The development of a co-researcher training with and for people with intellectual and developmental disabilities.

BACKGROUND: To build capacity among people with intellectual and developmental disabilities to become co-researchers they need the opportunity to learn about research. METHOD: An inclusive research team developed an online training to support people with intellectual and developmental disabilities to serve as co-researchers. Seven participants were recruited as pilot trainees. The co-researcher training consisted of two 1-h training sessions. Pre- and post-surveys and a focus group were conducted to examine participant experiences with the co-researcher training. RESULTS: The participants were actively engaged during the co-researcher training sessions and shared they had a positive experience with it. They expressed that people with intellectual and developmental disabilities add value to the research team because of their lived experiences. CONCLUSION: The co-researcher training can instill a baseline level of knowledge about research in people with intellectual and developmental disabilities, and can be adjusted for different types of research in different settings and organisations. LAY SUMMARY: People with intellectual and developmental disabilities would like to learn more about research. They would also like to learn more about how to do research. People with intellectual and developmental disabilities who work on research are called co-researchers. Two researchers and a co-researcher with disability wrote together about research for people with intellectual and developmental disabilities. Seven people with intellectual and developmental disabilities took part in the class. They answered questions about how they liked the class. They also gave their opinion about research. They learned about what research is and how to do research. The class can be changed so that it can be used by other organizations.

Enteral tube administration of oral chemotherapy drugs.

Objective: Patients receiving oral chemotherapies face treatment interruptions if they require placement of an enteral tube for nutrition, potentially leading to adverse outcomes in cancer treatment. Enteral tube medication administration can provide a suitable alternative. The purpose of this review is to compile available data that describe enteral tube administration of oral chemotherapy agents. Data sources: A systematic evaluation of all Food and Drug Administration-approved oral chemotherapy agents through 31 July 2019 was conducted. Information on crushing or opening of the tablet or capsule, enteral tube administration, and extemporaneous formulations was compiled from the prescribing information, tertiary resources, and primary literature. Drug manufacturers were contacted for additional information. Data summary: A total of 87 oral chemotherapy agents were evaluated. Of the 87 drugs, 33 agents (37.9%) had information regarding enteral tube administration with only four drugs with nasogastric or gastric tube administration instructions in their prescribing information. The strength of evidence varied from non-peer reviewed data to complete evaluations of efficacy and safety. The majority of chemotherapies (62%) had no available data on enteral tube administration. Conclusions: The results of this review suggest that there is limited data surrounding enteral tube administration of most oral chemotherapies, demonstrating the need for more studies to be conducted to provide more guidance to healthcare providers when administration via an enteral tube is needed in their patients.

Intravenous Push Administration of Antibiotics: Literature and Considerations.

Intravenous (IV) push administration can provide clinical and practical advantages over longer IV infusions in multiple clinical scenarios, including in the emergency department, in fluid-restricted patients, and when supplies of diluents are limited. In these settings, conversion to IV push administration may provide a solution. This review compiles available data on IV push administration of antibiotics in adults, including preparation, stability, and administration instructions. Prescribing information, multiple tertiary drug resources, and primary literature were consulted to compile relevant data. Several antibiotics are Food and Drug Administration-approved for IV push administration, including many beta-lactams. In addition, cefepime, ceftriaxone, ertapenem, gentamicin, and tobramycin have primary literature data to support IV push administration. While amikacin, ciprofloxacin, imipenem/cilastatin, and metronidazole have limited primary literature data on IV push administration, available data do not support that route. In addition, a discussion on practical considerations, such as IV push best practices and pharmacodynamic considerations, is provided.

Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22.

Myelin insulates axons in the peripheral nervous system to allow rapid propagation of action potentials, and proper myelination requires the precise regulation of genes encoding myelin proteins, including PMP22. The correct gene dosage of PMP22 is critical; a duplication of PMP22 is the most common cause of the peripheral neuropathy Charcot-Marie-Tooth Disease (CMT) (classified as type 1A), while a deletion of PMP22 leads to another peripheral neuropathy, hereditary neuropathy with liability to pressure palsies. Recently, duplications upstream of PMP22, but not containing the gene itself, were reported in patients with CMT1A like symptoms, suggesting that this region contains regulators of PMP22. Using chromatin immunoprecipitation analysis of two transcription factors known to upregulate PMP22-EGR2 and SOX10-we found several enhancers in this upstream region that contain open chromatin and direct reporter gene expression in tissue culture and in vivo in zebrafish. These studies provide a novel means to identify critical regulatory elements in genes that are required for myelination, and elucidate the functional significance of non-coding genomic rearrangements.

Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve.

Myelin is essential for the rapidity of saltatory nerve conduction, and also provides trophic support for axons to prevent axonal degeneration. Two critical determinants of myelination are SOX10 and EGR2/KROX20. SOX10 is required for specification of Schwann cells from neural crest, and is required at every stage of Schwann cell development. Egr2/Krox20 expression is activated by axonal signals in myelinating Schwann cells, and is required for cell cycle arrest and myelin formation. To elucidate the integrated function of these two transcription factors during peripheral nerve myelination, we performed in vivo ChIP-Seq analysis of myelinating peripheral nerve. Integration of these binding data with loss-of-function array data identified a range of genes regulated by these factors. In addition, although SOX10 itself regulates Egr2/Krox20 expression, leading to coordinate activation of several major myelin genes by the two factors, there is a large subset of genes that are activated independent of EGR2. Finally, the results identify a set of SOX10-dependent genes that are expressed in early Schwann cell development, but become subsequently repressed by EGR2/KROX20.

Regulation of the PMP22 gene through an intronic enhancer.

Successful myelination of the peripheral nervous system depends upon induction of major protein components of myelin, such as peripheral myelin protein 22 (PMP22). Myelin stability is also sensitive to levels of PMP22, as a 1.4 Mb duplication on human chromosome 17, resulting in three copies of PMP22, is the most common cause of the peripheral neuropathy Charcot-Marie-Tooth disease. The transcription factor Egr2/Krox20 is required for induction of high level expression of Pmp22 in Schwann cells but its activation elements have not yet been determined. Using chromatin immunoprecipitation analysis of the rat Pmp22 locus, we found a major peak of Egr2 binding within the large intron of the Pmp22 gene. Analysis of a 250 bp region within the largest intron showed that it is strongly activated by Egr2 expression in reporter assays. Moreover, this region contains conserved binding sites not only for Egr2 but also for Sox10, which is also required for Schwann cell development. Our analysis shows that Sox10 is required for optimal activity of the intronic site as well as PMP22 expression. Finally, mouse transgenic analysis revealed tissue-specific expression of this intronic sequence in peripheral nerve. Overall, these data show that Egr2 and Sox10 activity are directly involved in mediating the developmental induction of Pmp22 expression.

Locus-wide identification of Egr2/Krox20 regulatory targets in myelin genes.

Myelination of peripheral nerves by Schwann cells depends upon a gene regulatory network controlled by early growth response Egr2/Krox20, which is specifically required for Schwann cells to initiate and maintain myelination. To elucidate the mechanism by which Egr2 regulates gene expression during myelination, we have performed chromatin immunoprecipitation analysis on myelinating rat sciatic nerve in vivo. The resulting samples were applied to a tiled microarray consisting of a broad spectrum of genes that are activated or repressed in Egr2-deficient mice. The results show extensive binding within myelin-associated genes, as well as some genes that become repressed in myelinating Schwann cells. Many of the Egr2 peaks coincide with regions of open chromatin, which is a marker of enhancer regions. In addition, further analysis showed that there is substantial colocalization of Egr2 binding with Sox10, a transcription factor required for Schwann cell specification and other stages of Schwann cell development. Finally, we have found that Egr2 binds to promoters of several lipid biosynthetic genes, which is consistent with their dramatic up-regulation during the formation of lipid-rich myelin. Overall, this analysis provides a locus-wide profile of Egr2 binding patterns in major myelin-associated genes using myelinating peripheral nerve.

Bisphosphonate-induced osteonecrosis of the jaw.

