Miastenia gravis y enfermedad de Alzheimer: una asociación a estudio / Association between myasthenia gravis and Alzheimer’s disease

Introducción La miastenia gravis (MG) y la enfermedad de Alzheimer (EA) son dos de las enfermedades neurológicas en cuya fisiopatología interviene la acetilcolina en distintos niveles. En la primera, la alteración de este neurotransmisor se produce en la unión neuromuscular, y en la segunda, en el sistema nervioso central. Objetivo Analizar la posible relación entre dichas patologías estudiando la prevalencia y la odds ratio de la EA dentro de los pacientes diagnosticados de MG con respecto a la prevalencia de EA en la población general. Pacientes y métodos Se han examinado datos de las historias clínicas electrónicas del sistema de salud de Castilla-La Mancha utilizando el procesamiento de lenguaje natural a través de la plataforma clínica de inteligencia artificial Savana Manager?. Resultados Se ha identificado a 970.503 pacientes mayores de 60 años, de los que 1.028 tenían diagnóstico de MG. La proporción de pacientes con diagnóstico de EA dentro de este grupo (4,28%) es mayor que en el resto de la población (2,82%; p = 0,0047), con una odds ratio de 1,54 (intervalo de confianza al 95%: 1,13-2,08; p = 0,0051), sin que se encuentren diferencias significativas en el análisis bivariante del resto de los factores de riesgo para EA más importantes conocidos hasta ahora. Conclusiones Nuestros resultados sugieren que podría existir un aumento de la prevalencia de EA en pacientes con MG. (AU)

INTRODUCTION Myasthenia gravis (MG) and Alzheimer’s disease (AD) are two of the most important diseases where the dysregulation of acetylcholine activity plays a crucial role. In the first, this dysregulation happens at the level of the neu­romuscular junction and in the second, in the central nervous system (CNS). AIM To analyze the possible relationship between these two pathologies, analyzing the prevalence and the odds ratio of AD within patients previously diagnosed with MG. We will compare these data with respect to the prevalence of AD in the general population. PATIENTS AND METHODS We examined the data obtained by the electronic medical records of patients in the health care system of Castilla La Mancha using the Natural Language Process provided by a clinical platform of artificial intelligence known as the Savana Manager?. RESULTS We identified 970,503 patients over the age of 60 years, of which 1,028 were diagnosed with MG. The proportion of the patients diagnosed with AD within this group (4.28%) was greater than the rest of the population (2.82%) (p = 0,0047) with an odds ratio of 1.54 (confidence interval at 95% 1.13-2.08; p = 0.0051) without finding significant differences in the bivariate analysis for the rest of the most important actual known risk factors for AD. CONCLUSION. Our results suggest that there might be an increase in the prevalence of AD in patients previously diagnosed with MG. (AU)

Evolución de pacientes con ELA bajo seguimiento neumológico y comparación de dos áreas asistenciales en una provincia española / Evolution under respiratory follow-up of patients with ALS and comparison of two healthcare areas in a Spanish province

Introducción: Describir las características de pacientes con Esclerosis Lateral Amiotrófica (ELA) remitidos para valoración respiratoria, determinando si existen factores diferenciales en el manejo clínico y su evolución en dos áreas asistenciales. Métodos: Análisis retrospectivo (seguimiento de 16 años) de pacientes con ELA atendidos en dos Servicios de Neumología en la misma provincia. Se analizan características demográficas, tipo de ELA, clase de adaptación a la ventilación domiciliaria (VMD), modalidad ventilatoria, uso de asistencia mecánica para la tos e indicación de gastrostomía, comparando supervivencia. El Área Sanitaria de Talavera de la Reina cuenta con acreditación de Unidad de Ventilación Domiciliaria Especializada, siendo de Unidad Básica en el Área de Toledo. Resultados: Se analizaron 97 pacientes (60 en Toledo). La edad media fue de 63,3 años y el 60,8% varones. Inicio espinal en el 55,7% y bulbar 35,1%. Se inició VMD en el 88% de los pacientes, siendo programada en el 80%. Indicación de tos asistida mecánica en un 35,1% y en el 51,5% de los pacientes se realizó gastrostomía. La supervivencia media global fue de 32,3 meses, desde el inicio de la VMD de 26,2 meses y 17,1 meses desde la realización de gastrostomía. Los datos de supervivencia fueron similares comparando ambas áreas asistenciales. Conclusiones: Los pacientes con ELA atendidos en dos áreas asistenciales, con criterios clínicos similares, pero con estrategias diferenciadas según los recursos disponibles, presentaron una supervivencia global similar, así como tras el inicio de la VMD y la realización de gastrostomía y con un resultado equiparable al de centros de referencia.(AU)

