Golimumab pharmacokinetics in ulcerative colitis: a literature review

Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM’s exposure–response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient’s improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM

Quelle est la place de l’automatisation du spermogramme-spermocytogramme dans un laboratoire de Biologie de la Reproduction: performance et validation de méthode de l’automate du SQA-Vision®

International audienc

Evaluation de l’intérêt des technologies de l’information et de la communication éducatives dans l’apprentissage par les étudiants en Médecine Dentaire

Résumé Objectif- Evaluer l’intérêt de l’utilisation des technologies de l’information et de la communication éducatives dans la formation des étudiants à la Faculté de Médecine Dentaire de Monastir. Matériels et méthodes- Il s’agissait d’une étude descriptive menée auprès des appre­nants en sixième année. Les données ont été collectées par un questionnaire, composé de quatre parties et mis en ligne en 2022 sur les pages Facebook de la promotion. Résultats-Sur les 253 apprenants, 208 ont répondu parmi lesquels 31 questionnaires ont été exclus. Cent soixante dix-sept réponses ont été retenues. Les participants étaient tout le temps ou presque connectés sur internet, mais 26,1% passaient moins de 30 minutes par jour dans le cadre de leurs études. Les principaux moteurs de recherche étaient Google (93,8%) et Wikipédia (48%) ; Facebook était le principal réseau social (91%) utilisé lors de l’apprentissage. La moitié des apprenants connaissaient les plate­formes e-learning bien que 72% d’entre eux n’aient pas eu d’expériences antérieures. Ils préféraient les cours en lignes aux cours magistraux (68,4%). 90% des apprenants mécon­naissaient les MOOCs (Massive Open Online Courses). Conclusion-Cette étude a permis de démontrer l’intérêt des technologies de l’informa­tion et de la communication dans le cursus universitaire.   Abstract Objective- Evaluate the interest of the use of Information and Educational Technologies in the initial training of dental medicine students at the faculty of dental medicine of Monastir. Methods- This was a descriptive study conducted at the FDMM in 2022. Data was collected through a questionnaire. It was composed of four parts and posted beteween May 1st and June 30th, 2022. Results- Of the 253 interns, 208 responded and 177 responsers were retained. The survey participants were connected to the internet almost all the time but 26.1% spent less than 30 minutes a day on their studies, mainly to access online courses or conduct literature research. The principle search engine were Google (93.8%) and Wikipedia (48%); Facebook was the principal social media (91%) used during learning. Almost half of the internal trainees were familiar with e-learning platforms although 72% of them had no previous experience. They preferred online courses to lectures (68.4 %) in order to consult the course at any time. More than 90% of respondents were unaware of MOOCs (Massive Open Online Courses). Conclusion- This study demonstrated the importance of the introduction of the Information and Educational Technologies in the university curriculum

Multiple Arterial Thrombosis in a 78-Year-Old Patient: Catastrophic Thrombotic Syndrome in COVID-19

International audienceWe describe a patient with coronavirus disease 2019 (COVID-19) and multiple concomitant thromboses occurring on the 9th day of hospital stay. Thromboses were found in distinct zones of the aorta, as well as in the renal, humeral, and pulmonary arteries. The extensive biological workup performed following this catastrophic thrombotic syndrome found no evidence for underlying prothrombotic disease. In light of current evidence regarding endothelium abnormalities related to COVID-19, this extreme case of catastrophic thrombotic syndrome suggests that COVID-19 can induce severe arterial thrombosis following intense endothelial activation

Factor IX assays in treated hemophilia B patients

International audienceReplacement therapy with plasma-derived or recombinant FIX (pdFIX or rFIX) concentrates is the standard of treatment in patients with hemophilia B. The method predominantly used for measuring factor IX (FIX:C) levels is the one-stage clotting assay (OSA) but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FIX recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network), presents a review of the literature and proposals for the monitoring of FIX:C levels in treated hemophilia B patients. The use of OSA calibrated with a plasma reference tested against the current FIX WHO International Standard is recommended for the monitoring of patients treated with pdFIX or rFIX. Chromogenic substrate assays (CSA) are adequate for the monitoring of patients treated with Rixubis®, but data available for Benefix® are currently too limited. For extended half-life rFIX (EHL-rFIX), large discordances in the FIX:C levels measured were evidenced, depending on the method and reagents used. Great attention is therefore required for measuring FIX:C levels by OSA in patients substituted by EHL-rFIX. Commercial kits for CSA are not equivalent, and although potentially useful, they are not validated for all EHL-rFIX. Most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients

Factor VIII assays in treated hemophilia A patients

International audienceReplacement therapy with plasma-derived or recombinant FVIII (pdFVIII or rFVIII) concentrates is the standard of treatment in patients with hemophilia A. The reference method used for measuring factor VIII (FVIII:C) levels in patients treated by FVIII concentrates is the chromogenic substrate assay (CSA). However, the one-stage clotting assay (OSA) is predominantly used in current clinical practice, but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FVIII recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network) presents a review of the literature and proposals for the monitoring of FVIII:C levels in treated hemophilia A patients. The use of CSA calibrated with a plasma reference tested against the current FVIII WHO (World Health Organization) International Standard is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. OSA are adequate for the monitoring of patients treated with pdFVIII or with most of rFVIII concentrates. However, preliminary comparison with CSA is mandatory before measuring FVIII:C by OSA in patients treated by Refacto AF®. For rFVIII-EHL, OSA are only acceptable for Elocta®. Great caution is therefore required when measuring FVIII:C levels by OSA in patients substituted by other EHL-rFVIII. Indeed, most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients

Exome sequencing as a first-tier test for copy number variant detection: retrospective evaluation and prospective screening in 2418 cases

International audienceBackground Despite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES. Methods This study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed. Results On the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure. Conclusion Combining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered

Risk estimation of uniparental disomy of chromosome 14 or 15 in a fetus with a parent carrying a non‐homologous Robertsonian translocation. Should we still perform prenatal diagnosis?

International audienceObjective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. CC BY 4.0© 2022 The AuthorsCorrespondence: [email protected] (A.E.X.B.), [email protected] (K.P.)We thank all families that participated in this study. This project has received funding from the European Research Council under the European External Action Service Horizon 2020 Research and Innovation Program (grant agreement no. 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. H.T. was supported by the European External Action Service Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 608473.</p