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A social media intervention to improve hypoglycemia management at a multicenter hospital: a quality improvement pilot for clinical nurses.
BACKGROUND: Hypoglycemia poses significant risk to inpatients. Nursing management of hypoglycemia is a challenge, despite established best practice guidelines. Social media is an effective tool for sharing information and could overcome barriers to clinical education at a multicenter hospital. AIMS: The purpose of this quality improvement intervention was to create and disseminate social media posts about best practices in hypoglycemia management. DESIGN: An unmatched pre-and post-survey assessed nursing knowledge of hypoglycemia management. METHODS: Social media posts were created to visually outline the steps for hypoglycemia management over 2 weeks, across a nursing social media platform. We assessed the reach of the posts via Facebook and a survey. RESULTS: The posts reached 2962 users during the first week, and 1491 users the second week. CONCLUSIONS: A social media intervention can have a substantial reach and distribute information across a multicenter hospital. Additional study is needed to determine what factors could support an increase in nursing knowledge through a social media campaign.
Wound Healing In Surgery for Trauma (WHIST): statistical analysis plan for a randomised controlled trial comparing standard wound management with negative pressure wound therapy.
BACKGROUND: In the context of major trauma, the rate of wound infection in surgical incisions created during fracture fixation amongst patients with closed high-energy injuries is high. One of the factors which may reduce the risk of surgical site infection is the type of dressing applied over the closed incision. The WHIST trial evaluates the effects of negative-pressure wound therapy (NPWT) compared with standard dressings. METHODS/DESIGN: The WHIST trial is a multicentre, parallel group, randomised controlled trial. The primary outcome is the rate of deep surgical site infection at 30 days after major trauma. Secondary outcomes are measured at 3 and 6 months post-randomisation and include the Disability Rating Index, the EuroQoL EQ-5D-5 L, the Doleur Neuropathique Questionnaire, a patient-reported scar assessment, and record of complications. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full WHIST protocol has already been published. DISCUSSION: This paper provides details of the planned statistical analyses for this trial and will reduce the risks of outcome reporting bias and data driven results. TRIAL REGISTRATION: International Standard Randomised Controlled Trials database, ISRCTN12702354 . Registered on 9 December 2015.
COmmunity-based Rehabilitation after Knee Arthroplasty (CORKA): statistical analysis plan for a randomised controlled trial.
BACKGROUND: About 15% of patients fail to achieve a satisfactory clinical outcome following knee replacement, which may indicate the existing model of rehabilitation after surgery is possibly not the most efficacious. The COmmunity-based Rehabilitation after Knee Arthroplasty (CORKA) trial evaluates the effects of a new multi-component community-based rehabilitation programme following knee replacement compared with usual care. METHODS/DESIGN: The CORKA trial is a multi-centre, single-blind, two-arm randomised controlled trial. The primary outcome is the Late Life Function and Disability Instrument (LLFDI) overall function score measured at 12 months post-randomisation which will be analysed using a linear mixed effects model. Secondary outcomes are measured at 6 and 12 months post-randomisation and include the LLFDI frequency and limitation total dimension scores, the Oxford Knee Score, the Knee injury and Osteoarthritis Outcome Score quality of life subscale, the Physical Activity Scale for the Elderly, the EuroQol EQ-5D-5L, and several measurements of physical function. Full details of the planned analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. This is an update to the CORKA protocol which has already been published in this journal. DISCUSSION: This paper provides details of the planned statistical analyses for this trial and will reduce the risks of outcome reporting bias and data-driven results. TRIAL REGISTRATION: ISRCTN registry, 13517704 . Registered on 12 February 2015. FUNDING/SPONSOR: The trial is funded by the National Institute for Health Research Health Technology Assessment programme under its commissioned research programme (HTA 12/196/08). The trial sponsor is the University of Oxford.
Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine.
BACKGROUND: Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. METHODS: SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0-10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. DISCUSSION: The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. TRIAL REGISTRATION: ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017.
A scoping review of the problems and solutions associated with contamination in trials of complex interventions in mental health.
