Phosphorodiamidate morpholino oligomers suppress mutant huntingtin expression and attenuate neurotoxicity.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Disease pathogenesis derives, at least in part, from the long polyglutamine tract encoded by mutant HTT. Therefore, considerable effort has been dedicated to the development of therapeutic strategies that significantly reduce the expression of the mutant HTT protein. Antisense oligonucleotides (ASOs) targeted to the CAG repeat region of HTT transcripts have been of particular interest due to their potential capacity to discriminate between normal and mutant HTT transcripts. Here, we focus on phosphorodiamidate morpholino oligomers (PMOs), ASOs that are especially stable, highly soluble and non-toxic. We designed three PMOs to selectively target expanded CAG repeat tracts (CTG22, CTG25 and CTG28), and two PMOs to selectively target sequences flanking the HTT CAG repeat (HTTex1a and HTTex1b). In HD patient-derived fibroblasts with expanded alleles containing 44, 77 or 109 CAG repeats, HTTex1a and HTTex1b were effective in suppressing the expression of mutant and non-mutant transcripts. CTGn PMOs also suppressed HTT expression, with the extent of suppression and the specificity for mutant transcripts dependent on the length of the targeted CAG repeat and on the CTG repeat length and concentration of the PMO. PMO CTG25 reduced HTT-induced cytotoxicity in vitro and suppressed mutant HTT expression in vivo in the N171-82Q transgenic mouse model. Finally, CTG28 reduced mutant HTT expression and improved the phenotype of Hdh(Q7/Q150) knock-in HD mice. These data demonstrate the potential of PMOs as an approach to suppressing the expression of mutant HTT.

Use of Electronic Health Records and Documentation Burden Among Nurses in Acute and Critical Care.

Nurses who provide the majority of hands-on care for hospitalized patients are disproportionately affected by the current state of electronic health records (EHRs), and little is known about their lived perception of EHR use. Using a mixed-methods research design, we conducted an in-depth analysis and synthesis of data from EHR usage log files, interviews, and surveys and assessed factors contributing to the nurse documentation burden in acute and critical at a large academic medical center. There remain substantial spaces where we can develop viable solutions for enhancing the usability of multi-component EHR systems.

Electronic health record system use and documentation burden of acute and critical care nurse clinicians: a mixed-methods study.

OBJECTIVES: Examine electronic health record (EHR) use and factors contributing to documentation burden in acute and critical care nurses. MATERIALS AND METHODS: A mixed-methods design was used guided by Unified Theory of Acceptance and Use of Technology. Key EHR components included, Flowsheets, Medication Administration Records (MAR), Care Plan, Notes, and Navigators. We first identified 5 units with the highest documentation burden in 1 university hospital through EHR log file analyses. Four nurses per unit were recruited and engaged in interviews and surveys designed to examine their perceptions of ease of use and usefulness of the 5 EHR components. A combination of inductive/deductive coding was used for qualitative data analysis. RESULTS: Nurses acknowledged the importance of documentation for patient care, yet perceived the required documentation as burdensome with levels varying across the 5 components. Factors contributing to burden included non-EHR issues (patient-to-nurse staffing ratios; patient acuity; suboptimal time management) and EHR usability issues related to design/features. Flowsheets, Care Plan, and Navigators were found to be below acceptable usability and contributed to more burden compared to MAR and Notes. The most troublesome EHR usability issues were data redundancy, poor workflow navigation, and cumbersome data entry based on unit type. DISCUSSION: Overall, we used quantitative and qualitative data to highlight challenges with current nursing documentation features in the EHR that contribute to documentation burden. Differences in perceived usability across the EHR documentation components were driven by multiple factors, such as non-alignment with workflows and amount of duplication of prior data entries. Nurses offered several recommendations for improving the EHR, including minimizing redundant or excessive data entry requirements, providing visual cues (eg, clear error messages, highlighting areas where missing or incorrect information are), and integrating decision support. CONCLUSION: Our study generated evidence for nurse EHR use and specific documentation usability issues contributing to burden. Findings can inform the development of solutions for enhancing multi-component EHR usability that accommodates the unique workflow of nurses. Documentation strategies designed to improve nurse working conditions should include non-EHR factors as they also contribute to documentation burden.

Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis.

