The effect of hyperkalemia and long inter-dialytic interval on morbidity and mortality in patients receiving hemodialysis: a systematic review.

BACKGROUND: Patients with chronic kidney disease, especially those receiving hemodialysis (HD), are at risk of hyperkalemia (HK). This systematic review aimed to evaluate the prevalence of HK in patients with renal disease receiving HD and collate evidence on the effect of HK and differing HD patterns (i.e., long vs. short inter-dialytic intervals [LIDI and SIDI, respectively] in a thrice weekly schedule) on mortality. METHODS: Comprehensive searches were conducted across six databases and selected conference proceedings by two independent reviewers up to September 2020. A hundred and two studies reporting frequency of HK, mortality, or cardiovascular (CV) outcomes in adult patients with acute, chronic or end-stage renal disease in receipt of HD were included. Narrative synthesis of results was undertaken with key findings presented in tables and figures. RESULTS: Median prevalence of HK in patients with renal disease receiving HD was 21.6% and increased in patients receiving concomitant medications - mainly renin-angiotensin-aldosterone system inhibitors and potassium-sparing diuretics. Associations between elevated potassium levels and increased risk of both all-cause and CV mortality in the HD population were consistent across the included studies. In addition, there was a rise in all-cause and CV mortality on the day following LIDI compared with the day after the two SIDIs in patients on HD. CONCLUSIONS: Evidence identified in this systematic review indicates a relationship between HK and LIDI with mortality in patients with renal disease receiving HD, emphasizing the need for effective monitoring and management to control potassium levels both in emergency and chronic HD settings.

Improving health, wellbeing and parenting skills in parents of children with special health care needs and medical complexity - a scoping review.

BACKGROUND: Parenting children with special health care needs can be challenging particularly if children have complex conditions. Parents may struggle to manage their child's health and their own emotions, contributing to poorer health outcomes for the family. Frequent healthcare contact presents opportunities to intervene, but current evidence review is limited. This review scopes and synthesizes interventions to improve health, wellbeing and parenting skills. METHODS: Using formal scoping review methodology MEDLINE, EMBASE, PsycINFO, CINAHL, The Cochrane Library, ERIC, ASSIA, HMIC and OpenGrey were searched to February 2017. Citations were double screened according to predetermined eligibility criteria. Data were extracted and synthesized on study design, population, measurement tools, and results. RESULTS: Sixty-five studies from 10,154 citations were included spanning parenting programs, other parent behavior change interventions, peer support, support for hospital admission and discharge and others. Interventions for parents of children with a wide range of conditions were included. These targeted a broad selection of parent outcomes, delivered by a wide variety of professionals and lay workers. Most studies reported positive outcomes. No serious adverse events were noted but issues identified included group and peer relationship dynamics, timing of interventions in relation to the child's disease trajectory, the possibility of expectations not fulfilled, and parent's support needs following intervention. Children with medical complexity were not identified explicitly in any studies. CONCLUSIONS: The range of interventions identified in this review confirms that parents have significant and diverse support needs, and are likely to benefit from a number of interventions targeting specific issues and outcomes across their child's condition trajectory. There is much scope for these to be provided within existing multi-disciplinary teams during routine health care contacts. Careful tailoring is needed to ensure interventions are both feasible for delivery within routine care settings and relevant and accessible for parents of children across the complexity spectrum. Further review of the existing literature is needed to quantify the benefits for parents and assess the quality of the evidence. Further development of interventions to address issues that are relevant and meaningful to parents is needed to maximize intervention effectiveness in this context.

Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets.

OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif-containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif-containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored. In this study, we investigate the role of LAIR-1 in megakaryocyte development and platelet production by generating LAIR-1-deficient mice. APPROACH AND RESULTS: Mice lacking LAIR-1 exhibit a significant increase in platelet counts, a prolonged platelet half-life in vivo, and increased proplatelet formation in vitro. Interestingly, platelets from LAIR-1-deficient mice exhibit an enhanced reactivity to collagen and the glycoprotein VI-specific agonist collagen-related peptide despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery after ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signaling downstream of the glycoprotein VI-FcRγ-chain and integrin αIIbß3 in megakaryocytes because of enhanced Src family kinase activity. CONCLUSIONS: Findings from this study demonstrate that ablation of LAIR-1 in megakaryocytes leads to increased Src family kinase activity and downstream signaling in response to collagen that is transmitted to platelets, rendering them hyper-reactive specifically to agonists that signal through Syk tyrosine kinases, but not to G-protein-coupled receptors.

VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes.

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis and a marked reduction in platelet α-granules. We generated a tamoxifen-inducible mouse model of VPS33B deficiency, Vps33b(fl/fl)-ER(T2), and studied the platelet phenotype and α-granule biogenesis. Ultrastructural analysis of Vps33b(fl/fl)-ER(T2) platelets identified a marked reduction in α-granule count and the presence of small granule-like structures in agreement with the platelet phenotype observed in ARC patients. A reduction of ∼65% to 75% was observed in the α-granule proteins von Willebrand factor and P-selectin. Although platelet aggregation responses were not affected, a defect in δ-granule secretion was observed. Under arteriolar shear conditions, Vps33b(fl/fl)-ER(T2) platelets were unable to form stable aggregates, and tail-bleeding measurement revealed a bleeding diathesis. Analysis of bone marrow-derived megakaryocytes (MKs) by conventional and immuno-electron microscopy from Vps33b(fl/fl)-ER(T2) mice revealed a reduction in mature type-II multivesicular bodies (MVB II) and an accumulation of large vacuoles. Proteins that are normally stored in α-granules were underrepresented in MVB II and proplatelet extensions. These results demonstrate that abnormal protein trafficking and impairment in MVB maturation in MKs underlie the α-granule deficiency in Vps33b(fl/fl)-ER(T2) mouse and ARC patients.

The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation.

A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage. These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation. No effect on tail bleeding time or in thrombosis models was observed. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets.

Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay.

Up to 1% of the population have mild bleeding disorders, but these remain poorly characterized, particularly with regard to the roles of platelets. We have compared the usefulness of Optimul, a 96-well plate-based assay of 7 distinct pathways of platelet activation to characterize inherited platelet defects in comparison with light transmission aggregometry (LTA). Using Optimul and LTA, concentration-response curves were generated for arachidonic acid, ADP, collagen, epinephrine, Thrombin receptor activating-peptide, U46619, and ristocetin in samples from (1) healthy volunteers (n = 50), (2) healthy volunteers treated with antiplatelet agents in vitro (n = 10), and (3) patients with bleeding of unknown origin (n = 65). The assays gave concordant results in 82% of cases (κ = 0.62, P < .0001). Normal platelet function results were particularly predictive (sensitivity, 94%; negative predictive value, 91%), whereas a positive result was not always substantiated by LTA (specificity, 67%; positive predictive value, 77%). The Optimul assay was significantly more sensitive at characterizing defects in the thromboxane pathway, which presented with normal responses with LTA. The Optimul assay is sensitive to mild platelet defects, could be used as a rapid screening assay in patients presenting with bleeding symptoms, and detects changes in platelet function more readily than LTA. This trial was registered at www.isrctn.org as #ISRCTN 77951167.

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects.

Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.

Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.

We analyzed candidate platelet function disorder genes in 13 index cases with a history of excessive bleeding in association with a significant reduction in dense granule secretion and impaired aggregation to a panel of platelet agonists. Five of the index cases also had mild thrombocytopenia. Heterozygous alterations in FLI1 and RUNX1, encoding Friend leukemia integration 1 and RUNT-related transcription factor 1, respectively, which have a fundamental role in megakaryocytopoeisis, were identified in 6 patients, 4 of whom had mild thrombocytopenia. Two FLI1 alterations predicting p.Arg337Trp and p.Tyr343Cys substitutions in the FLI1 DNA-binding domain abolished transcriptional activity of FLI1. A 4-bp deletion in FLI1, and 2 splicing alterations and a nonsense variation in RUNX1, which were predicted to cause haploinsufficiency of either FLI1 or RUNX1, were also identified. Our findings suggest that alterations in FLI1 and RUNX1 may be common in patients with platelet dense granule secretion defects and mild thrombocytopenia.

Loss-of-function mutations in RAB18 cause Warburg micro syndrome.

Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration.

Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel.