BACKGROUND: In a randomised controlled trial, contamination is defined as the receipt of active intervention amongst participants in the control arm. This review assessed the processes leading to contamination, its typical quantity, methods used to mitigate it, and impact of use of cluster randomisation to prevent it on study findings in trials of complex interventions in mental health. METHODS: This is a scoping review of trial design approaches and methods of study conduct to address contamination. Studies included were randomised controlled trials of complex interventions in mental health that described the process leading to, amount of, or solution used to counter contamination. The Medline, Embase, and PsycInfo databases were searched for trials published between 2000 and 2015. Risk of bias was assessed using the Jadad score and domains recommended by Cochrane plus some relevant to cluster randomised trials. RESULTS: Two hundred and thirty-four articles were included in the review. The main processes that led to contamination were health professionals delivering both active and comparator treatments and communication among clinicians and participants from the different trial arms. Twenty-three trials (10%) measured binary treatment receipt in the control arm with median 13% of participants found to be contaminated (IQR 5-33%). The most common design approach for dealing with contamination was the use of cluster randomisation (n = 93). In addition, many researchers used simple trial conduct methods to minimise contamination due to suspected contamination processes, such as organising for each clinician to provide only one treatment and separating trial arms spatially or temporally. There was little evidence for a relationship between cluster randomisation to avoid contamination and size of treatment effect estimate. CONCLUSION: There was some evidence of modest levels of treatment contamination with a large range, although a minority of studies reported the amount of contamination. A limitation was that many trials described the problem in little detail. Overall there is a need for greater measurement and reporting of treatment receipt in the control arm of trials. Researchers should be aware of trial conduct methods that can be used to minimise contamination without resorting to cluster randomisation.
Immunophenotypic expression of UCP1 in hibernoma and other adipose/non adipose soft tissue tumours.
Background: Uncoupling protein 1 (UCP1) is a mitochondral protein transporter that uncouples electron transport from ATP production. UCP1 is highly expressed in brown adipose tissue (BAT), including hibernomas, but its expression in other adipose tumours is uncertain. UCP1 has also been found in other tissues (e.g. smooth muscle) but whether it is expressed in non-adipose benign and malignant soft tissue tumours is unknown. Methods: Immunohistochemical staining of normal (axillary) BAT and subcutaneous/abdominal white adipose tissue (WAT) as well as a wide range of benign and malignant primary soft tissue tumours (n = 171) was performed using a rabbit polyclonal antibody to UCP1. BAT and hibernomas were also stained by immunohistochemistry with monoclonal and polyclonal antibodies to adipose/non-adipose tumour markers in order to characterise the immunophenotype of BAT cells. Results: UCP1 was strongly expressed in the cytoplasm of brown fat cells in BAT and hibernomas, both of which also expressed aP2, S100, CD31, vimentin and calponin. UCP1 was not expressed in WAT or other adipose tumours with the exception a few tumour cells in pleomorphic liposarcoma. UCP1 was variably expressed by tumour cells in a few non-adipose sarcomas including leiomyosarcoma, rhabdomyosarcoma, alveolar soft part sarcoma, synovial sarcoma and clear cell sarcoma. Conclusions: UCP1 is strongly expressed in BAT but not WAT and is found in all hibernomas and a few pleomorphic liposarcomas but not in other adipose tumours. UCP1 expression in a few non-adipose soft tissue sarcomas may possibly reflect origin of tumour cells from a common mesenchymal stem cell precursor and/or developmental pathway.
The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma.
Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radio-therapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. TRAIL (TNF Related Apoptosis Inducing Ligand) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells. GBM cells frequently develop resistance to TRAIL which renders clinical application of TRAIL therapeutics inefficient. In this study, we undertook a chemical screening approach using a library of epigenetic modifier drugs to identify compounds that could augment TRAIL response. We identified the fungal metabolite chaetocin, an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through ROS generation and consequent DNA damage induction that involved P53 activity. Chaetocin induced transcriptomic changes showed induction of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent and HMOX1 depletion enhanced chaetocin mediated TRAIL sensitization. Finally, chaetocin and TRAIL combination treatment revealed efficacy in vivo. Taken together, our results provide a novel role for chaetocin as an apoptosis priming agent and its combination with pro-apoptotic therapies might offer new therapeutic approaches for GBMs.
A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.
Biosynthesis of 6-deoxy sugars, including l-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hexose nucleotide precursors as the first committed step. Here, we determined pre- and postcatalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5″ and C6″, coupled to NADP-mediated hydride transfer from C4″ to C6″. We show that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate. We also show that the overall multistep catalytic reaction involves the fewest position changes of enzyme and substrate groups and that it proceeds under conserved exploitation of the basic (minimal) catalytic machinery of short-chain dehydrogenase/reductases.
AKR1D1 regulates glucocorticoid availability and glucocorticoid receptor activation in human hepatoma cells.
