Failure Mode, Effect, and Criticality Analysis of the Parenteral Nutrition Process in a Mother-Child Hospital: The AMELIORE Study.

BACKGROUND: The parenteral nutrition (PN) process is complex and involves multiple steps and substeps, especially in pediatrics and neonatology, given the particular needs of these patients. The objective of this study was to perform a critical analysis of the PN process at the Centre Hospitalier Universitaire Sainte-Justine to determine which potential pitfalls are related to this process and which should be prioritized when implementing corrective measures. METHODS: This is a Failure Mode, Effect, and Criticality Analysis (FMECA) study. A multidisciplinary team assessed each step of the PN process and identified associated failure modes. Adapted rating scales were used to determine severity, frequency, and detectability of the failure modes. Ratings were established through multidisplinary consensus, and a criticality index (CI) was calculated for each failure mode. RESULTS: A total of 265 failure modes were identified in the 5 major steps of the PN process. The failure mode with the highest CI was the inscription of an inaccurate weight at prescription, with a CI of 800. The step with the highest cumulative CIs was administration to patients, with a CI sum of 7691. Various recommendations aimed at minimizing the risks associated with the PN process were made following this FMECA. Additional interventions are expected to emanate from this project because data will be presented throughout the departments involved. CONCLUSION: This study is a successful example for other hospitals interested in carrying out the same kind of healthcare improvement initiative.

Analyse des modes de défaillance, de leurs effets et de leur criticité dans le circuit du médicament: revue de littérature.

BACKGROUND: Failure mode, effects, and criticality analysis (FMECA) is a systematic and proactive risk analysis method to determine major failures in complex processes. OBJECTIVE: To identify all articles involving the use of failure mode and effects analysis (FMEA), FMECA, or FMECA in health care within the medication use system. DATA SOURCES STUDY SELECTION AND DATA EXTRACTION: The MEDLINE database was searched, for the period January 1990 to January 2017. The search included studies using the FMECA method, in part or in full, and dealing with one or several components of the medication use system. The reference lists of articles identified in the initial search were checked manually for additional pertinent references. DATA SYNTHESIS: The researchers identified 171 articles, and retained 39 for analysis: 32 describing use of the FMEA or FMECA approach and 7 describing use of the FMECA in health care approach. They identified between 4 to 378 failure modes, according to the published studies. Among the 39 articles, 10 reported a pre- and post-implementation analysis of corrective measures. In 4 of those 10 articles, the analysis was conducted on a theoretical basis, that is, before the corrective measures were actually implemented. Using the articles retained for analysis, a summary table was developed with the following elements: publication year, main author, country, primary objective, secondary objectives, descriptions of both method and results, and comments. The summary table gave the opportunity to comment on the use of the FMECA-type analysis within the medication use system. CONCLUSIONS: This literature review included 39 published articles using an FMEA, FMECA, or FMECA in health care approach within the medication use system. Most studies used either the FMEA or the FMECA approach, whereas the FMECA in health care approach was used only rarely. Only a minority of studies assessed the effects of corrective measures that were implemented. This overall approach allows for mapping of a care process, determination of failure modes, and prioritization of corrective measures. Its use for the assessment of the medication use system should be promoted.

Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities.

Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication and repair. Here, we present the results of a large-scale proteome analysis that has been undertaken to determine protein partners of different polymorphic WRN proteins found with relatively high prevalence in the human population. We expressed different fluorescently tagged-WRN (eYFP-WRN) variants in human 293 embryonic kidney cells (HEK293) and used a combination of affinity-purification and mass spectrometry to identify different compositions of WRN-associated protein complexes. We found that a WRN variant containing a phenylalanine residue at position 1074 and an arginine at position 1367 (eYFP-WRN(F-R)) possesses more affinity for DNA-PKc, KU86, KU70, and PARP1 than a variant containing a leucine at position 1074 and a cysteine at position 1367 (eYFP-WRN(L-C)). Such results were confirmed in a WRN-deficient background using WS fibroblasts. Interestingly, the exonuclase activity of WRN recovered from immunoprecipitated eYFP-WRN(L-C) variant was lower than the eYFP-WRN(F-R) in WS cells. Finally, HEK293 cells and WS fibroblasts overexpressing the eYFP-WRN(F-R) variant were more resistant to the benzene metabolite hydroquinone than cells expressing the eYFP-WRN(L-C) variant. These results indicate that the protein-protein interaction landscape of WRN is subject to modulation by polymorphic amino acids, a characteristic associated with distinctive cell survival outcome.

