigation sessions anchored to case identification and surgical care transitions. Intervention components include the following: (1) patient education, (2) travel support, (3) a standardized process for initiating the discussion of expectations for PORT, (4) PORT care plans, (5) referral tracking and follow-up, and (6) organizational restructuring. NDURE was feasible, as judged by accrual (88% of eligible patients [100% Blacks] enrolled) and dropout (n = 0). One hundred percent of patients reported moderate or strong agreement that NDURE helped solve challenges starting PORT; 86% were highly likely to recommend NDURE. The rate of timely, guideline-adherent PORT was 86% overall and 100% for Black patients. CONCLUSION: NDURE is a navigation-based MLI that is feasible, is acceptable, and has the potential to improve the timely, equitable, guideline-adherent PORT.
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Neoplasias de Cabeza y Cuello , Terapia Combinada , Neoplasias de Cabeza y Cuello/terapia , Humanos , Derivación y Consulta , Carcinoma de Células Escamosas de Cabeza y Cuello/terapiaRESUMEN
PURPOSE: Delays initiating guideline-adherent postoperative radiation therapy (PORT) in head and neck squamous cell carcinoma (HNSCC) are common, contribute to excess mortality, and are a modifiable target for improving survival. However, the barriers that prevent the delivery of timely, guideline-adherent PORT remain unknown. This study aims to identify the multilevel barriers to timely, guideline-adherent PORT and organize them into a conceptual model. MATERIALS AND METHODS: Semi-structured interviews with key informants were conducted with a purposive sample of patients with HNSCC and oncology providers across diverse practice settings until thematic saturation (n = 45). Thematic analysis was performed to identify the themes that explain barriers to timely PORT and to develop a conceptual model. RESULTS: In all, 27 patients with HNSCC undergoing surgery and PORT were included, of whom 41% were African American, and 37% had surgery and PORT at different facilities. Eighteen clinicians representing a diverse mix of provider types from 7 oncology practices participated in key informant interviews. Five key themes representing barriers to timely PORT were identified across 5 health care delivery levels: (1) inadequate education about timely PORT, (2) postsurgical sequelae that interrupt the tight treatment timeline (both intrapersonal level), (3) insufficient coordination and communication during care transitions (interpersonal and health care team levels), (4) fragmentation of care across health care organizations (organizational level), and (5) travel burden for socioeconomically disadvantaged patients (community level). CONCLUSION: This study provides a novel description of the multilevel barriers that contribute to delayed PORT. Interventions targeting these multilevel barriers could improve the delivery of timely, guideline-adherent PORT and decrease mortality for patients with HNSCC.
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Neoplasias de Cabeza y Cuello , Terapia Combinada , Atención a la Salud , Neoplasias de Cabeza y Cuello/terapia , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapiaRESUMEN
Early pregnancy loss affects â¼15% of all implantation-confirmed human conceptions. However, evolutionarily conserved molecular mechanisms that regulate self-renewal of trophoblast progenitors and their association with early pregnancy loss are poorly understood. Here, we provide evidence that transcription factor TEAD4 ensures survival of postimplantation mouse and human embryos by controlling self-renewal and stemness of trophoblast progenitors within the placenta primordium. In an early postimplantation mouse embryo, TEAD4 is selectively expressed in trophoblast stem cell-like progenitor cells (TSPCs), and loss of Tead4 in postimplantation mouse TSPCs impairs their self-renewal, leading to embryonic lethality before embryonic day 9.0, a developmental stage equivalent to the first trimester of human gestation. Both TEAD4 and its cofactor, yes-associated protein 1 (YAP1), are specifically expressed in cytotrophoblast (CTB) progenitors of a first-trimester human placenta. We also show that a subset of unexplained recurrent pregnancy losses (idiopathic RPLs) is associated with impaired TEAD4 expression in CTB progenitors. Furthermore, by establishing idiopathic RPL patient-specific human trophoblast stem cells (RPL-TSCs), we show that loss of TEAD4 is associated with defective self-renewal in RPL-TSCs and rescue of TEAD4 expression restores their self-renewal ability. Unbiased genomics studies revealed that TEAD4 directly regulates expression of key cell cycle genes in both mouse and human TSCs and establishes a conserved transcriptional program. Our findings show that TEAD4, an effector of the Hippo signaling pathway, is essential for the establishment of pregnancy in a postimplantation mammalian embryo and indicate that impairment of the Hippo signaling pathway could be a molecular cause for early human pregnancy loss.
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Autorrenovación de las Células/genética , Proteínas de Unión al ADN/genética , Desarrollo Embrionario/genética , Proteínas Musculares/genética , Factores de Transcripción/genética , Trofoblastos/citología , Trofoblastos/metabolismo , Aborto Habitual/etiología , Aborto Habitual/metabolismo , Aborto Espontáneo/etiología , Aborto Espontáneo/metabolismo , Animales , Biomarcadores , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Implantación del Embrión , Femenino , Técnica del Anticuerpo Fluorescente , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Proteínas Musculares/metabolismo , Placenta/metabolismo , Embarazo , Factores de Transcripción de Dominio TEA , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVES: Distress with self-perceived changes in appearance and function can result in body image disturbance (BID), which is common in head and neck cancer (HNC) survivors and a major source of psychosocial morbidity. To address the lack of psychometrically sound patient-reported outcome measures (PROMs) of HNC-related BID, we aim to create and validate the Inventory to Measure and Assess imaGe disturbancE-Head & Neck (IMAGE-HN). STUDY DESIGN: Survey study. SETTING: Multiple academic centers. SUBJECTS AND METHODS: Following item development, HNC survivors from 4 academic centers completed the IMAGE-HN. Item responses were psychometrically analyzed using confirmatory factor analysis (CFA) and Rasch analysis. RESULTS: Item development resulted in a 31-item PROM consisting of 5 individual domains and a global domain. In total, 305 HNC survivors of diverse ages, HNC subsites, and reconstructive paradigms completed the initial items. After removal of 3 items for local dependence, CFA confirmed the unidimensionality and local independence (item residual correlations <|0.20|) for each domain. Rasch analysis indicated acceptable fit (infit and outfit mean squares <2.0), monotonicity of all rating scale categories, and low person misfit (<4%). Person separation indices and person reliability were adequate for each domain except appearance concealment, which was removed (4 items). This resulted in the IMAGE-HN, a psychometrically acceptable 24-item PROM of HNC-related BID consisting of a global scale and 4 subscales measuring unique constructs and comprised independent items. CONCLUSIONS: IMAGE-HN is a novel, psychometrically sound, multidomain PROM of HNC-related BID for use in clinical and research settings.