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Background: Transcriptomes present a rich, multi-dimensional subset of genomics data. They provide broad insights into genetic sequence, and more significantly gene expression, across biological samples. This technology is frequently employed for describing the genetic response to experimental conditions and has created vast libraries of datasets which shed light on gene function across different tissues, diseases, diets and developmental stages in many species. However, public accessibility of these data is impeded by a lack of suitable software interfaces and databases with which to locate and analyse them. BODY: Here we present an update on the status of CrustyBase.org, an online resource for analysing and sharing crustacean transcriptome datasets. Since its release in October 2020, the resource has provided many thousands of transcriptome sequences and expression profiles to its users and received 19 new dataset imports from researchers across the globe. In this article we discuss user analytics which point towards the utilization of this resource. The architecture of the application has proven robust with over 99.5% uptime and effective reporting of bugs through both user engagement and the error logging mechanism. We also introduce several new features that have been developed as part of a new release of CrustyBase.org. Two significant features are described in detail, which allow users to navigate through transcripts directly by submission of transcript identifiers, and then more broadly by searching for encoded protein domains by keyword. The latter is a novel and experimental feature, and grants users the ability to curate gene families from any dataset hosted on CrustyBase in a matter of minutes. We present case studies to demonstrate the utility of these features., Conclusion: Community engagement with this resource has been very positive, and we hope that improvements to the service will further enable the research of users of the platform. Web-based platforms such as CrustyBase have many potential applications across life science domains, including the health sector, which are yet to be realised. This leads to a wider discussion around the role of web-based resources in facilitating an open and collaborative research community., (© 2024. The Author(s).)

Objectives: There is significant heterogeneity in the results of published model-based economic evaluations of low-dose computed tomography (LDCT) screening for lung cancer. We sought to understand and demonstrate how these models differ., Methods: An expansion and update of a previous systematic review (N = 19). Databases (including MEDLINE and Embase) were searched. Studies were included if strategies involving (single or multiple) LDCT screening were compared with no screening or other imaging modalities, in a population at risk of lung cancer. More detailed data extraction of studies from the previous review was conducted. Studies were critically appraised using the Consensus Health Economic Criteria list., Results: A total of 16 new studies met the inclusion criteria, giving a total of 35 studies. There are geographic and temporal differences and differences in screening intervals and eligible populations. Studies varied in the types of models used, for example, decision tree, Markov, and microsimulation models. Most conducted a cost-effectiveness analysis (using life-years gained) or cost-utility analysis. The potential for overdiagnosis was considered in many models, unlike with other potential consequences of screening. Some studies report considering lead-time bias, but fewer mention length bias. Generally, the more recent studies, involving more complex modeling, tended to meet more of the critical appraisal criteria, with notable exceptions., Conclusions: There are many differences across the economic evaluations contributing to variation in estimates of the cost-effectiveness of LDCT screening for lung cancer. Several methodological factors and evidence needs have been highlighted that will require consideration in future economic evaluations to achieve better agreement., (Copyright © 2021 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Comparative diagnostic test accuracy studies assess and compare the accuracy of 2 or more tests in the same study. Although these studies have the potential to yield reliable evidence regarding comparative accuracy, shortcomings in the design, conduct, and analysis may bias their results. The currently recommended quality assessment tool for diagnostic test accuracy studies, QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), is not designed for the assessment of test comparisons. The QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies-Comparative) tool was developed as an extension of QUADAS-2 to assess the risk of bias in comparative diagnostic test accuracy studies. Through a 4-round Delphi study involving 24 international experts in test evaluation and a face-to-face consensus meeting, an initial version of the tool was developed that was revised and finalized following a pilot study among potential users. The QUADAS-C tool retains the same 4-domain structure of QUADAS-2 (Patient Selection, Index Test, Reference Standard, and Flow and Timing) and comprises additional questions to each QUADAS-2 domain. A risk-of-bias judgment for comparative accuracy requires a risk-of-bias judgment for the accuracy of each test (resulting from QUADAS-2) and additional criteria specific to test comparisons. Examples of such additional criteria include whether participants either received all index tests or were randomly assigned to index tests, and whether index tests were interpreted with blinding to the results of other index tests. The QUADAS-C tool will be useful for systematic reviews of diagnostic test accuracy addressing comparative questions. Furthermore, researchers may use this tool to identify and avoid risk of bias when designing a comparative diagnostic test accuracy study.

Objectives: (1) To identify and classify comparative diagnostic test accuracy (DTA) study designs; (2) to describe study design labels used by authors of comparative DTA studies., Methods: We performed a methodological review of 100 comparative DTA studies published between 2015 and 2017, randomly sampled from studies included in 238 comparative DTA systematic reviews indexed in MEDLINE in 2017. From each study report, we extracted six design elements characterizing participant flow and the labels used by authors., Results: We identified a total of 46 unique combinations of study design features in our sample, based on six design elements characterizing participant flow. We classified the studies into five study design categories based on how participants were allocated to receive each index test: 'fully paired' (n=79), 'partially paired, random subset' (n=0), 'partially paired, nonrandom subset' (n=2), 'unpaired randomized' (n=1) and 'unpaired nonrandomized' (n=3). The allocation method used in 15 studies was unclear. Sixty-one studies reported, in total, 29 unique study design labels but only four labels referred to specific design features of comparative studies., Conclusion: Our classification scheme can help systematic review authors define study eligibility criteria, assess risk of bias, and communicate the strength of the evidence. A standardized labelling scheme could be developed to facilitate communication of specific design features., (Copyright © 2021. Published by Elsevier Inc.)

