Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study

Autoimmune hemolytic anemia (AIHA) is a group of acquired autoimmune disorders characterized by red blood cell hemolysis. In a phase 2, open-label, multicenter study, adults with warm AIHA, cold agglutinin disease, or mixed-type AIHA were administered once-daily 1.0 or 2.5 mg parsaclisib (selective phosphoinositide 3-kinase δ inhibitor) orally for 12 weeks, followed by an extension period. Dose increases (for AIHA worsening) or decreases (for tolerability) were permitted. Primary efficacy endpoint was the proportion of patients with complete (≥12 g/dL hemoglobin [Hgb]) or partial (10–12 g/dL Hgb or ≥2 g/dL increase from baseline) response at any visit during weeks 6–12 not attributable to transfusion. Among 25 enrolled patients (median age, 63 y), 16 (64%) achieved a partial or complete Hgb response during weeks 6–12. Responses were observed by week 1 in 52.0% of patients with incremental improvements during weeks 6–12 and sustained responses during the extension period. Responses were higher among patients with warm AIHA versus other types (75.0% vs. 44.4%). Clinically meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue scores were observed at weeks 6 and 12. All patients had treatment-emergent adverse events (TEAEs), most commonly diarrhea (32.0%) and pyrexia (28.0%). Grade ≥3 TEAEs occurred in 13 patients (52.0%). TEAEs considered possibly related to treatment occurred in 11 patients (44.0%). No dose reductions were required; six patients (24%) discontinued for a TEAE. In summary, parsaclisib was well tolerated and resulted in substantial improvements in Hgb response at week 1, with durable responses through the extension period. Clinical trial registration: This trial was registered at ClinicalTrials.gov (NCT03538041)

Birth after TESE–ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation

DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12–40) with low FSH and LH levels at 2.1 IU/l (N: 1–5 IU/l) and 0.1 IU/l (N: 1–4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur®:150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen–thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE–ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH

Semen May Harbor HIV Despite Effective HAART: Another Piece in the Puzzle

The risk of male-to-female intravaginal HIV-1 transmission is estimated at about 1 event per 200–2000 coital acts. The aim of this study was to assess the residual risk of HIV presence in semen in patients under HAART therapy.The study took place in France from October 2001 to March 2009. 394 paired blood and semen samples were provided from 332 HIV-1 infected men. The Roche Cobas AMPLICOR Monitor HIV assay was used to quantify HIV-1 RNA in blood and in seminal plasma. Three percent of 394 HIV-1 infected men enrolled in an assisted reproductive technology program harbored detectable HIV-1 RNA in semen, although they had no other sexually transmitted disease and their blood viral load was undetectable for at least 6 months under antiretroviral treatment.These data suggest that undetectable plasma HIV RNA means a lower risk of viral transmission through seminal fluid on a population level, but not necessarily at the level of the individual

Impact of female age and male infertility on ovarian reserve markers to predict outcome of assisted reproduction technology cycles

<p>Abstract</p> <p>Background</p> <p>This study was designed to assess the capability of ovarian reserve markers, including baseline FSH levels, baseline anti-Müllerian hormone (AMH) levels, and antral follicle count (AFC), as predictors of live births during IVF cycles, especially for infertile couples with advanced maternal age and/or male factors.</p> <p>Methods</p> <p>A prospective cohort of 336 first IVF/ICSI cycles undergoing a long protocol with GnRH agonist was investigated. Patients with endocrine disorders or unilateral ovaries were excluded.</p> <p>Results</p> <p>Among the ovarian reserve tests, AMH and age had a greater area under the receiving operating characteristic curve than FSH in predicting live births. Furthermore, AMH and age were the sole predictive factors of live births for women greater than or equal to 35 years of age; while AMH was the major determinant of live births for infertile couples with absence of male factors by multivariate logistic regression analysis. However, all the studied ovarain reserve tests were not preditive of live births for women < 35 years of age or infertile couples with male factors.</p> <p>Conclusion</p> <p>The serum AMH levels were prognostic for pregnancy outcome for infertile couples with advanced female age or absence of male factors. The predictive capability of ovarian reserve tests is clearly influenced by the etiology of infertility.</p

Br J Haematol

International audienc

Mathematical methodology to obtain and compare different embryo scores

In Vitro Fertilization (IVF) units need to decrease multiple pregnancies without affecting their overall success rate. In this study we propose a mathematical model to evaluate an embryo’s potential ability to implant in the uterus. Embryos are graded by the embryologist based on the number of blastomeres, evenness of growth and degree of fragmentation. Therefore, the following variables were considered: number of blastomeres produced by division of the egg after fertilisation (blastomeres), symmetry and fragmentation of the embryo (grade). This model evaluates the embryos assigning them a score which represents their quality. The main result derived from this model is the estimation of the significant improvement in the implantation rate due to the increase in blastomere values and the decrease in grade factor values. But the increase from two–three to four produces more improvement in the implantation rate than two–three to five–six blastomeres. First, statistical models were used to study embryo traceability from transfer to implantation and to evaluate the effect of the quality of the embryos (embryo score) and women’s age on implantation potential. This score was obtained by making predictions from the fitted model which was used to rank embryos in terms of implantation potential. Then we totalled the scores of embryos that had been transferred to each woman for obtaining the Embryo Quality Index (EQI). In addition, we studied the effects of EQI and women’s age on pregnancy. Finally, statistical techniques such as Receiver Operating Characteristics (ROC) and bootstrap procedures were used to assess the accuracy of this model. This embryo score is a quick, efficient and accurate tool to optimise embryo selection for transfers on the second day after fertilisation. This tool is especially useful for transfers involving non-top embryos.This work was partially supported by a grant from the Generalitat Valenciana (grant no. GVPRE/2008/103). The research of AD and SC was partially supported by a grant from Ministerio de Asuntos Exteriores (grant no. A/023444/09) too. The authors are indebted to the anonymous referee whose comments and suggestions improved the paper considerably.Debón Aucejo, AM.; Molina Botella, MI.; Cabrera García, S.; Pellicer, A. (2013). Mathematical methodology to obtain and compare different embryo scores. Mathematical and Computer Modelling. 57(5-6):1380-1394. https://doi.org/10.1016/j.mcm.2012.11.027S13801394575-