The Werner syndrome helicase protein is required for cell proliferation, immortalization, and tumorigenesis in Scaffold attachment factor B1 deficient mice.

Werner syndrome (WS) is a rare disorder characterized by the premature onset of several pathologies associated with aging. The gene responsible for WS codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. We recently identified the Scaffold attachment factor B1 (SAFB1) as a potential interactants in human cells. SAFB1 is a multifunctional protein that binds both nucleic acids and is involved in the attachment of chromatin to the nuclear matrix, transcription, and stress response. Mice lacking SAFB1 exhibit developmental abnormalities in their lungs, high incidence of perinatal lethality, and adults develop different types of tumors. Mouse embryonic fibroblasts from Safb1-null animals are immortalized in culture. In this study, mice with a mutation in the helicase domain of the Wrn gene were crossed to Safb1-null mice. Double homozygous mutant mice exhibited increased apoptosis, a lower cell proliferation rate in their lungs and a higher incidence of perinatal death compared to Safb1-null mice. Few double homozygous mutants survived weaning and died before the age of six months. Finally, mouse embryonic fibroblasts lacking a functional Wrn helicase inhibited the immortalization of Safb1-null cells. These results indicate that an intact Wrn protein is required for immortalization and tumorigenesis in Safb1-null mice.

Proteome-wide identification of WRN-interacting proteins in untreated and nuclease-treated samples.

Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, telomere maintenance, and transcription. Here, we present the results of a large-scale proteome analysis to determine protein partners of WRN. We expressed fluorescent tagged-WRN (eYFP-WRN) in human 293 embryonic kidney cells and detected interacting proteins by co-immunoprecipitation from cell extract. We identified by mass spectrometry 220 nuclear proteins that complexed with WRN. This number was reduced to 40 when broad-spectrum nucleases were added to the lysate. We consider these 40 proteins as directly interacting with WRN. Some of these proteins have previously been shown to interact with WRN, whereas most are new partners. Among the top 15 hits, we find the new interactors TMPO, HNRNPU, RPS3, RALY, RPS9 DDX21, and HNRNPM. These proteins are likely important components in understanding the function of WRN in preventing premature aging and deserve further investigation. We have confirmed endogenous WRN interaction with endogenous RPS3, a ribosomal protein with endonuclease activities involved in oxidative DNA damage recognition. Our results suggest that the use of nucleases during cell lysis severely restricts interacting protein partners and thus enhances specificity.

Perinatal exposure to low-dose BDE-47, an emergent environmental contaminant, causes hyperactivity in rat offspring.

BACKGROUND: Polybrominated diphenyl ethers (PBDE) are a group of environmental contaminants increasing in North America. Few data are available on neurobehavioral effects at low-dose exposure. OBJECTIVES: Our goal in the present study was to evaluate whether low-dose BDE-47, which is the most abundant PBDE in human samples, affects the neurobehavioral development of rats. METHODS: Dams were exposed to vehicle or low-dose BDE-47 (0.002, 0.02 and 0.2 mg/kg body weight) each 5 days from gestational day 15 to postnatal day (PND) 20 by intravenous injections. Spontaneous locomotor activity of pups was assessed using the open field test on PND 15, 20 and 25. Sensorimotor coordination was assessed using a RotaRod on PND 30. RESULTS: Exposure to BDE-47 increased locomotor activity of pups. Developmental landmarks and sensorimotor coordination were not influenced by exposure to BDE-47. BDE-47 content in adipose tissue of exposed rats was similar to that known for human populations. CONCLUSION: These results indicate neurodevelopmental disruption induced in rats by BDE-47 at levels found in the human population.