There is an increasing need for the use of additive manufacturing (AM) to produce improved critical application engineering components. However, the materials manufactured using AM perform well below their traditionally manufactured counterparts, particularly for creep and fatigue. Research has shown that this difference in performance is due to the complex relationships between AM process parameters which affect the material microstructure and consequently the mechanical performance as well. Therefore, it is necessary to understand the impact of different AM build parameters on the mechanical performance of parts. Machine learning (ML) models are able to find hidden relationships in data using iterative statistical analyses and have the potential to develop process-structure-property-performance relationships for manufacturing processes, including AM. The aim of this work is to apply ML techniques to materials testing data in order to understand the effect of AM process parameters on the creep rate of additively built nickel-based superalloy and to predict the creep rate of the material from these process parameters. In this work, the predictive capabilities of ML and its ability to develop process-structure-property relationships are applied to the creep properties of laser powder bed fused alloy 718. The input data for the ML model included the Laser Powder Bed Fusion (LPBF) build parameters used-build orientation, scan strategy and number of lasers-and geometrical material descriptors which were extracted from optical microscope porosity images using image analysis techniques. The ML model was used to predict the minimum creep rate of the Laser Powder Bed Fused alloy 718 samples, which had been creep tested at 650 ∘ C and 600 MPa. The ML model was also used to identify the most relevant material descriptors affecting the minimum creep rate of the material (determined by using an ensemble feature importance framework). The creep rate was accurately predicted with a percentage error of 1.40 % in the best case. The most important material descriptors were found to be part density, number of pores, build orientation and scan strategy. These findings show the applicability and potential of using ML to determine and predict the mechanical properties of materials fabricated via different manufacturing processes, and to find process-structure-property relationships in AM. This increases the readiness of AM for use in critical applications., (© The Author(s) 2021.)

Background: Tools based on diagnostic prediction models are available to help general practitioners (GP) diagnose colorectal cancer. It is unclear how well they perform and whether they lead to increased or quicker diagnoses and ultimately impact on patient quality of life and/or survival. The aim of this systematic review is to evaluate the development, validation, effectiveness, and cost-effectiveness, of cancer diagnostic tools for colorectal cancer in primary care., Methods: Electronic databases including Medline and Web of Science were searched in May 2017 (updated October 2019). Two reviewers independently screened titles, abstracts and full-texts. Studies were included if they reported the development, validation or accuracy of a prediction model, or assessed the effectiveness or cost-effectiveness of diagnostic tools based on prediction models to aid GP decision-making for symptomatic patients presenting with features potentially indicative of colorectal cancer. Data extraction and risk of bias were completed by one reviewer and checked by a second. A narrative synthesis was conducted., Results: Eleven thousand one hundred thirteen records were screened and 23 studies met the inclusion criteria. Twenty-studies reported on the development, validation and/or accuracy of 13 prediction models: eight for colorectal cancer, five for cancer areas/types that include colorectal cancer. The Qcancer models were generally the best performing. Three impact studies met the inclusion criteria. Two (an RCT and a pre-post study) assessed tools based on the RAT prediction model. The third study looked at the impact of GP practices having access to RAT or Qcancer. Although the pre-post study reported a positive impact of the tools on outcomes, the results of the RCT and cross-sectional survey found no evidence that use of, or access to, the tools was associated with better outcomes. No study evaluated cost effectiveness., Conclusions: Many prediction models have been developed but none have been fully validated. Evidence demonstrating improved patient outcome of introducing the tools is the main deficiency and is essential given the imperfect classification achieved by all tools. This need is emphasised by the equivocal results of the small number of impact studies done so far.

Sexual development involves the successive and overlapping processes of sex determination, sexual differentiation, and ultimately sexual maturation, enabling animals to reproduce. This provides a mechanism for enriched genetic variation which enables populations to withstand ever-changing environments, selecting for adapted individuals and driving speciation. The molecular mechanisms of sexual development display a bewildering diversity, even in closely related taxa. Many sex determination mechanisms across animals include the key family of "doublesex- and male abnormal3-related transcription factors" (Dmrts). In a few exceptional species, a single Dmrt residing on a sex chromosome acts as the master sex regulator. In this study, we provide compelling evidence for this model of sex determination in the ornate spiny lobster Panulius ornatus , concurrent with recent reports in the eastern spiny lobster Sagmariasus verreauxi . Using a multi-tissue transcriptomic database established for P. ornatus , we screened for the key factors associated with sexual development (by homology search and using previous knowledge of these factors from related species), providing an in-depth understanding of sexual development in decapods. Further research has the potential to close significant gaps in our understanding of reproductive development in this ecologically and commercially significant order.

