RESUMO
STUDY QUESTION: What is the cumulative delivery rate (CDR) per aspiration IVF/ICSI cycle in low-prognosis patients as defined by the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? SUMMARY ANSWER: The CDR of POSEIDON patients was on average â¼50% lower than in normal responders and varied across POSEIDON groups; differences were primarily determined by female age, number of embryos obtained, number of embryo transfer (ET) cycles per patient, number of oocytes retrieved, duration of infertility, and BMI. WHAT IS KNOWN ALREADY: The POSEIDON criteria aim to underline differences related to a poor or suboptimal treatment outcome in terms of oocyte quality and quantity among patients undergoing IVF/ICSI, and thus, create more homogenous groups for the clinical management of infertility and research. POSEIDON patients are presumed to be at a higher risk of failing to achieve a live birth after IVF/ICSI treatment than normal responders with an adequate ovarian reserve. The CDR per initiated/aspiration cycle after the transfer of all fresh and frozen-thawed/warmed embryos has been suggested to be the critical endpoint that sets these groups apart. However, no multicenter study has yet substantiated the validity of the POSEIDON classification in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment using real-world data. STUDY DESIGN, SIZE, DURATION: Multicenter population-based retrospective cohort study involving 9073 patients treated in three fertility clinics in Brazil, Turkey and Vietnam between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women with infertility between 22 and 42 years old in their first IVF/ICSI cycle of standard ovarian stimulation whose fresh and/or frozen embryos were transferred until delivery of a live born or until all embryos were used. Patients were retrospectively classified according to the POSEIDON criteria into four groups based on female age, antral follicle count (AFC), and the number of oocytes retrieved or into a control group of normal responders (non-POSEIDON). POSEIDON patients encompassed younger (<35 years) and older (35 years or above) women with an AFC ≥5 and an unexpected poor (<4 retrieved oocytes) or suboptimal (4-9 retrieved oocytes) response to stimulation, and respective younger and older counterparts with an impaired ovarian reserve (i.e. expected poor responders; AFC <5). Non-POSEIDON patients were those with AFC ≥5 and >9 oocytes retrieved. CDR was computed per one aspirated cycle. Logistic regression analysis was carried out to examine the association between patient classification and CDR. MAIN RESULTS AND ROLE OF CHANCE: The CDR was lower in the POSEIDON patients than in the non-POSEIDON patients (33.7% vs 50.6%; P < 0.001) and differed across POSEIDON groups (younger unexpected poor responder [Group 1a; n = 212]: 27.8%, younger unexpected suboptimal responder [Group 1b; n = 1785]: 47.8%, older unexpected poor responder [Group 2a; n = 293]: 14.0%, older unexpected suboptimal responder [Group 2b; n = 1275]: 30.5%, younger expected poor responder [Group 3; n = 245]: 29.4%, and older expected poor responder [Group 4; n = 623]: 12.5%. Among unexpected suboptimal/poor responders (POSEIDON Groups 1 and 2), the CDR was twice as high in suboptimal responders (4-9 oocytes retrieved) as in poor responders (<4 oocytes) (P = 0.0004). Logistic regression analysis revealed that the POSEIDON grouping, number of embryos obtained, number of ET cycles per patient, number of oocytes collected, female age, duration of infertility and BMI were relevant predictors for CDR (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Our study relied on the antral follicle count as the biomarker used for patient classification. Ovarian stimulation protocols varied across study centers, potentially affecting patient classification. WIDER IMPLICATIONS OF THE FINDINGS: POSEIDON patients exhibit lower CDR per aspirated IVF/ICSI cycle than normal responders; the differences are mainly determined by female age and number of oocytes retrieved, thereby reflecting the importance of oocyte quality and quantity. Our data substantiate the validity of the POSEIDON criteria in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment. Efforts in terms of early diagnosis, prevention, and identification of specific interventions that might benefit POSEIDON patients are warranted. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted investigator-sponsored study grant (MS200059_0013) from Merck KGaA, Darmstadt, Germany. The funder had no role in study design, data collection, analysis, decision to publish or manuscript preparation. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD) and Ferring and research grants from MSD and Ferring. J.F.C. declares receipt of statistical services fees from ANDROFERT Clinic. T.M.H. received speaker fees and conferences from Merck, MSD and Ferring. P.H. declares receipt of unrestricted research grants from Merck, Ferring, Gedeon Richter and IBSA and lecture fees from Merck, Gedeon Richter and Med.E.A. C.A. declares receipt of unrestricted research grants from Merck and lecture fees from Merck. The remaining authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.