OBJECTIVE: Huntington disease-like 2 (HDL2) is a progressive, late onset autosomal dominant neurodegenerative disorder, with remarkable similarities to Huntington disease (HD). HDL2 is caused by a CTG/CAG repeat expansion. In the CTG orientation, the repeat is located within the alternatively spliced exon 2A of junctophilin-3 (JPH3), potentially encoding polyleucine and polyalanine, whereas on the strand antisense to JPH3, the repeat is in frame to encode polyglutamine. The JPH3 protein product serves to stabilize junctional membrane complexes and regulate neuronal calcium flux. We have previously demonstrated the potential pathogenic properties of JPH3 transcripts containing expanded CUG repeats. The aim of this study was to test the possibility that loss of JPH3 expression or expanded amino acid tracts also contribute to HDL2 pathogenesis. METHODS: Transcripts from the HDL2 locus, and their protein products, were examined in HDL2, HD, and control frontal cortex. The effect of loss of Jph3 was examined in mice with partial or complete loss of Jph3. RESULTS: Bidirectional transcription occurs at the HDL2 locus, although expression of antisense transcripts with expanded CAG repeats is limited. Protein products with expanded amino acid tracts were not detected in HDL2 brain. However, JPH3 transcripts and full-length JPH3 protein are decreased in HDL2 brain, and Jph3 hemizygous and null mice exhibit abnormal motor function. INTERPRETATION: Our results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression.

Oral Care in Critically Ill Infants and the Potential Effect on Infant Health: An Integrative Review.

BACKGROUND: Critically ill infants admitted to the neonatal intensive care unit are at risk for ventilator-associated pneumonia and abnormal oral colonization. Adherence to evidence-based guidelines for oral care in critically ill adults is associated with improved short- and long-term health outcomes. However, oral care guidelines for critically ill infants admitted to the neonatal intensive care unit have not been established, possibly increasing their risk of ventilator-associated pneumonia and other health complications. OBJECTIVE: To describe and summarize the evidence regarding oral care for critically ill infants admitted to the neonatal intensive care unit and to identify gaps needing further investigation. METHODS: The MEDLINE (through PubMed) and CINAHL databases were searched for observational studies and randomized controlled trials investigating the effect of oral care on oral colonization, ventilator-associated pneumonia, and health outcomes of infants in the neonatal intensive care unit. RESULTS: This review of 5 studies yielded evidence that oral care may promote a more commensal oral and endotracheal tube aspirate microbiome. It may also reduce the risk of ventilator-associated pneumonia and length of stay in the neonatal intensive care unit. However, the paucity of research regarding oral care in this population and differences in oral care procedures, elements used, and timing greatly limit any possible conclusions. CONCLUSIONS: Oral care in critically ill infants may be especially important because of their suppressed immunity and physiological immaturity. Further appropriately powered studies that control for potential covariates, monitor for adverse events, and use recommended definitions of ventilator-associated pneumonia are needed to make clinical recommendations.

Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46).

OBJECTIVE: To evaluate the efficacy and safety of tigilanol tiglate (TT) for local intratumoral treatment of mast cell tumors (MCTs) in dogs. METHODS: A randomized controlled clinical study in 2 phases involving 123 dogs with cytologically diagnosed MCT. Phase 1 compared 81 TT-treated dogs with 42 control dogs; phase 2 allowed TT treatment of control dogs and retreatment of dogs that failed to achieve tumor resolution after TT treatment in phase 1. Tigilanol tiglate (1 mg/mL) was injected intratumorally with dose based on tumor volume. Concomitant medications were used to minimize potential for MCT degranulation. Modified response evaluation criteria in solid tumors were used to evaluate treatment response at 28 and 84 days. Adverse events and quality of life were also assessed. RESULTS: A single TT treatment resulted in 75% complete response (CR) (95% confidence interval [CI] = 61-86) by 28 days, with no recurrence in 93% (95% CI = 82-97) of dogs by 84 days. Eight TT-treated dogs that did not achieve CR in phase 1 achieved CR after retreatment, increasing the overall CR to 88% (95% CI = 77-93). Control dogs had 5% CR (95% CI = 1-17) at 28 days. Wound formation after tumor slough and wound size relative to tumor volume were strongly associated with efficacy. Adverse events typically were low grade, transient, and directly associated with TT's mode of action. CONCLUSIONS: Tigilanol tiglate is efficacious and well tolerated, providing a new option for the local treatment of MCTs in dogs.

Content barriers to pediatric uptake of electronic health records.

EHR systems provide significant opportunities to enhance pediatric care. Well-constructed clinical content, HIE, automated reminders and alerts, and reporting at practice, community, and public health levels are available in several current systems and products. However, the general focus on inpatient and adult populations in the design and marketing of these systems should be seen as a significant barrier to EHR adoption among pediatric primary care providers. Weight-based medication dosing, specialty growth charts, units of measurement and time, and measures to address minor consent and adolescent confidentiality are not universal in quality and availability to the pediatric practice. However, there are opportunities for pediatricians to provide input and to clearly state minimum requirements when dealing with vendors or when government agencies (eg, ONCHIT and AHRQ) seek comment on standards, practices, and expectations. This article uses cases and examples to describe some areas in which pediatricians should take an active role to advocate for pediatric-appropriate EHR tools. Virtually every child born and cared for in the United States today will have their data and information recorded in an EHR. The quality of the information and the HIT in which it is recorded can affect the care they get as children, and the information they carry into adulthood.