Transcriptome sequencing has opened the field of genomics to a wide variety of researchers, owing to its efficiency, applicability across species and ability to quantify gene expression. The resulting datasets are a rich source of information that can be mined for many years into the future, with each dataset providing a unique angle on a specific context in biology. Maintaining accessibility to this accumulation of data presents quite a challenge for researchers.The primary focus of conventional genomics databases is the storage, navigation and interpretation of sequence data, which is typically classified down to the level of a species or individual. The addition of expression data adds a new dimension to this paradigm - the sampling context. Does gene expression describe different tissues, a temporal distribution or an experimental treatment? These data not only describe an individual, but the biological context surrounding that individual. The structure and utility of a transcriptome database must therefore reflect these attributes. We present an online database which has been designed to maximise the accessibility of crustacean transcriptome data by providing intuitive navigation within and between datasets and instant visualization of gene expression and protein structure.The site is accessible at https://crustybase.org and currently holds 10 datasets from a range of crustacean species. It also allows for upload of novel transcriptome datasets through a simple web interface, allowing the research community to contribute their own data to a pool of shared knowledge.

Neuropeptides are ancient endocrine components which have evolved to regulate many aspects of biology across the animal kingdom including behaviour, development and metabolism. To supplement current knowledge, we have utilized a transcriptome series describing larval development in the ornate spiny lobster, Panulirus ornatus. The biology of this animal has been leveraged to provide insights into the roles of molting, metamorphosis and metabolism across the neuropeptide family. We report an extensive list of neuropeptides across three distinct life phases of the animal. We show distinct groups of neuropeptides with differential expression between larval phases, indicating phase-specific roles for these peptides. For selected neuropeptides, we describe and discuss expression profiles throughout larval development and report predicted peptide cleavage sites and mature peptide sequences. We also report the neuropeptide nesfatin for the first time in a crustacean, and report secondary peptide products with a level of evolutionary conservation similar to the conventional mature peptide nesfatin-1, indicating a conserved role in these secondary products which are widely regarded as biologically inactive. In addition, we report a trend of downregulation in the neuropeptides as the animal undergoes extensive neural remodelling in fulfillment of metamorphosis. We suggest that this downregulation in neuropeptides relates to the brief, yet dramatic changes in morphology experienced by the central nervous system in the process of metamorphosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A multiplexed biophotonic assay platform has been developed using the localised particle plasmon in gold nanoparticles assembled in an array and functionalised for two assays: total IgG and C-reactive protein (CRP). A protein A/G (PAG) assay, calibrated with a NIST reference material, shows a maximum surface coverage of θ max = 7.13 ± 0.19 mRIU, equivalent to 1.5 ng mm -2 of F(ab)-presenting antibody. The CRP capture antibody has an equivalent surface binding density of θ max = 2.95 ± 0.41 mRIU indicating a 41% capture antibody availability. Free PAG binding to the functionalised anti-CRP surface shows that only 47 ± 3% of CRP capture antibodies are correctly presenting Fab regions for antigen capture. The accuracy and precision of the CRP sensor assay was assessed with 54 blood samples containing spiked CRP in the range 2-160 mg L -1 . The mean accuracy was 0.42 mg L -1 with Confidence Interval (CI) at 95% from -14.7 to 13.8 mg L -1 and the precision had a Coefficient of Variation (CV) of 10.6% with 95% CI 0.9%-20.2%. These biophotonic platform performance metrics indicate a CRP assay with 2-160 mg L -1 dynamic range, performed in 8 minutes from 5 μL of whole blood without sample preparation.

The fraction of intact monomer in a sample (moles/moles), the monomeric purity, is measured as a quality control in therapeutic monoclonal antibodies but is often unknown in research samples and remains a major source of variation in quantitative antibody-based techniques such as immunoassay development. Here, we describe a novel multiplex technique for estimating the monomeric purity and antigen affinity of research grade antibody samples. Light scattering was used to simultaneously observe the mass of antibody binding to biosensor surfaces functionalised with antigen (revealing Fab binding kinetics) or protein A/G (PAG). Initial estimates of monomeric purity in 7 antibody samples including a therapeutic infliximab biosimilar were estimated by observing a mass deficit on the PAG surface compared to the NISTmAb standard of high monomeric purity. Monomeric purity estimates were improved in a second step by observing the mass of antigen binding to the mass of antibody on the PAG surface. The NISTmAb and infliximab biosimilar displayed tightly controlled stoichiometries for antigen binding of 1.31 ± 0.57 and 1.71 ± 0.16 (95% confidence interval)-within the theoretical limit of 1-2 antigens per antibody depending on avidity. The other antibodies in the panel displayed antigen binding stoichiometries in the range 0.06-1.15, attributed to lower monomeric purity. The monomeric purity estimates were verified by electrospray ionization mass spectrometry (ESI), the gold standard technique for structural characterization of antibodies. ESI data indicated that the NISTmAb and infliximab biosimilar samples had monomeric purity values of 93.5% and 94.7%, respectively, whilst the research grade samples were significantly lower (54-89%). Our results demonstrate rapid quality control testing for monomeric purity of antibody samples (< 15 min) which could improve the reproducibility of antibody-based experiments.

Background: Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer., Methods: A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used., Results: Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over., Conclusions: Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation., Competing Interests: IMF is an Honorary Medical Advisor to Lynch Syndrome UK and reports support from St Vincent’s University Hospital (Dublin), Impact Genetics (Bowmanville, Ontario, Canada), and Ambry Genetics (Aliso Viejo, CA, USA), for travel, outside the submitted work. Other authors declare no potential conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Following publication of the original article.