Assuntos
Indução da Ovulação , Injeções de Esperma Intracitoplásmicas , Adulto , Coeficiente de Natalidade , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Oócitos , Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
Objective: To estimate the prevalence of low-prognosis patients according to the POSEIDON criteria using real-world data. Design: Multicenter population-based cohort study. Settings: Fertility clinics in Brazil, Turkey, and Vietnam. Patients: Infertile women undergoing assisted reproductive technology using standard ovarian stimulation with exogenous gonadotropins. Interventions: None. Main outcome measures: Per-period prevalence rates of POSEIDON patients (overall, stratified by POSEIDON groups and by study center) and the effect of covariates on the probability that a patient be classified as "POSEIDON". Results: A total of 13,146 patients were included. POSEIDON patients represented 43.0% (95% confidence interval [CI] 42.0-43.7) of the studied population, and the prevalence rates varied across study centers (range: 38.6-55.7%). The overall prevalence rates by POSEIDON groups were 44.2% (group 1; 95% CI 42.6-45.9), 36.1% (group 2; 95% CI 34.6-37.7), 5.2% (group 3; 95% CI 4.5-6.0), and 14.4% (group 4; 95% CI: 13.3-15.6). In general, POSEIDON patients were older, had a higher body mass index (BMI), lower ovarian reserve markers, and a higher frequency of female factor as the primary treatment indication than non-POSEIDON patients. The former required larger doses of gonadotropin for ovarian stimulation, despite achieving a 2.5 times lower number of retrieved oocytes than non-POSEIDON patients. Logistic regression analyses revealed that female age, BMI, ovarian reserve, and a female infertility factor were relevant predictors of the POSEIDON condition. Conclusions: The estimated prevalence of POSEIDON patients in the general population undergoing ART is significant. These patients differ in clinical characteristics compared with non-POSEIDON patients. The POSEIDON condition is associated with female age, ovarian reserve, BMI, and female infertility. Efforts in terms of diagnosis, counseling, and treatment are needed to reduce the prevalence of low-prognosis patients.
Assuntos
Fertilização in vitro , Infertilidade/diagnóstico , Infertilidade/epidemiologia , Reserva Ovariana/fisiologia , Indução da Ovulação , Técnicas de Reprodução Assistida , Adulto , Brasil/epidemiologia , Estudos de Coortes , Feminino , Gonadotropinas/sangue , Humanos , Prevalência , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Turquia/epidemiologia , Vietnã/epidemiologiaRESUMO
STUDY QUESTION: What is the agreement between antral follicle count (AFC) and anti-Müllerian hormone (AMH) levels when used to patient classification according to the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? SUMMARY ANSWER: Our study indicates a strong agreement between the AFC and the AMH levels in classifying POSEIDON patients; thus, either can be used for this purpose, although one in four women will have discordant values when both biomarkers are used. WHAT IS KNOWN ALREADY: According to the POSEIDON criteria, both AFC and AMH may be used to classify low-prognosis patients. Proposed AFC and AMH thresholds of 5 and 1.2 ng/ml, respectively, have their basis in published literature; however, no study has yet determined the reproducibility of patient classification in comparing one biomarker with the other, nor have their thresholds ever been validated within this patient population. STUDY DESIGN, SIZE, DURATION: A population-based cohort study involving 9484 consecutive patients treated in three fertility clinics in Brazil, Turkey and Vietnam between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were infertile women between 22 and 46 years old in their first in vitro fertilization/intracytoplasmic sperm injection cycle of standard ovarian stimulation with exogenous gonadotropins whose baseline ovarian reserves had been assessed by both AFC and AMH. Details of pre- and post-treatment findings were input into a coded research file. Two indicators of interest were created to classify patients according to the POSEIDON criteria based upon AFC and AMH values. Patients who did not fit any of the four POSEIDON groups were classified as non-POSEIDON. AFC was determined in the early follicular phase using two-dimensional (2D) transvaginal ultrasonography, whereas AMH values were based on the modified Beckman Coulter generation II enzyme-linked immunosorbent assay. Agreement