Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Impact of a Paper-Based Dynamic Insulin Infusion Protocol on Glycemic Variability, Time in Target, and Hypoglycemic Risk: A Stepped Wedge Trial in Medical Intensive Care Unit Patients.

BACKGROUND: Stress-induced hyperglycemia is a common feature of intensive care unit (ICU) patients. Besides mean blood glucose (BG) level, glucose variability and hypoglycemia have been highlighted as independent predictors of ICU and hospital mortality. Recent ICU recommendations suggest using insulin infusion protocols that can minimize glucose variability and hypoglycemic risk. Our aim was to assess the efficacy, safety, and acceptance by nurses of a paper-based simple dynamic insulin protocol compared with those by nurses of a paper-based static protocol. METHODS: This is a 1 year stepped-wedge study that compared a static sliding scale protocol (SP - static protocol) with a validated dynamic paper-based intravenous insulin infusion protocol (DP - dynamic protocol) in medical ICU patients of a single university hospital. Patients with stress-induced hyperglycemia >9.9 mmol/L and ≥48 h intravenous insulin infusion were included in this trial. RESULTS: One hundred thirty-one patients were included and received continuous intravenous insulin infusion managed with SP (n = 65) or DP (n = 66). Glucose variability was significantly higher in the SP group than in the DP group (mean average glucose excursion index: 0.90 [0.00-1.91] mmol/L vs. 0.00 [0.00-0.90] mmol/L, respectively; P = 0.001). The percentage of time spent in the target range (7.7-9.9 mmol/L) was lower in the SP group than in the DP group (42.5% [28.8%-54.2%] vs. 47.5% [36.6%-57.1%]; P = 0.037). Low BG (<4.4 mmol/L) and hypoglycemia (<3.3 mmol/L) were more frequent in the SP group than in the DP group. According to a satisfaction survey, this protocol was well accepted by nurses. CONCLUSIONS: Our simple and feasible paper-based, dynamic insulin infusion protocol reduced glycemic variability and hypoglycemic risk in a medical ICU.