Background: The Crustacea are an evolutionarily diverse taxon which underpins marine food webs and contributes significantly to the global economy. However, our knowledge of crustacean endocrinology and development is far behind that of terrestrial arthropods. Here we present a unique insight into the molecular pathways coordinating crustacean metamorphosis, by reconciling nuclear receptor (NR) gene activity from a 12-stage, 3-replicate transcriptome in the ornate spiny lobster (Panulirus ornatus) during larval development., Results: We annotated 18 distinct nuclear receptor genes, including three novel NRs which are upregulated prior to metamorphosis and have hence been named the "molt-associated receptors" (MARs). We also demonstrate the ecdysone-responsive expression of several known molt-related NRs including ecdysone receptor, fushi-tarazu-F1 and E75. Phylogenetic analysis of the curated NR family confirmed gene annotations and suggested that the MARs are a recent addition to the crustacean superfamily, occurring across the Malacostraca from the Stomatopoda to the Decapoda. The ligand-binding domain of these receptors appears to be less conserved than that of typical group-1 NRs. Expression data from two other crustacean species was utilized to examine MAR expression. The Y-organ of the tropical land crab showed a decline in expression of all MARs from intermolt to post-molt. Tissue distributions showed gonad-enriched expression in the Eastern rock lobster and antennal gland-enriched expression in the tropical land crab, although expression was evident across most tissues., Conclusion: By mining transcriptome data, we have curated an extensive list of NR genes expressed during the metamorphic molts of P. ornatus, including three novel crustacean NRs which appear to play a role in the molting process. Divergence of the E-region of these new receptors indicates that they may have adopted a function that is unconventional for NRs. Based on expression patterns, we can confirm that a number of NRs play a role in the ecdysone cassette which regulates molting in crustaceans. This study describes in detail the molecular events surrounding crustacean molting and metamorphosis by taking advantage of the distinctive life history unique to achelatan crustaceans.

Arthropods have long been utilized as models to explore molecular function, and the findings derived from them can be applied throughout metazoa, including as a basis for medical research. This has led to the adoption of many representative insect models beyond Drosophila, as each lends its own unique perspective to questions in endocrinology and genetics. However, non-insect arthropods are yet to be realised for the potential insight they may provide in such studies. The Crustacea are among the most ancient arthropods from which insects descended, comprising a huge variety of life histories and ecological roles. Of the events in a typical crustacean development, metamorphosis is perhaps the most ubiquitous, challenging and highly studied. Despite this, our knowledge of the endocrinology which underpins metamorphosis is rudimentary at best; although several key molecules have been identified and studied in depth, the link between them is quite nebulous and leans heavily on well-explored insect models, which diverged from the Pancrustacea over 450 million years ago. As omics technologies become increasingly accessible, they bring the prospect of explorative molecular research which will allow us to uncover components and pathways unique to crustaceans. This review reconciles known components of crustacean metamorphosis and reflects on our findings in insects to outline a future search space, with focus given to the ecdysone cascade. To expand our knowledge of this ubiquitous endocrine system not only aids in our understanding of crustacean metamorphosis, but also provides a deeper insight into the adaptive capacity of arthropods throughout evolution., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy., Objective: To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews., Design: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group., Findings: The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted., Conclusions and Relevance: The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

Background: Improved dementia identification is a global health priority, and general practitioners (GPs) are often the first point of contact for people with concerns about their cognition. However, GPs often express uncertainty in using assessment tools and the evidence based on which tests are most accurate in identifying dementia is unclear. In particular, there is little certainty around how the accuracy of available brief cognitive assessments compares within a clinical family practice setting.Grounded in existing brief cognitive assessment evidence, we will compare the diagnostic test accuracy of the Mini Mental State Examination (MMSE) to the General Practitioner Assessment of Cognition (GPCOG) against the best available reference standard when used within a family practice setting., Methods: We will employ robust systematic review methods to assess studies of diagnostic accuracy where both the MMSE and GPCOG have been evaluated as direct comparisons, i.e. within the same study population. This approach will enable us to minimise between-study heterogeneity, to eliminate the risk of bias due to confounding and increase the opportunity to make clinically useful and useable comparisons of diagnostic accuracy across both the MMSE and GPCOG. This systematic review will be conducted using a pragmatic search strategy, refining searches that build upon studies identified as part of our overview of systematic reviews of the diagnostic accuracy of brief cognitive assessments for identifying dementia in primary care., Discussion: Through this systematic review, we aim to improve existing evidence on how the diagnostic accuracy of MMSE and GPCOG compares when used to identify dementia within the family practice setting. We also aim to make clinical practice recommendations based upon the variations in diagnostic accuracy identified between the MMSE and GPCOG., Competing Interests: The authors declare that they have no competing interests.