rates were computed between AFC and AMH to classify patients using Cohen's kappa statistics. Logistic regression analyzes were carried out to examine the association between ovarian markers and low (<4) and suboptimal (4-9) oocyte yield. MAIN RESULTS AND THE ROLE OF CHANCE: The degree of agreement in classifying patients according to POSEIDON groups was strong overall (kappa = 0.802; 95% CI: 0.792-0.811). A total of 73.8% of individuals were classified under the same group using both biomarkers. The disagreement rates were â¼26% and did not diverge when AFC or AMH was used as the primary biomarker criterion. Significant regression equations were found between ovarian markers and oocyte yield (P < 0.0001). For low oocyte yield, the optimal AFC and AMH cutoff values were 5 and 1.27 ng/ml with sensitivities of 0.61 and 0.66, specificities of 0.81 and 0.72, and AUC receiver operating characteristics of 0.791 and 0.751, respectively. For suboptimal oocyte yield respective AFC and AMH cutoffs were 12 and 2.97 ng/ml with sensitivities of 0.74 and 0.69, specificities of 0.76 and 0.66 and AUCs of 0.81 and 0.80. LIMITATIONS, REASONS FOR CAUTION: Our study relied on 2D transvaginal sonography to quantify the AFC and manual Gen II assay for AMH determination and classification of patients. AMH data must be interpreted in an assay-specific manner. Treatment protocols varied across centers potentially affecting patient classification. WIDER IMPLICATIONS OF THE FINDINGS: Three of four patients will be classified the same using either AFC or AMH values. Both biomarkers provide acceptable and equivalent accuracy in predicting oocyte yield further supporting their use and proposed thresholds in daily clinical practice for patient classification according to the POSEIDON criteria. However, the sensitivity of POSEIDON thresholds in predicting low oocyte yield is low. Clinicians should adopt the biomarker that may best reflect their clinical setting. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted investigator-sponsored study grant (MS200059_0013) from Merck KGaA, Darmstadt, Germany. The funder had no role in study design, data collection, analysis, decision to publish or manuscript preparation. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD) and Ferring and research grants from MSD and Ferring. T.M.H. received speaker fees and conferences from Merck, MSD and Ferring. The remaining authors have nothing to disclose. TRIAL REGISTRATION NUMBER: not applicable.
Assuntos
Hormônio Antimülleriano , Infertilidade Feminina , Adulto , Brasil , Estudos de Coortes , Feminino , Alemanha , Humanos , Infertilidade Feminina/diagnóstico , Pessoa de Meia-Idade , Oócitos , Indução da Ovulação , Prognóstico , Reprodutibilidade dos Testes , Turquia , Vietnã , Adulto JovemRESUMO
High risk types of human papillomavirus (HR-HPV) play a major role in cervical cancer oncogenesis. This study aims to evaluate the efficacy of HPV detection and typing as a means of identifying cervical neoplasia in a high risk population. A management algorithm for implementation of HPV detection in clinical practice is also proposed. A nested case-control within a cohort study was undertaken in Recife (Brazil). All 479 participants had cervical scrapes collected for HPV detection followed by colposcopy. Samples were blindly analyzed by polymerase chain reaction (PCR) and typed by restriction fragment length polymorphism (RFLP). HPV detection by PCR and typing with RFLP cost US$ 4.92 per woman screened in this study and is significantly better than cytology in identifying women at risk of developing cervical cancer (P = 0.0001). Women who tested positive for HR-HPV had over 35-fold increased risk of having high grade squamous intraepithelial lesion (HSIL) or cervical cancer, although this does not necessarily translate into the same risk rate for women with latent HPV infection developing major cervical neoplasia. HPV typing offers 90% sensitivity and 85% specificity for cervical cancer detection. In combination with cytology it provides a negative predictive value of 99.4% and a sensitivity of over 96% for detection of HSIL and cervical cancer. We conclude that HPV typing is an inexpensive and effective method for identification of cervical neoplasia and women at risk of developing it. It improves quality control for both false negative and false positive cytology results. Routine screening intervals could safely be increased to 3-5 years, decreasing anxiety and socio-economic inconveniences.