Light transmission aggregometry (LTA) is used worldwide for the investigation of heritable platelet function disorders (PFDs), but interpretation of results is complicated by the feedback effects of ADP and thromboxane A(2) (TxA(2)) and by the overlap with the response of healthy volunteers. Over 5 years, we have performed lumi-aggregometry on 9 platelet agonists in 111 unrelated research participants with suspected PFDs and in 70 healthy volunteers. Abnormal LTA or ATP secretion test results were identified in 58% of participants. In 84% of these, the patterns of response were consistent with defects in Gi receptor signaling, the TxA(2) pathway, and dense granule secretion. Participants with defects in signaling to Gq-coupled receptor agonists and to collagen were also identified. Targeted genotyping identified 3 participants with function-disrupting mutations in the P2Y(12) ADP and TxA(2) receptors. The results of the present study illustrate that detailed phenotypic analysis using LTA and ATP secretion is a powerful tool for the diagnosis of PFDs. Our data also enable subdivision at the level of platelet-signaling pathways and in some cases to individual receptors. We further demonstrate that most PFDs can be reliably diagnosed using a streamlined panel of key platelet agonists and specified concentrations suitable for testing in most clinical diagnostic laboratories.

Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.

Incidence of Respiratory Syncytial Virus Infection in Older Adults: Limitations of Current Data.

INTRODUCTION: Respiratory syncytial virus (RSV) is an important cause of severe respiratory illness in older adults and adults with respiratory or cardiovascular comorbidities. Published estimates of its incidence and prevalence in adult groups vary widely. This article reviews the potential limitations affecting RSV epidemiology studies and suggests points to consider when evaluating or designing them. METHODS: Studies reporting the incidence or prevalence of RSV infection in adults in high-income Western countries from 2000 onwards were identified via a rapid literature review. Author-reported limitations were recorded, together with presence of other potential limitations. Data were synthesized narratively, with a focus on factors affecting incidence estimates for symptomatic infection in older adults. RESULTS: A total of 71 studies met the inclusion criteria, most in populations with medically attended acute respiratory illness (ARI). Only a minority used case definitions and sampling periods tailored specifically to RSV; many used influenza-based or other criteria that are likely to result in RSV cases being missed. The great majority relied solely on polymerase chain reaction (PCR) testing of upper respiratory tract samples, which is likely to miss RSV cases compared with dual site sampling and/or addition of serology. Other common limitations were studying a single season, which has potential for bias due to seasonal variability; failure to stratify results by age, which underestimates the burden of severe disease in older adults; limited generalizability beyond a limited study setting; and absence of measures of uncertainty in the reporting of results. CONCLUSIONS: A significant proportion of studies are likely to underestimate the incidence of RSV infection in older adults, although the effect size is unclear and there is also potential for overestimation. Well-designed studies, together with increased testing for RSV in patients with ARI in clinical practice, are required to accurately capture both the burden of RSV and the potential public health impact of vaccines.

Stroke risk following traumatic brain injury: Systematic review and meta-analysis.

BACKGROUND: Traumatic brain injury is a global health problem; worldwide, >60 million people experience a traumatic brain injury each year and incidence is rising. Traumatic brain injury has been proposed as an independent risk factor for stroke. AIMS: To investigate the association between traumatic brain injury and stroke risk. SUMMARY OF REVIEW: We undertook a systematic review of MEDLINE, EMBASE, CINAHL, and The Cochrane Library from inception to 4 December 2020. We used random-effects meta-analysis to pool hazard ratios for studies which reported stroke risk post-traumatic brain injury compared to controls. Searches identified 10,501 records; 58 full texts were assessed for eligibility and 18 met the inclusion criteria. The review included a large sample size of 2,606,379 participants from four countries. Six studies included a non-traumatic brain injury control group, all found traumatic brain injury patients had significantly increased risk of stroke compared to controls (pooled hazard ratio 1.86; 95% confidence interval 1.46-2.37). Findings suggest stroke risk may be highest in the first four months post-traumatic brain injury, but remains significant up to five years post-traumatic brain injury. Traumatic brain injury appears to be associated with increased stroke risk regardless of severity or subtype of traumatic brain injury. There was some evidence to suggest an association between reduced stroke risk post-traumatic brain injury and Vitamin K antagonists and statins, but increased stroke risk with certain classes of antidepressants. CONCLUSION: Traumatic brain injury is an independent risk factor for stroke, regardless of traumatic brain injury severity or type. Post-traumatic brain injury review and management of risk factors for stroke may be warranted.

