Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: A pharmacogenetic study

Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH 64 8 IU/l and DFI >15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G>T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G>T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35

Neonatal Assessment Visual European Grid (NAVEG): Unveiling neurological risk

Highlights • Evaluation of visual function in newborns is of utmost importance. • A tailored non invasive evaluation of visual function in newborns is proposed (NAVEG). • NAVEG’s discriminating capability as a marker of brain lesions is evaluated. • NAVEG provides information on the early functioning of the visual system. • Visual function assessment could integrate ophthalmologic and neurologic evaluatio

Sociedad, Estado y Derecho. Homenaje a Álvaro Tafur Galvis. Tomo III: Derechos y garantías. Entre lo público y lo privado: la zona de frontera

El Colegio Mayor de Nuestra Señora del Rosario ha querido exaltar la vida y obra del Señor Colegial, Catedrático, Profesor Titular y Honorario, Decano y Rector magnífico, Álvaro Tafur Galvis. En homenaje al gran intelectual, jurista, magistrado y maestro, que ha honrado a cabalidad la definición dada por Fray Cristóbal de Torres para este Colegio Mayor, como varón insigne ilustrador de la República, que con sus grandes letras y destinos que ha merecido con ellas, ha sido en todo dechado del culto divino y de las buenas costumbres conforme al estado de su profesión, las directivas de la Institución lideradas por su actual Rector, Hans Peter Knudsen y su Vicerrector, Alejandro Venegas Franco, en asocio con sus discípulos, colegas, compañeros y amigos, han preparado en su honor la obra que aquí se presenta bajo el título Sociedad, Estado y Derecho. Pocas veces ha visto la Academia colombiana tan entusiasta y calificada respuesta a una iniciativa de esta naturaleza. La persona y la obra del homenajeado lo explican sin duda. Él ha sido un verdadero modelo admirado y respetado por todos. Y es él también quien nos recuerda con cada una de sus actuaciones cómo la humildad, la discreción y el decoro son los hilos indelebles con los que se encadena la gloria. Los autoresThe Colegio Mayor de Nuestra Señora del Rosario has wanted to exalt the life and work of the Collegiate, Professor, Titular and Honorary Professor, Dean and Grand Rector, Álvaro Tafur Galvis. In homage to the great intellectual, jurist, magistrate and teacher, who has Fully honored the definition given by Fray Cristóbal de Torres for this Colegio Mayor, as an illustrious male illustrator of the Republic, who with his great letters and destinies that he has deserved with them, has been a paragon of divine worship and good customs. According to the state of his profession, the directives of the Institution led by its current Rector, Hans Peter Knudsen and his Vice-Rector, Alejandro Venegas Franco, in association with his disciples, colleagues, colleagues and friends, have prepared in his honor the work that here It is presented under the title Society, State and Law. Rarely has the Colombian Academy seen such an enthusiastic and qualified response to an initiative of this nature. The person and the work of the honoree explain it without a doubt. He has been a true role model admired and respected by all. And he is also the one who reminds us with each of his performances how humility, discretion and decorum are the indelible threads with which glory is chained. The autor

A community effort to discover small molecule SARS-CoV-2 inhibitors

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of a community effort, the “Billion molecules against Covid-19 challenge”, to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 potentially active molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (Nsp12 domain), and (alpha) spike protein S. Overall, 27 potential inhibitors were experimentally confirmed by binding-, cleavage-, and/or viral suppression assays and are presented here. All results are freely available and can be taken further downstream without IP restrictions. Overall, we show the effectiveness of computational techniques, community efforts, and communication across research fields (i.e., protein expression and crystallography, in silico modeling, synthesis and biological assays) to accelerate the early phases of drug discovery