Objective: To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes., Research Design and Methods: We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with β-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change., Results: Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ≤ 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol [-0.5 vs. -1.4%], P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol [-0.2 vs. -1.4%], P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change., Conclusions: Clinical markers of low β-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aim: To assess the diagnostic accuracy of computed tomography coronary angiography (CTCA) using a combination of high-definition CT (HD-CTCA) and high level of reader experience, with invasive coronary angiography (ICA) as the reference standard, in high-risk patients for the investigation of coronary artery disease (CAD)., Materials and Methods: Three hundred high-risk patients underwent HD-CTCA and ICA. Independent experts evaluated the images for the presence of significant CAD, defined primarily as the presence of moderate (≥ 50%) stenosis and secondarily as the presence of severe (≥ 70%) stenosis in at least one coronary segment, in a blinded fashion. HD-CTCA was compared to ICA as the reference standard., Results: No patients were excluded. Two hundred and six patients (69%) had moderate and 178 (59%) had severe stenosis in at least one vessel at ICA. The sensitivity, specificity, positive predictive value, and negative predictive value were 97.1%, 97.9%, 99% and 93.9% for moderate stenosis, and 98.9%, 93.4%, 95.7% and 98.3%, for severe stenosis, on a per-patient basis., Conclusion: The combination of HD-CTCA and experienced readers applied to a high-risk population, results in high diagnostic accuracy comparable to ICA. Modern generation CT systems in experienced hands might be considered for an expanded role., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7-15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes., Design: Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide)., Data Sources: 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide)., Eligibility Criteria: Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin., Results: 10,917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being <30 years or <40 years. Use of/time to insulin treatment and body mass index (BMI) were also discriminatory. When combining features, BMI added little over age at diagnosis and/or time to insulin (<1% improvement in classification)., Conclusions: Despite finding only 11 studies, and considerable heterogeneity between studies, age at diagnosis and time to insulin were consistently the most discriminatory criteria. BMI, despite being widely used in clinical practice, adds little to these two criteria. The criteria identified are similar to the Royal College of General Practitioners National Health Service (RCGP/NHS) Diabetes classification guidelines, which use age at diagnosis <35 years and time to insulin <6 m. Until further studies are carried out, these guidelines represent a suitable classification scheme., Systematic Review Registration: PROSPERO reference CRD42012001736., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: Diagnostic test accuracy studies and meta-analyses may, in some cases, provide estimates that are highly improbable in practice; tailored meta-analysis provides a potential solution. To investigate the utility of tailored meta-analysis in synthesizing estimates of a test's accuracy compared with conventional meta-analysis for three case examples., Study Design and Setting: MEDLINE, Embase, and CINAHL were searched for relevant studies, and routine data were collected on the test positive rate and disease prevalence from the case settings to define an applicable region for each setting. Three cases were evaluated: mammography in the NHS Breast Screening Programme, Patient Health Questionnaire-9 to screen for depression in general practice, and Centor's criteria used to diagnose group A β-hemolytic streptococcus in general practice. For conventional meta-analysis, studies were selected using standard systematic review methods; for tailored meta-analysis, this selection was refined to those with results compatible with the applicable region for the setting., Results: In each example, studies were excluded as a result of incorporating an applicable region for the setting. Comparing tailored with conventional meta-analysis, the positive likelihood ratios (with 95% confidence intervals in brackets) were 36.5 (23.0, 57.9) and 19.8 (12.8, 30.9), respectively, for mammography and 4.89 (2.02, 11.8) and 2.35 (1.51, 3.67), respectively, for Centor's criteria. This had the effect of increasing the positive predictive value from 17% to 27% for mammography and 23% to 38% for Centor's criteria., Conclusion: Tailored meta-analysis has the potential to provide a plausible estimate for a test's accuracy, which is specific to the practice setting. When compared with conventional meta-analysis, the difference may, in some cases, be sufficient to lead to different decisions on patient management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen., Methods: We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response., Results: Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p<0.001), high C-peptide (p<0.001) and shorter diabetes duration (p = 0.01) whereas response defined by HbA1c change was associated with high HbA1c (p<0.001) only. We describe a simple novel method of defining treatment response based on a combination of HbA1c change and HbA1c achieved that defines response groups with similar baseline glycaemia., Conclusions: The outcome of studies aiming to identify predictors of treatment response to glucose lowering therapy may depend on how response is defined. Alternative definitions of response should be considered which minimise influence of baseline glycaemia.

Objectives: To determine a plausible estimate for a test's performance in a specific setting using a new method for selecting studies., Study Design and Setting: It is shown how routine data from practice may be used to define an "applicable region" for studies in receiver operating characteristic space. After qualitative appraisal, studies are selected based on the probability that their study accuracy estimates arose from parameters lying in this applicable region. Three methods for calculating these probabilities are developed and used to tailor the selection of studies for meta-analysis. The Pap test applied to the UK National Health Service (NHS) Cervical Screening Programme provides a case example., Results: The meta-analysis for the Pap test included 68 studies, but at most 17 studies were considered applicable to the NHS. For conventional meta-analysis, the sensitivity and specificity (with 95% confidence intervals) were estimated to be 72.8% (65.8, 78.8) and 75.4% (68.1, 81.5) compared with 50.9% (35.8, 66.0) and 98.0% (95.4, 99.1) from tailored meta-analysis using a binomial method for selection. Thus, for a cervical intraepithelial neoplasia (CIN) 1 prevalence of 2.2%, the post-test probability for CIN 1 would increase from 6.2% to 36.6% between the two methods of meta-analysis., Conclusion: Tailored meta-analysis provides a method for augmenting study selection based on the study's applicability to a setting. As such, the summary estimate is more likely to be plausible for a setting and could improve diagnostic prediction in practice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To identify the psychological effects of false-positive screening mammograms in the UK., Methods: Systematic review of all controlled studies and qualitative studies of women with a false-positive screening mammogram. The control group participants had normal mammograms. All psychological outcomes including returning for routine screening were permitted. All studies had a narrative synthesis., Results: The searches returned seven includable studies (7/4423). Heterogeneity was such that meta-analysis was not possible. Studies using disease-specific measures found that, compared to normal results, there could be enduring psychological distress that lasted up to 3 years; the level of distress was related to the degree of invasiveness of the assessment. At 3 years the relative risks were, further mammography, 1.28 (95% CI 0.82 to 2.00), fine needle aspiration 1.80 (95% CI 1.17 to 2.77), biopsy 2.07 (95% CI 1.22 to 3.52) and early recall 1.82 (95% CI 1.22 to 2.72). Studies that used generic measures of anxiety and depression found no such impact up to 3 months after screening. Evidence suggests that women with false-positive mammograms have an increased likelihood of failing to reattend for routine screening, relative risk 0.97 (95% CI 0.96 to 0.98) compared with women with normal mammograms., Conclusions: Having a false-positive screening mammogram can cause breast cancer-specific distress for up to 3 years. The degree of distress is related to the invasiveness of the assessment. Women with false-positive mammograms are less likely to return for routine assessment than those with normal ones.