Steroid hormones, including glucocorticoids and androgens, have potent actions to regulate many cellular processes within the liver. The steroid A-ring reductase, 5β-reductase (AKR1D1), is predominantly expressed in the liver, where it inactivates steroid hormones and, in addition, plays a crucial role in bile acid synthesis. However, the precise functional role of AKR1D1 to regulate steroid hormone action in vitro has not been demonstrated. We have therefore hypothesised that genetic manipulation of AKR1D1 has the potential to regulate glucocorticoid availability and action in human hepatocytes. In both liver (HepG2) and non-liver cell (HEK293) lines, AKR1D1 over-expression increased glucocorticoid clearance with a concomitant decrease in the activation of the glucocorticoid receptor and the down-stream expression of glucocorticoid target genes. Conversely, knockdown of AKR1D1 using siRNA decreased glucocorticoid clearance and reduced the generation of 5β-reduced metabolites. In addition, the two 5α-reductase inhibitors finasteride and dutasteride failed to effectively inhibit AKR1D1 activity in either cell-free or hepatocellular systems. Through manipulation of AKR1D1 expression and activity, we have demonstrated its potent ability to regulate glucocorticoid availability and receptor activation within human hepatoma cells. These data suggest that AKR1D1 may have an important role in regulating endogenous (and potentially exogenous) glucocorticoid action that may be of particular relevance to physiological and pathophysiological processes affecting the liver.
Role of protein structure in variant annotation: structural insight of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency.
Genetic defects on 6-pyruvoyl-tetrahydropterin synthase (PTPS) are the most prevalent cause of hyperphenylalaninaemia not due to phenylalanine hydrolyase deficiency (phenylketonuria). PTPS catalyses the second step of tetrahydrobiopterin (BH4) cofactor biosynthesis, and its deficiency represents the most common form of BH4 deficiency. Untreated PTPS deficiency results in depletion of the neurotransmitters dopamine, catecholamine and serotonin causing neurological symptoms. We archived reported missense variants of the PTS gene. Common in silico algorithms were used to predict the effects of such variants, and substantial proportions (up to 19%) of the variants were falsely classified as benign or uncertain. We have determined the crystal structure of the human PTPS hexamer, allowing another level of interpretation to understand the potential deleterious consequences of the variants from a structural perspective. The in silico and structure approaches appear to be complimentary and may provide new insights that are not available from each alone. Information from the protein structure suggested that the variants affecting amino acid residues required for interaction between monomeric subunits of the PTPS hexamer were those misclassified as benign by in silico algorithms. Our findings illustrate the important utility of 3D protein structure in interpretation of variants and also current limitations of in silico prediction algorithms. However, software to analyse mutation in the perspective of 3D protein structure is far less readily available than other in silico prediction tools.
Periostin expression in neoplastic and non-neoplastic diseases of bone and joint.
Background: Periostin is a matricellular protein that is expressed in bone and joint tissues. To determine the expression of periostin in primary bone tumours and to assess whether it plays a role in tumour progression, we carried out immunohistochemistry and ELISA for periostin in a range of neoplastic and non-neoplastic bone and joint lesions. Methods: 140 formalin-fixed paraffin-embedded sections of bone tumours and tumour-like lesions were stained by an indirect immunoperoxidase technique with a polyclonal anti-periostin antibody. Periostin expression was also assessed in rheumatoid arthritis (RA) and non-inflammatory osteoarthritis (OA) synovium and synovial fluid immunohistochemistry and ELISA respectively. Results: Periostin was most strongly expressed in osteoid/woven bone of neoplastic and non-neoplastic bone-forming lesions, including osteoblastoma, osteosarcoma, fibrous dysplasia, osteofibrous dysplasia, fracture callus and myositis ossificans, and mineralised chondroid matrix/woven bone in chondroblastoma and clear cell chondrosarcoma. Reactive host bone at the edge of growing tumours, particularly in areas of increased vascularity and fibrosis, also stained strongly for periostin. Vascular elements in RA synovium strongly expressed periostin, and synovial fluid levels of periostin were higher in RA than OA. Conclusions: In keeping with its known role in modulating the synthesis of collagen and other extracellular matrix proteins in bone, strong periostin expression was noted in benign and malignant lesions forming an osteoid or osteoid-like matrix. Periostin was also noted in other bone tumours and was found in areas of reactive bone and increased vascularity at the edge of growing tumours, consistent with its involvement in tissue remodelling and angiogenesis associated with tumour progression.
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.
Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.
Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding.
Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template-based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2.
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors
Histone lysine demethylase (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.
Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.
Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial.
BACKGROUND: Osteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain. METHODS/DESIGN: HERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis. DISCUSSION: The HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a new treatment for OA, which could be of particular use in the primary care setting. TRIAL REGISTRATION: ISRCTN91859104.
Fibroblast growth factor 2: good or bad guy in the joint?
Fibroblast growth factor 2 (FGF2) is a highly abundant growth factor found within the pericellular matrix of articular chondrocytes, but studies investigating its role have been conflicting. The paper reported by Yan and colleagues in the previous issue of Arthritis Research & Therapy proposes that differences in responses to FGF2 are most likely due to changes in the balance between the two major articular cartilage FGF receptors, FGFR1 and FGFR3. They show that the catabolic and anti-anabolic effects of FGF2 are mediated primarily through FGFR1 whereas the beneficial effects are through FGFR3. This balance is dynamic and is altered in disease and following growth factor stimulation in vitro.