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The analytical procedure life cycle (APLC) provides a holistic framework to ensure analytical procedure fitness for purpose. USP’s general chapter <1220> considers the validation activities that take place across the entire analytical procedure lifecycle and provides a three-stage framework for its implementation. Performing ongoing analytical procedure performance verification (OPPV) (stage 3) ensures that the procedure remains in a state of control across its lifecycle of use post validation (qualification) and involves an ongoing program to collect and analyze data that relate to the performance of the procedure. Knowledge generated during stages 1 (procedure design) and 2 (procedure performance qualification) is used as the basis for the design of the routine monitoring plan to support performance verification (stage 3). The extent of the routine monitoring required should be defined based on risk assessment, considering the complexity of the procedure, its intended purpose, and knowledge about process/procedure variability. The analytical target profile (ATP) can be used to provide or guide the establishment of acceptance criteria used to verify the procedure performance during routine use (e.g., through a system/sample suitability test (SST) or verification criteria applicable to procedure changes or transfers). An ATP however is not essentially required to perform OPPV, and a procedure performance monitoring program can be implemented even if the full APLC framework has not been applied. In these situations, verification criteria can be derived from existing validation or system suitability criteria. Elements of the life cycle approach can also be applied retrospectively if deemed useful.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

The creation of the National Freight Network as part of the Moving Ahead for Progress in the 21st Century Act (MAP-21) requires states to designate critical rural freight corridors (CRFCs). The MAP-21 act lists the criteria for designating CRFCs but does not specify the method. This paper proposes mileage-based, segment-based, and weighted average approaches to determine whether a corridor meets one of the CRFC criteria: a rural principal arterial that has a minimum 25% of truck traffic. The three approaches are explained, assessed, and mapped for the reader to compare the resulting networks. The paper then uses policy analysis techniques to assess the advantages and disadvantages of each approach. The analysis compares the approaches on the basis of network connectivity of the resulting CRFCs, the mileage of non-Interstate rural principal arterials, and robustness. Results indicate that state departments of transportation should use the mileage-based approach for computing truck traffic percentages when determining whether a corridor meets the minimum threshold of 25% truck traffic. The mileage approach combines the highest network connectivity, designates the highest number of non-Interstate rural principal arterial miles, and is a robust technique that controls for variable segment lengths.

The creation of the National Freight Network as part of the Moving Ahead for Progress in the 21st Century Act (MAP-21) requires states to designate critical rural freight corridors (CRFCs). The MAP-21 act lists the criteria for designating CRFCs but does not specify the method. This paper proposes mileage-based, segment-based, and weighted average approaches to determine whether a corridor meets one of the CRFC criteria: a rural principal arterial that has a minimum 25% of truck traffic. The three approaches are explained, assessed, and mapped for the reader to compare the resulting networks. The paper then uses policy analysis techniques to assess the advantages and disadvantages of each approach. The analysis compares the approaches on the basis of network connectivity of the resulting CRFCs, the mileage of non-Interstate rural principal arterials, and robustness. Results indicate that state departments of transportation should use the mileage-based approach for computing truck traffic percentages when determining whether a corridor meets the minimum threshold of 25% truck traffic. The mileage approach combines the highest network connectivity, designates the highest number of non-Interstate rural principal arterial miles, and is a robust technique that controls for variable segment lengths.

Copy‐number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in ∼10–20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole‐genome exon‐targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non‐polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole‐genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies. © 2012 Wiley Periodicals, Inc.

The “peroxidase” activity of the copper-zinc superoxide dismutase is a poorly sustained activity because of the competing inactivation of the enzyme. New evidence suggests that the bound oxidant may be partitioning between oxidizing the enzyme or oxidizing small anions. At constant peroxide, nitrite and azide only partially protect the enzyme (50%) against loss of copper(I) and inactivation up to one anion per copper. Beyond that level, there is no further protection. Bicarbonate ion also protects, but larger amounts are required. These data suggest that there is significant oxidation of the enzyme even in the presence of the small anions and therefore the formation of the bound oxidant cannot be sustained in a true catalytic process.