Purpose of Review: Spontaneous preterm birth complicates 3-11% of pregnancies and is a major cause of neonatal mortality and morbidity worldwide. If accurate tests can be identified, a potentially effective screening strategy with an adjunct preventive therapy may be trialled to reduce the rate of spontaneous preterm birth or effective measures be deployed at an early stage of a suspected spontaneous preterm labour before the onset of cervical changes to ameliorate prematurity complications., Recent Findings: There are many tests predicting spontaneous preterm births, published in the literature individually or in a systematic review. The information has not been collated about all candidate tests simultaneously in a systematic review incorporating a framework on how these tests may be evaluated, modelled with an intervention to provide a number needed to treat and test to inform decision-making., Summary: There were 319 studies evaluating 22 tests. There are many promising tests, for example, history of previous spontaneous preterm birth, cervicovaginal swabs for markers such as fibronectin or HCG, cervical ultrasound, serum CRP and amniotic fluid interleukins for predicting spontaneous preterm birth, but none have exceptional accuracy and the quality of studies was generally poor. Some tests were able to achieve high LR+, but at the expense of LR-, that is, tests good for ruling in disease were poor for ruling out disease and vice versa.

Transfusion medicine has become a large and complex specialty. Although there are now systematic reviews covering many aspects of transfusion, these span a large number of clinical areas and are published across more than a hundred different medical journals, making it difficult for transfusion medicine practitioners and researchers to keep abreast of the current high-level evidence. In response to this problem, NHS Blood and Transplant's Systematic Review Initiative (SRI) has produced a comprehensive overview of systematic reviews in transfusion medicine. A systematic search (to December 2009) and screening procedure were followed by the appraisal of systematic reviews according to predefined inclusion criteria. The 340 eligible systematic reviews were mapped to 10 transfusion intervention groups and 14 topic groups within clinical medicine. Trends in the systematic review literature were examined and gaps in the literature described. The spread of systematic reviews across clinical areas was found to be very uneven, with some areas underreviewed and others with multiple systematic reviews on the same topic, making the identification of the best evidence for current transfusion practice a continuing challenge. References and links to all systematic reviews included in this overview can be freely accessed via the SRI's new online database, the Transfusion Evidence Library (www.transfusionguidelines.org)., (Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.)

Aims: Previous evaluation of autologous bone-marrow stem-cell (BMSC) therapy following acute myocardial infarction (AMI) suggests that cell dose and timing of stem-cell administration post-MI are important factors in the efficacy of cellular therapy. This study aimed to assess whether route of delivery and baseline left ventricular ejection fraction (LVEF) of the participants may also affect the outcome of BMSC treatment in patients with AMI and ischaemic heart disease (IHD)., Methods and Results: Randomized controlled trials of BMSCs as treatment for AMI and IHD were identified by searching MEDLINE, EMBASE, the Cochrane Library, and the Current Controlled Trials Register through to November 2008. Twenty-one trials (25 comparisons) with a total of 1091 participants were eligible. Data were analysed using a random-effects model. Improvement in LVEF in favour of the control was observed when BMSC were administered by intracoronary infusion [-0.19% (95% CI, -0.24 to -0.14; P < 0.00001)] in IHD patients. However, the effect on LVEF was statistically significant and in favour of BMSC when cells were delivered by intra-myocardial injection [5.85% (95% CI, 2.50-9.19; P = 0.0006)]. The significant improvement in LVEF observed in AMI patients was independent from the baseline LVEF of the participants. However, in patients suffering from chronic IHD, increase in LVEF was significant only in the group with lower LVEF at baseline [4.42% (CI, 1.87-6.96; P = 0.0007)]., Conclusion: Clinical evidence suggests that route of delivery and baseline LVEF influence the effect of BMSC therapy in treating AMI and chronic IHD.