Background: We aim to describe the characteristics of patients with Amyotrophic Lateral Sclerosis (ALS) referred for respiratory assessment, and whether there are differential factors in the evolution of patients according to two different healthcare areas. Methods: Retrospective analysis of patients with ALS in two Pulmonology services at the same province in Spain (16-year follow-up). We analysed demographic variables, ALS subtype, Home Mechanical Ventilation (HMV) modality and way of adaptation, use of mechanical assisted cough and gastrostomy indication, comparing survival. In the Health Area of Talavera there is a Specialized Unit of HMV according to accreditation by Spanish Respiratory Society, with a Basic Unit in the Toledo Area. Results: A total of 97 patients were analysed (60 in Toledo). The mean age was 63,3 years and 60,8% were male. The form of onset was spinal: 55,7% and bulbar: 35,1%. HMV was started in 88% of the patients, programmed in 80% of them. The use of mechanical assisted cough reached 35,1% of the patients and up to 51,5% of them underwent gastrostomy. Median survival was 32,3 months, being 26,2 months from the start of HMV and 17,1 months after gastrostomy. When comparing the two areas survival data were similar. Conclusions: Patients with ALS assisted in two healthcare areas at the same province, with similar clinical criteria, but with differentiated strategies according to the available resources, present a similar overall survival, as well as after the start of HMV and the performance of gastrostomy and with a similar outcome compared with reference units.(AU)

The impact of using the combined oral contraceptive pill for cycle scheduling on gene expression related to endometrial receptivity.

STUDY QUESTION: Does the combined oral contraceptive pill (COCP) change endometrial gene expression when used for cycle programming? SUMMARY ANSWER: COCP used for scheduling purposes does not have a significant impact on endometrial gene expression related to endometrial receptivity. WHAT IS KNOWN ALREADY: Controversy exists around COCP pretreatment for IVF cycle programming, as some authors claim that it might be detrimental to the live birth rate. Microarray technology applied to the study of tissue gene expression has previously revealed the behavior of genes related to endometrial receptivity under different conditions. STUDY DESIGN, SIZE, AND DURATION: Proof-of-concept study of 10 young healthy oocyte donors undergoing controlled ovarian stimulation (COS) recruited between June 2012 and February 2013. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Microarray data were obtained from endometrial biopsies from 10 young healthy oocyte donors undergoing COS with GnRH antagonists and recombinant FSH. In group A (n = 5), COCP pretreatment was used for 12-16 days, and stimulation began after a 5-day pill-free interval. Stimulation in group B (n = 5) was initiated on cycle day 3 after a spontaneous menses. Endometrial biopsies were collected 7 days after triggering with hCG. MAIN RESULTS AND THE ROLE OF CHANCE: No individual genes exhibited increased or decreased expression (fold change (FC) >2) in patients with prior COCP treatment (group A) compared with controls (group B). However, the results of the functional analysis showed a total of 11 biological processes that were significantly enriched in group A compared with group B (non-COCP). LIMITATIONS, REASONS FOR CAUTION: The Endometrial Receptivity Array (ERA) has only been validated on endometrial samples obtained in natural cycles and after hormonal replacement treatment (HRT). Therefore, it was not possible in this study to classify the endometrial samples as receptive or non-receptive. We used the ERA to focus on 238 genes that are intimately related to endometrial receptivity, thus simplifying the analysis and understanding of the data. WIDER IMPLICATIONS OF THE FINDINGS: Cycle scheduling is common in IVF units and is used to avoid weekend retrievals and/or to distribute evenly the workload for better efficiency. Our failure to detect any relevant changes in the genes related to the window of implantation when cycles were programmed with COCP pretreatment suggests that, despite controversial clinical results in previous studies, the use of COCPs in this way does not affect uterine receptivity adversely. STUDY FUNDING/COMPETING INTEREST(S): Funding for this study was provided by an unrestricted grant from Merck Sharp & Dohme. C.S. and A.P. are co-inventors (with Patricia Diaz-Gimeno) of the Endometrial Receptivity Array and hold the patent. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: EudraCT registration number is 2011-003250-34.

Impact of final oocyte maturation using gonadotropin-releasing hormone agonist triggering and different luteal support protocols on endometrial gene expression.