OBJECTIVE: To review the risk of osteonecrosis of the jaw associated with bisphosphonates. DATA SOURCES: A MEDLINE search (1966-January 2007) and a search of International Pharmaceutical Abstracts (1970-January 2007) were conducted to identify relevant literature. Additional references were reviewed from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles related to bisphosphonate-induced osteonecrosis of the jaw were reviewed and summarized. Inclusion criteria required that articles be either case studies or case series that were reporting actual cases linking osteonecrosis of the jaw with bisphosphonate use. Articles that addressed sites of osteonecrosis not involving the jaw, teaching cases (fictitious patients), and a retrospective claims analysis paper were excluded from consideration. DATA SYNTHESIS: Bisphosphonates have recently been linked to osteonecrosis of the jaw, with the greatest incidence seen with the intravenous preparations zoledronic acid and pamidronate. Osteonecrosis refers to death of a part of the bone, resulting in decreased bone density. Although the majority of occurrences have been associated with the intravenous bisphosphonates, oral bisphosphonates have also been implicated. Other risk factors noted from reported cases include dental extraction or trauma to the jaw exposing part of the bone. It is difficult to determine an exact incidence of osteonecrosis of the jaw in the general population of patients prescribed bisphosphonates; however, the incidence in cancer patients is approximately 6-7%. CONCLUSIONS: Although discontinuation of intravenous bisphosphonates in cancer patients has been recommended, stopping oral bisphosphonates prior to dental work cannot be universally endorsed at this time, since it is unknown whether this is effective in reducing the risk of osteonecrosis of the jaw. Treatment of this condition is not well established; therefore, efforts should be directed toward prevention. Pharmacists may further counsel patients to practice good oral hygiene and regularly follow up with their dentist during therapy. Current evidence suggests limited surgical debridement with systemic and local antibiotics as treatments.

Prolonged anticoagulation after discontinuation of argatroban and warfarin therapy in an obese patient with heparin-induced thrombocytopenia.

A 32-year-old, morbidly obese African-American woman developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery. Three days later, after receiving heparin and warfarin, she developed heparin-induced thrombocytopenia type II (HIT-II). An argatroban 1.5-microg/kg/minute infusion was administered for approximately 2.5 days. The patient also received four doses of warfarin, totaling 37.5 mg. The argatroban infusion was discontinued early on hospital day 6, at which time the patient's international normalized ratio (INR) was 4.36 and activated partial thromboplastin time (aPTT) 85.9 seconds. Her INR and aPTT values continued to rise after the argatroban was discontinued and peaked 3 days later at 5.28 and 123.6 seconds, respectively. At this time her platelet count had improved from 139 x 10(3)/mm(3) to 543 x 10(3)/mm(3). No additional warfarin was administered before discharge. On hospital day 11, the patient was discharged home with an INR of 4.12 and an aPTT of 67.1 seconds. Her aPTT and INR values remained elevated for 19 days after receiving her last dose of warfarin and for 20 days after argatroban discontinuation. She experienced no bleeding complications from these supratherapeutic coagulation parameters. She resumed treatment with warfarin as an outpatient and completed a 6-month course of anticoagulation without further incident. Clinicians should be aware that coagulation parameters may remain elevated longer than expected after argatroban discontinuation in certain patients taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.

Developmental regulation of microRNA expression in Schwann cells.

Schwann cell differentiation and subsequent myelination of the peripheral nervous system require the action of several transcription factors, including Sox10, which is vital at multiple stages of development. The transition from immature to myelinating Schwann cell is also regulated posttranscriptionally and depends upon Dicer-mediated processing of microRNAs (miRNAs). Although specific miRNA targets have begun to be identified, the mechanisms establishing the dynamic regulation of miRNA expression have not been elucidated. We performed expression profiling studies and identified 225 miRNAs differentially expressed during peripheral myelination. A subset of 9 miRNAs is positively regulated by Sox10, including miR-338 which has been implicated in oligodendrocyte maturation. In vivo chromatin immunoprecipitation (ChIP) of sciatic nerve cells revealed a Sox10 binding site upstream of an alternate promoter within the Aatk gene, which hosts miR-338. Sox10 occupied this site in spinal cord ChIP experiments, suggesting a similar regulatory mechanism in oligodendrocytes. Cancer profiling studies have identified clusters of miRNAs that regulate proliferation, termed "oncomirs." In Schwann cells, the expression of many of these proproliferative miRNAs was reduced in the absence of Sox10. Finally, Schwann cells with reduced Sox10 and oncomir expression have an increase in the CDK inhibitor p21 and a concomitant reduction in cell proliferation.