Clarifying the existing evidence base is crucial to improve the effectiveness of transfusion practice. The UK Systematic Review Initiative has been pursuing this objective primarily through writing systematic reviews on important topics in transfusion medicine. Here, we describe our progress for the past 5 years. We are the only research group that identifies transfusion medicine randomized controlled trials (RCTs) for the Cochrane Central Register of Controlled Trials, and to date, we have contributed 3002 RCT citations. The article considers future challenges including the need for wider involvement from the transfusion medicine community in the process of maintaining and updating systematic reviews and the identification and prioritization of topics for further clinical research including clinical trials. Collaboration between international and local research groups is important if these challenges are to be met.

Objective: To investigate the potential cost-effectiveness of alternative 'test-and-treat' strategies in the prevention of spontaneous pre-term birth before 34 and 37 weeks' gestation., Design: Model-based economic evaluation. Setting. Clinics, general practices, health centers or any setting delivering antenatal care., Population: Asymptomatic women in early pregnancy and symptomatic women with threatened pre-term labor in later pregnancy., Methods: Data from systematic reviews of effectiveness and accuracy were combined into strategies and analyzed using a decision-tree model. Full deterministic and probabilistic sensitivity analyses were carried out., Main Outcome Measures: Spontaneous pre-term labor avoided for asymptomatic women and spontaneous pre-term birth avoided for symptomatic women., Results: The systematic reviews identified evidence on the accuracy of 22 types of tests and on the effectiveness of 40 possible interventions. Cost data were based on secondary evidence, supplemented with primary data from local sources. Testing prior to intervention was not shown to be the most cost-effective strategy in the main analyses for 34 and 37 weeks. Prophylactic fish oil in asymptomatic women, without prior testing, was highlighted as potentially cost-effective in preventing threatened pre-term labor before 34 weeks. In symptomatic women with a viable pregnancy, indomethacin without prior testing was a potentially cost-effective strategy to prevent pre-term birth occurring before 37 weeks., Conclusion: An effective, affordable and safe intervention applied to all mothers without prior testing is likely to be the most cost-effective strategy in the prevention of spontaneous pre-term labor and birth. The results reported in this paper are important for prioritizing future research, world-wide.

Aims: To provide systematic assessment of the safety and efficacy of autologous bone marrow-derived stem cell (BMSC) transplantation in acute myocardial infarction (AMI) based on clinical evidence., Methods and Results: The search strategy included MEDLINE, EMBASE, the Cochrane Library, and Current Controlled Trials Register through to August 2007 for randomized controlled trials of BMSC treatment for AMI. Thirteen trials (14 comparisons) with a total of 811 participants were included. Data were analysed using a random effects model. Overall, stem cell therapy improved left ventricular ejection fraction (LVEF) by 2.99% [95% confidence interval (CI), 1.26-4.72%, P = 0.0007], significantly reduced left ventricular end-systolic volume (LVESV) by 4.74 mL (95% CI, -7.84 to -1.64 mL, P = 0.003), and myocardial lesion area by 3.51% (95% CI, -5.91 to -1.11%, P = 0.004) compared with controls. Subgroup analysis revealed that there was statistical significant difference in LEVF in favour of BMSCs when cells were infused within 7 days following AMI and when the BMSC dose administered was higher than 10(8) BMSCs. In addition, there were trends in favour of benefit for most clinical outcomes examined, although it should be acknowledged that the 95%CI included no significant difference., Conclusion: Stem cell treatment for AMI still holds promise. Clinically, these data suggest that improvement over conventional therapy can be achieved. Further, adequately powered trials using optimal dosing, longer term outcome assessments, more reliable, and more patient-centred outcomes are required.

Objectives: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia., Data Sources: Major electronic databases were searched to January 2005 at least., Review Methods: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model., Results: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case., Conclusions: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

There continues to be a general but unfounded enthusiasm for fresh frozen plasma (FFP) usage across a range of clinical specialties in hospital practice. Clinical use of plasma has grown steadily over the last two decades in many countries. In England and Wales, there has not been a significant reduction in the use of FFP over the last few years, unlike red cells. There is also evidence of variation in usage among countries--use in England and Wales may be proportionately less per patient than current levels of usage in other European countries and the United States. Plasma for transfusion is most often used where there is abnormal coagulation screening tests, either therapeutically in the face of bleeding, or prophylactically in non-bleeding subjects prior to invasive procedures or surgery. Little evidence exists to inform best therapeutic plasma transfusion practice. Most studies have described plasma use in a prophylactic setting, in which laboratory abnormalities of coagulation tests are considered a predictive risk factor for bleeding prior to invasive procedures. The strongest randomised controlled trial (RCT) evidence indicates that prophylactic plasma for transfusion is not effective across a range of different clinical settings and this is supported by data from non-randomised studies in patients with mild to moderate abnormalities in coagulation tests. There are also uncertainties whether plasma consistently improves the laboratory results for patients with mild to moderate abnormalities in coagulation tests. There is a need to undertake new trials evaluating the efficacy and adverse effects of plasma, both in bleeding and non-bleeding patients, to understand whether the "presumed" benefits outweigh the "real risks". In addition, new haemostatic tests should be validated which better define risk of bleeding.