RESUMO
Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.
Assuntos
Albinismo Oculocutâneo/genética , Mutação da Fase de Leitura , Heterogeneidade Genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Consanguinidade , Etnicidade/genética , Ligação Genética , Homozigoto , Humanos , Porto Rico/etnologia , Splicing de RNARESUMO
Hermansky-Pudlak syndrome (HPS) is an often-fatal autosomal recessive disease in which albinism, bleeding, and lysosomal storage result from defects of diverse cytoplasmic organelles: melanosomes, platelet dense bodies, and lysosomes. HPS is the most common single-gene disorder in Puerto Rico, with an incidence of 1 in 1,800. We have identified the HPS gene by positional cloning, and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish and Japanese HPS patients. The HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and that is apparently crucial for their normal development and function. The different clinical phenotypes associated with the different HPS frameshifts we observed suggests that differentially truncated HPS polypeptides may have somewhat different consequences for subcellular function.
Assuntos
Albinismo Oculocutâneo/genética , Citoplasma/genética , Doenças por Armazenamento dos Lisossomos/genética , Proteínas de Membrana/genética , Mutação , Albinismo Oculocutâneo/complicações , Albinismo Oculocutâneo/epidemiologia , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Citoplasma/patologia , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Irlanda , Japão , Doenças por Armazenamento dos Lisossomos/complicações , Doenças por Armazenamento dos Lisossomos/epidemiologia , Dados de Sequência Molecular , Fenótipo , Porto Rico , Suíça , SíndromeRESUMO
Binding of aflatoxin B1 (AFB1) to DNA and AFB1-glutathione conjugation during the metabolism of AFB1 have been examined with freshly isolated hepatocytes from male Fischer rats and Syrian hamsters. Even though there was no significant difference in cytochrome P450 and glutathione contents, there were marked differences in the metabolism of AFB1 (33 nM) in hepatocytes from these two species. Thus, AFB1-DNA binding was six-fold higher in the rat than in hamster hepatocytes, whereas AFB1-glutathione conjugation was 12-fold higher in hamster than in rat hepatocytes. The addition of 0.5 mM diethylmaleate had no significant effect in rats, whereas its presence produced a nine-fold increase in AFB1-DNA binding with 85% inhibition of thiol conjugation in hamster hepatocytes. Styrene oxide (1 mM) produced 50% and 25-fold increases in AFB1-DNA binding in rat and hamster hepatocytes, respectively, with corresponding decreases in thiol conjugation. Triethyltin bromide (50 microM) inhibited both processes by 50% in rat hepatocytes, whereas it produced a nine-fold increase in AFB1-DNA binding with a concomitant decrease in thiol conjugation in hamster hepatocytes. These results suggest that glutathione S-transferases play a more significant role in modulating AFB1-DNA binding in hamster than in rat hepatocytes.
Assuntos
Aflatoxinas/metabolismo , Carcinógenos/metabolismo , DNA/metabolismo , Glutationa/metabolismo , Fígado/metabolismo , Aflatoxina B1 , Animais , Cricetinae , Compostos de Epóxi/farmacologia , Técnicas In Vitro , Maleatos/farmacologia , Ratos , Especificidade da Espécie , Compostos de Trietilestanho/farmacologiaRESUMO
Effects of catechin, a plant phenolic flavonoid, and of the commonly used organic solvents dimethyl sulfoxide (DMSO) and ethanol (EtOH) on the microsome-mediated metabolism of two hepatocarcinogens, N-nitrosodimethylamine (NDMA) and aflatoxin B1 (AFB1), are presented. Using hamster liver microsomes as a source of mixed-function oxidases, it was shown that catechin at 0.1-0.2 mM levels had no effect on the oxidation of either carcinogen. However, at 1-5 mM levels it caused a concentration-dependent inhibition (38-70%) of the formation of formaldehyde from NDMA, and at the 5 mM level it caused a 40% inhibition of AFB1-DNA binding. DMSO and EtOH totally inhibited NDMA demethylase activity but had little effect on the binding of AFB1 to DNA. These observations indicate that the mixed-function oxidases (cytochrome P450) essential for the metabolic activation of these carcinogens exhibit different sensitivities to different inhibitors.