Patients' and health professionals' attitudes and perceptions towards the initiation of preventive drugs for primary prevention of cardiovascular disease: a systematic review of qualitative studies.

BACKGROUND: Statins and antihypertensive agents are recommended for primary prevention of cardiovascular disease (CVD), but they are not always prescribed to eligible patients. DESIGN & SETTING: A systematic review of qualitative studies. AIM: To explore health professionals' and patients' attitudes towards cardiovascular preventive drugs. METHOD: MEDLINE, Embase, PsychINFO, CINAHL, ASSIA, HMIC, Conference Proceedings Citation Index, and Open Grey were searched for studies of qualitative design without restrictions on date or language. Two reviewers performed study selection, data extraction, quality assessment, and thematic synthesis. RESULTS: In total, 2585 titles and abstracts were screened, yielding 27 studies, of which five met eligibility criteria on full text assessment. These included 62 patients and 47 health professionals. Five themes emerged about patient attitudes: questioning preventive drugs; perceived benefit and risks, such as improving quality of life; patient preferences; trust in health professional judgement; and family, friends, and media influences. Five themes emerged about health professional attitudes: addressing patient concerns and information; duty as a health professional to prescribe; uncertainty about preventive drug prescribing; recognising consequences of prescribing, such as unnecessary medicalisation; and personalised treatment. CONCLUSION: The attitudes of patients and health professionals regarding drug initiation for primary prevention reflect the complexity of the patient-health professional encounter in primary practice. For prescribing to be more adherent to guidelines, research should further investigate the patient-health professional relationship and the appropriate communication methods required when discussing drug initiation, specifically for primary prevention.

Clinicians' views and experiences of prescribing oral anticoagulants for stroke prevention in atrial fibrillation: A qualitative meta-synthesis.

BACKGROUND: Globally, over 33 million people have atrial fibrillation (AF). In eligible patients, oral anticoagulation (OAC) is recommended for stroke risk reduction. Despite recent increases in OAC prescribing, global under-prescription to high-risk AF patients and inappropriate prescription to low-risk patients is leading to unnecessary risk of stroke and haemorrhage. This meta-synthesis explored clinicians' beliefs and experiences regarding OAC prescription to AF patients, highlighting barriers to stroke prevention and informing future clinician-focused interventions. METHODS AND RESULTS: A qualitative meta-synthesis exploring clinicians' views and experiences of prescribing OACs for stroke prevention in AF patients. Databases including MEDLINE, EMBASE, PsychINFO and CINAHL were searched to June 2018, with a further Medline search to February 2020. Thematic synthesis was performed with data coding, descriptive theme categorisation and generation of analytical themes. From 3499 records, 101 full text papers were screened, with 13 eligible studies identified. Four analytical themes were found to affect clinicians' prescribing: (i) 'Clinicians' intellectual and emotional responses to the evidence'; (ii) 'Prescribing in primary and secondary care'; (iii) 'Clinicians' views of how patients' characteristics and opinions influence prescribing'; and (iv) 'Clinicians' views on their interactions with patients'. CONCLUSIONS: This review highlights focal points for future clinician-focused interventions to improve guideline-adherent OAC prescription in AF patients. Interventions should aim to improve clinicians' knowledge around NOAC prescription and stroke and haemorrhage risk assessment tools as well as their emotional responses to difficult prescribing scenarios. Multidisciplinary interventions promoting cohesive care and input from different clinicians to overcome time-related barriers may increase guideline-adherent OAC prescription for AF patients.

Patients' and health professionals' attitudes and perceptions towards the initiation of preventive drugs for primary prevention of cardiovascular disease: protocol for a systematic review of qualitative studies.

INTRODUCTION: Lipid-lowering drugs and antihypertensive agents can be prescribed for the primary prevention of cardiovascular disease. In some cases, patients eligible for primary prevention of cardiovascular disease according to the European guidelines are not always started on preventive drugs. Existing research explores the attitudes of health professionals and patients towards cardiovascular preventive drugs but does not always differentiate between the attitudes towards drug initiation for primary or secondary prevention. We aim to systematically review qualitative studies assessing health professionals' and patients' attitudes and perceptions towards drug initiation for primary prevention of cardiovascular disease. METHODS AND ANALYSIS: MEDLINE, MEDLINE In Process, EMBASE, PsycINFO, CINAHL, Applied Social Sciences Index and Abstracts, Conference Proceedings Citation Index (Web of Science), Healthcare Management Information Consortium, and Open Grey will be searched without restrictions on date or language of publication. Searches will be limited to studies of qualitative design, standalone or in the context of a mixed-method design, focusing on cardiovascular drug initiation for primary prevention. The primary outcome is the attitudes of health professionals and patients towards drug initiation for primary prevention of cardiovascular disease. Two reviewers will independently carry out the study selection, data extraction and quality assessment. The Critical Appraisal Skills Programme Qualitative Research Checklist will be used to assess the quality of included studies. The findings will be analysed using Thomas and Harden's thematic synthesis approach. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval as primary data will not be collected. The results of the study will be published in a peer-reviewed journal and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42018095346.