OBJECTIVE: To use microarray technology to analyze endometrial gene expression after gonadotropin-releasing hormone agonist (GnRH-a) triggering with four different protocols of luteal support in comparison with results obtained after a human chorionic gonadotropin (hCG) trigger. DESIGN: Prospective, randomized, controlled trial. SETTING: University-affiliated private assisted-reproduction center. PATIENT(S): 25 healthy oocyte donors undergoing controlled ovarian stimulation. INTERVENTION(S): On day of final oocyte maturation, randomization to [1] GnRH-agonist triggering and luteal support with oral estradiol (2 mg/8 hours) and vaginal progesterone (200 mg/12 hours), [2] GnRH-a and a daily dose of 150 IU of recombinant LH from oocyte pickup, [3] GnRH-a and a single bolus of 60 µg of recombinant hCG on oocyte pickup, [4] GnRH-a and three doses of 20 µg of recombinant hCG separated by 48 hours, or [5] 250 µg of recombinant hCG for trigger and standard luteal support; with endometrial biopsy samples collected 7 days after triggering. MAIN OUTCOME MEASURE(S): Gene expression using the Endometrial Receptivity Array (ERA) and pathway and network analysis of study groups 1-4 compared with controls (group 5). RESULT(S): The 56 genes in group 1 (25 up-regulated and 31 down-regulated) exhibited altered expression compared with the 36 genes from group 2 (13 up-regulated and 23 down-regulated), 44 from group 3 (28 up-regulated and 16 down-regulated), and 30 (20 up-regulated and 10 down-regulated) from group 4. CONCLUSION(S): Differences were seen in endometrial gene expression related to the type of ovulation trigger and luteal support. However, gene expression after the GnRH-a trigger and modified luteal support adding LH/hCG activity more closely resembles the pattern seen in the hCG group. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2011-003250-34.

Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial.

BACKGROUND: Both oral contraceptive pills (OCPs) and estradiol (E2) valerate have been used to schedule gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles and, consequently, laboratory activities. However, there are no studies comparing treatment outcomes directly between these two pretreatment methods. This randomized controlled trial was aimed at finding differences in ongoing pregnancy rates between GnRH antagonist IVF cycles scheduled with OCPs or E2 valerate. METHODS: Between January and May 2012, one hundred consecutive patients (nonobese, regularly cycling women 18-38 years with normal day 3 hormone levels and <3 previous IVF/ICSI attempts) undergoing IVF with the GnRH antagonist protocol were randomized to either the OCP or E2 pretreatment arms, with no restrictions such as blocking or stratification. Authors involved in data collection and analysis were blinded to group assignment. Fifty patients received OCP (30 µg ethinyl E2/150 µg levonorgestrel) for 12-16 days from day 1 or 2, and stimulation was started 5 days after stopping OCP. Similarly, 50 patients received 4 mg/day oral E2 valerate from day 20 for 5-12 days, until the day before starting stimulation. RESULTS: Pretreatment with OCP (mean±SD, 14.5±1.7 days) was significantly longer than with E2 (7.8±1.9 days). Stimulation and embryological characteristics were similar. Ongoing pregnancy rates (46.0% vs. 44.0%; risk difference, -2.0% [95% CI -21.2% to 17.3%]), as well as implantation (43.5% vs. 47.4%), clinical pregnancy (50.0% vs. 48.0%), clinical miscarriage (7.1% vs. 7.7%), and live birth (42.0% vs. 40.0%) rates were comparable between groups. CONCLUSIONS: This is the first study to directly compare these two methods of cycle scheduling in GnRH antagonist cycles. Our results fail to show statistically significant differences in ongoing pregnancy rates between pretreatment with OCP and E2 for IVF with the GnRH antagonist protocol. Although the study is limited by its sample size, our results may contribute to a future meta-analysis. An interesting future direction would be to extend our study to women with decreased ovarian reserve, as these are the patients in whom an increase in oocyte yield-due to the hypothetical beneficial effect of steroid pretreatment on follicular synchronization-could more easily be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov http://NCT01501448.

In vitro fertilization outcome in women with unoperated bilateral endometriomas.

