A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

Objective - This project sought to identify students’ strengths and weaknesses in locating, retrieving, and citing information in order to deliver information skills workshops more effectively. Methods - Bibliographies submitted from first-year engineering and second- and fourth-year chemical engineering students’ project reports were analysed for the number of items cited, the variety of items cited, and the correct use of citation style. The topics of the project reports were also reviewed to see the relationships between the topics and the items cited. Results - The results show that upper level students cited more items in total than did lower level students in their bibliographies. Second- and fourth-year engineering students cited more books and journal articles than first-year students cited. Web sites were used extensively by all three groups of students, and for some first-year students these were the most frequently used sources. Students from all three groups had difficulties with citation style. Conclusion - There was a clear difference in citation frequency between upper and lower level engineering students. Different strategies of information skills instruction are needed for different levels of students. Librarians and department faculty members need to include good quality Internet resources in their teaching and to change the emphasis from finding information to finding, interpreting, and citing accurately.

We evaluated the prenatal diagnosis utilization patterns of advanced maternal age (AMA) patients who underwent serum screening to assess how screening results correlated with their decisions regarding amniocentesis. A 6-year review (1994-1999) of laboratory records identified 2,456 AMA patients who underwent multiple-marker serum screening. The relationship between screening results and patients' decisions on whether or not to undergo amniocentesis was assessed. Among the 841 AMA patients with positive screens, more than half (52%) declined amniocentesis. Of the 1,615 patients with negative serum screening results, 208 (13%) opted for amniocentesis. We concluded that decisions by AMA patients regarding amniocentesis may not always correlate clinically with maternal serum screening results. Possible explanations, including how the state of informed consent may or may not contribute to these decisions, are discussed. It is suggested that understanding the reasons for these decisions may identify opportunities for improving service delivery to all pregnant patients considering prenatal testing. Use of a questionnaire is proposed as one mechanism for gaining a clearer understanding of the possible factors contributing to AMA patient decisions.

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Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically‐based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid ( CSF ) samples from 22 infants ( postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration‐time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF , respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.