How do stakeholders experience the adoption of electronic prescribing systems in hospitals? A systematic review and thematic synthesis of qualitative studies.

BACKGROUND: Electronic prescribing (ePrescribing) or computerised provider/physician order entry (CPOE) systems can improve the quality and safety of health services, but the translation of this into reduced harm for patients remains unclear. This review aimed to synthesise primary qualitative research relating to how stakeholders experience the adoption of ePrescribing/CPOE systems in hospitals, to help better understand why and how healthcare organisations have not yet realised the full potential of such systems and to inform future implementations and research. METHODS: We systematically searched 10 bibliographic databases and additional sources for citation searching and grey literature, with no restriction on date or publication language. Qualitative studies exploring the perspectives/experiences of stakeholders with the implementation, management, use and/or optimisation of ePrescribing/CPOE systems in hospitals were included. Quality assessment combined criteria from the Critical Appraisal Skills Programme Qualitative Checklist and the Standards for Reporting Qualitative Research guidelines. Data were synthesised thematically. RESULTS: 79 articles were included. Stakeholders' perspectives reflected a mixed set of positive and negative implications of engaging in ePrescribing/CPOE as part of their work. These were underpinned by further-reaching change processes. Impacts reported were largely practice related rather than at the organisational level. Factors affecting the implementation process and actions undertaken prior to implementation were perceived as important in understanding ePrescribing/CPOE adoption and impact. CONCLUSIONS: Implementing organisations and teams should consider the breadth and depth of changes that ePrescribing/CPOE adoption can trigger rather than focus on discrete benefits/problems and favour implementation strategies that: consider the preimplementation context, are responsive to (and transparent about) organisational and stakeholder needs and agendas and which can be sustained effectively over time as implementations develop and gradually transition to routine use and system optimisation.

Improving the Prescription of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review.

OBJECTIVE: Oral anticoagulant (OAC) prescription for stroke prevention in atrial fibrillation (AF) patients frequently does not follow current guidelines, with underuse in patients at high risk of stroke and substantial overuse in those at low risk. This review aims to systematically evaluate the effectiveness of interventions to improve appropriate OAC prescription in eligible AF patients for stroke prevention. METHODS: Systematic review of controlled and uncontrolled studies published up to July 2017 with interventions designed to improve appropriate OAC prescription for stroke prevention in eligible AF patients (according to risk assessment tool or guidelines). Categorization of intervention types was pre-specified. The main outcome was change in proportion of eligible AF patients prescribed OACs for stroke prevention. RESULTS: Twenty studies conducted in 392 settings were included (cluster randomized controlled trials, controlled trials and uncontrolled before-after designs; n = 29,868 patients at baseline). Fifteen studies reported significant improvements in appropriate prescription of OACs in AF patients. All interventions with a persuasive element (8/8); all studies targeting health care professional (HCP) education or guideline/protocol implementation (7/7); and all medical care programs (4/4) achieved significant increases in appropriate OAC prescription. Computerized decision support interventions (3/5) and reviews of prescribing (2/4) were less likely to report significant improvements in appropriate OAC prescription. CONCLUSION: Interventions designed to improve appropriate prescription of OACs in eligible AF patients for stroke prevention can be effective. Successful approaches include education of HCPs; implementation of local guidelines; interdisciplinary medical care programs educating both HCPs and patients and persuasive interventions utilizing peer-group experts. Protocol registration: PROSPERO (CRD42016039654).

Preclinical therapies to prevent or treat fracture non-union: A systematic review.