OBJECTIVE: To evaluate IVF outcome in women with unoperated bilateral endometriomas. DESIGN: Multicenter retrospective cohort study. SETTINGS: Two infertility units. PATIENT(S): Thirty-nine women with bilateral endometriomas matched with 78 unexposed control subjects. INTERVENTION(S): Analysis of data from patients who underwent in vitro fertilization (IVF)-intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Ovarian responsiveness and oocyte quality. RESULT(S): Responsiveness to ovarian hyperstimulation was significantly reduced in women with bilateral endometriomas. The total numbers of developing follicles in case and control subjects were 9.6 ± 3.3 and 14.1 ± 6.8, respectively. The numbers of oocytes retrieved were 7.1 ± 3.2 and 9.8 ± 5.5, respectively. Conversely, oocyte retrieval was not hampered by the presence of the ovarian endometriomas. The rates (interquartile range) of oocytes retrieved per total number of developing follicles in case and control subjects were 77% (57%-88%) and 71% (63%-79%), respectively. Moreover, the quality of the retrieved oocytes did not differ. The fertilization rates (IQR) were 67% (56%-100%) and 70% (57%-100%), respectively. The rates (IQR) of top quality embryos per oocyte used were 33% (25%-50%) and 33% (20%-43%), respectively. The implantation rates were 22% and 23%, respectively. The clinical pregnancy rate and the delivery rate also did not differ. CONCLUSION(S): Although the presence of bilateral endometriomas at the time of IVF affects responsiveness to hyperstimulation, the quality of the oocytes retrieved and the chances of pregnancy are not affected.

Pregnancy outcome in women with endometriomas achieving pregnancy through IVF.

BACKGROUND: There is a growing consensus that ovarian endometriomas should not be systematically removed in women selected for IVF. However, some recent evidence suggested that the presence of these cysts may negatively affect the course of pregnancy. METHODS: We set up a multicenter retrospective cohort study, including two infertility units. We analyzed data from patients achieving singleton clinical pregnancies through IVF comparing the pregnancy outcome between 78 pregnant women with endometriomas at the time of IVF and 156 patients who achieved pregnancy through IVF without endometriomas. RESULTS: The number of live births in women with and without endometriomas were 61 (78%) and 130 (83%), respectively (P = 0.39). The adjusted odds ratio (OR) of live birth in affected cases was 0.79 [95% confidence interval (CI): 0.38-1.68]. No differences were observed in late pregnancy and neonatal outcomes between the two groups. In particular, the rate of preterm birth and small-for-gestational age (SGA) was similar. The adjusted ORs were 0.47 (95% CI: 0.14-1.54) and 0.56 (95% CI: 0.12-2.56), respectively. CONCLUSIONS: Women with endometriomas achieving pregnancy through IVF do not seem to be exposed to a significant increased risk of obstetrical complications.

Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial.

OBJECTIVE: To compare cycle outcomes after scheduling with the standard long protocol versus the use of oral contraceptive pills (OCPs) in patients undergoing GnRH antagonist cycles. DESIGN: Prospective, randomized, controlled trial. SETTING: University-affiliated private assisted reproduction center. PATIENT(S): Regularly cycling women aged ≤38 years with fewer than three previous IVF attempts were enrolled. Previous low responses to controlled ovarian hyperstimulation, ovarian surgery, or polycystic ovary were exclusion criteria. INTERVENTION(S): One hundred fifteen patients received OCP (0.030 ethinyl E(2)/0.15 desogestrel) for 12-16 days, and controlled ovarian hyperstimulation was started on day 5 after OCP treatment; similarly, 113 patients received the long protocol from day 20-22 of the previous cycle. MAIN OUTCOME MEASURE(S): The primary outcome was ongoing pregnancy rate; secondary outcome variables were clinical pregnancy rate, live birth rate, implantation rate, and miscarriage rate. RESULT(S): Patients receiving the GnRH antagonist treatment showed a lower peak serum E(2) (1,334 vs. 1,823 pg/mL) but similar peak serum PE (0.58 vs. 0.65 ng/mL), lower duration of the stimulation (10.3 vs. 11.4 days) with similar FSH consumption (1,613 vs. 1,807 IU), and ovarian response (10.2 vs. 11.7 oocytes). No differences were observed in the fertilization rates (68.1% vs. 64.8%), total number of embryos obtained (5.9 vs. 6.2), mean number of embryos transferred (1.8 vs. 1.8), implantation rate (36% vs. 39%), miscarriage rate (8.9% vs. 17%), ongoing pregnancy rate (47.8% vs. 53.9%), or live birth rate (44.3% vs. 47%). CONCLUSION(S): Comparable outcomes can be obtained using OCP containing 0.030 ethinyl E(2)/0.15 desogestrel to schedule patients undergoing the antagonist protocol.