BACKGROUND: Non-union affects up to 10% of fractures and is associated with substantial morbidity. There is currently no single effective therapy for the treatment or prevention of non-union. Potential treatments are currently selected for clinical trials based on results from limited animal studies, with no attempt to compare results between therapies to determine which have the greatest potential to treat non-union. AIM: The aim of this systematic review was to define the range of therapies under investigation at the preclinical stage for the prevention or treatment of fracture non-union. Additionally, through meta-analysis, it aimed to identify the most promising therapies for progression to clinical investigation. METHODS: MEDLINE and Embase were searched from 1St January 2004 to 10th April 2017 for controlled trials evaluating an intervention to prevent or treat fracture non-union. Data regarding the model used, study intervention and outcome measures were extracted, and risk of bias assessed. RESULTS: Of 5,171 records identified, 197 papers describing 204 therapies were included. Of these, the majority were only evaluated once (179/204, 88%), with chitosan tested most commonly (6/204, 3%). Substantial variation existed in model design, length of survival and duration of treatment, with results poorly reported. These factors, as well as a lack of consistently used objective outcome measures, precluded meta-analysis. CONCLUSION: This review highlights the variability and poor methodological reporting of current non-union research. The authors call for a consensus on the standardisation of animal models investigating non-union, and suggest journals apply stringent criteria when considering animal work for publication.

Transcatheter aortic valve implantation for aortic stenosis in high surgical risk patients: A systematic review and meta-analysis.

BACKGROUND: Symptomatic aortic stenosis has a poor prognosis. Many patients are considered inoperable or at high surgical risk for surgical aortic valve replacement (SAVR), reflecting their age, comorbidities and frailty. The clinical effectiveness and safety of TAVI have not been reviewed systematically for these high levels of surgical risk. This systematic review compares mortality and other important clinical outcomes up to 5 years post treatment following TAVI or other treatment in these risk groups. METHODS: A systematic review protocol was registered on the PROSPERO database (CRD42016048396). The Cochrane Library, Centre for Reviews and Dissemination Databases, MEDLINE, EMBASE, and ZETOC were searched from January 2002 to August 2016. Clinical trials or matched studies comparing TAVI with other treatments for AS in patients surgically inoperable or operable at a high risk were included. Data extraction and quality assessment were conducted by two reviewers. Data were pooled using random-effects meta-analysis. The main outcomes were all-cause mortality, efficacy and major complications. RESULTS: Three good quality randomised controlled trials (RCTs) were included. Patients' mean age ranged from 83-85 years, around half were female and New York Heart Association (NYHA) functional class III or IV ranged from 83.8% to 94.2% with frequent comorbidities. In 358 surgically inoperable patients from one RCT, TAVI was superior to medical therapy for all-cause mortality at 1 year (hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.36-0.92), 2 years (HR 0.50, 95% CI 0.39-0.65), 3 years (HR 0.53, 95% CI 0.41to 0.68) and 5 years (HR 0.50, 95% CI 0.39-0.65), and NYHA class III or IV at 2 years (TAVI 16.8% (16/95), medical therapy 57.5% (23/40), p<0.001), quality of life and re-hospitalisation. TAVI had higher risks of major bleeding up to 1 year, of stroke up to 3 years (at one year 11.2% versus 5.5%, p = .06; HR at 2 years 2.79, 95% CI 1.25-6.22; HR at 3 years 2.81; 95% CI 1.26-6.26) and of major vascular complication at 3 years (HR 8.27, 95% CI 2.92-23.44). Using the GRADE tool, this evidence was considered to be of moderate quality. In a meta-analysis including 1,494 high risk surgically operable patients from two non-inferiority RCTs TAVI showed no significant differences from SAVR in all-cause mortality at two years (HR 1.03, 95% CI 0.82-1.29) and up to 5 years (HR 0.83, 95% CI 0.83-1.12). There were no statistically significant differences in major vascular complications and myocardial infarction at any time point, discrepant results for major bleeding on variable definitions and no differences in stroke rate at any time point. Using the GRADE tool, this evidence was considered of low quality. CONCLUSIONS: Symptomatic aortic stenosis can be lethal without intervention but surgical resection is contraindicated for some patients and high risk for others. We found that all-cause mortality up to 5 years of follow-up did not differ significantly between TAVI and SAVR in patients surgically operable at a high risk, but favoured TAVI over medical therapy in patients surgically inoperable. TAVI is a viable life-extending treatment option in these surgical high risk groups.