Background: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine., Objectives: To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine., Search Strategy: We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine. Most recent searches: June 2006., Selection Criteria: Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators., Main Results: Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials. No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, relative risk 2.24 (95% confidence interval 1.19 to 4.23)., Authors' Conclusions: We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

Randomised, controlled trials of good quality are a recognised means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomised trials involving fresh frozen plasma (FFP) indicates that most clinical indications for FFP, as currently recommended by practice guidelines, are not supported by evidence from randomised trials. This chapter will largely consider the implications of some of the findings from this systematic review. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias; no studies had taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. In addition, there is little evidence for the effectiveness of the prophylactic use of FFP. There is a pressing need to consider how best to develop new trials to determine the effectiveness of FFP. How this can be achieved can be illustrated by reference to studies of albumin in critical care. A recent, large and well-designed randomised trial (Saline versus Albumin Fluid Evaluation study; SAFE) in critical care found no evidence of an increase in mortality with the use of albumin compared to saline, which had been hypothesised in an earlier systematic review. How the study findings will actually now influence the clinical use of albumin remains to be seen. Although the SAFE trial showed no increase in mortality with albumin compared with saline, it is difficult to justify its use in critical care given its considerably greater cost.

Summary Randomized controlled trials of good quality are a recognized means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomized trials involving fresh frozen plasma (FFP) has been undertaken in parallel to the drafting of the updated British Committee for Standards in Haematology guidelines on the use of FFP. A total of 57 trials met the criteria for inclusion in the review. Most clinical uses of FFP, currently recommended by practice guidelines, are not supported by evidence from randomized trials. In particular, there is little evidence for the effectiveness of the prophylactic use of FFP. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias. No studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. There is a need to consider how best to develop new trials to determine the efficacy of FFP in different clinical scenarios to provide the evidence base to support national guidelines for transfusion practice. Trials of modified FFP (e.g. pathogen inactivated) are of questionable value when there is little evidence that the standard product is an effective treatment.

Aim: To ascertain and describe the number and epidemiology of randomised controlled trials (RCTs) focused on orthopaedic fractures., Methods: A sensitive literature search was carried out for the period 1966-May 1999. Labels were applied to each identified RCT to indicate the fracture type, and the main type of intervention., Results: 648 RCTs related to surgery of which 123 focused on adjuvant therapies and 88 related mainly to anaesthesia, analgesia, and radiography. The number of trials have increased exponentially with time so that the present decade has seen more RCTs published than all the other years added together., Conclusion: There is clearly an encouraging trend in the number of RCTs published. However there is a need to ensure that trials are on fracture types where there is most need for guidance. This growing evidence base should fuel systematic reviews and clinical guidelines within orthopaedics.

Objective: to investigate the effects of supported discharge after an acute admission in older people with undifferentiated clinical problems., Design: a systematic review of randomized controlled trials., Methods: we searched MEDLINE, CINAHL, the Cochrane Library, PsycLit and the Social Science Citation Index up to the end of 1997. This was augmented by hand-searching, follow-up of bibliographies and.direct enquiry of authors of included studies. Application of inclusion decisions, quality assessment and data abstraction were carried out independently by at least two of the reviewers. We tabulated the results of the included studies and used meta-analysis where appropriate to refine conclusions., Results: we finally included nine studies in the review, assessment of which revealed that bias was present, dictating the need for caution in interpreting results. Despite this, there was relative certainty that the proportion of those at home 6-12 months after admission is greater with supported discharge (odds ratio 1.4, 95% confidence interval 1.1- 2.0). This was associated with a consistent pattern of reduction in admission to long-stay care over the same period, without apparent increases in mortality. There was uncertainty about the effect of supported discharge on hospitalization. There were no rigorous research data on functional status, patient and carer satisfaction, and, in consequence, uncertainty about the overall effectiveness of supported discharge., Conclusions: we believe that the results of this review provide reassurance that supporting discharge from hospital to home is of value. However, important sources of uncertainty remain, suggesting the need for further research.

Objective: To identify and qualitatively synthesise the findings from all studies that have examined the performance and effect of near patient tests in the primary care setting., Design: Systematic review of published and unpublished research 1986-99., Main Outcome Measures: Test performance characteristics, measures of effect on clinical practice or patient outcome., Results: 101 relevant publications were identified. The general quality of these papers was low, and consequently only 32 papers were assessed in detail. Although these papers gave some indication of the value of near patient testing in areas such as anticoagulation monitoring and group A beta haemolytic streptococcus testing, the research raised many more questions than it answered. Almost no reports were found of unbiased assessment of the effect of near patient tests in primary care on patient outcomes, organisational outcomes, or cost., Conclusions: Available research provides little evidence to guide the expansion of use of near patient testing in primary care. Further research is needed in areas of clinical practice where near patient tests might be most beneficial.

Aims and Objectives: The aim was to identify publications relating to near patient testing (NPT), the use of alternative delivery systems between laboratory and general practice, including electronic data interchange (EDI), and computerised diagnostic decision support (CDDS), in the primary care setting to answer the following questions. What is the availability of NPT for primary care? What evidence is available to support the clinical effectiveness of NPT? What evidence is available on the accuracy and reliability of NPT within primary care? What evidence is available on the cost-effectiveness of different NPTs? How may CDDS improve the effectiveness of NPT? What evidence is available that compares NPT and existing laboratory services? What evidence is available on the cost-effectiveness of EDI or alternative delivery systems?, How the Research Was Conducted: Eight databases were searched, and the bibliographies from relevant publications checked for completeness. Unpublished work and publications not included in the databases were obtained by personal contact with collaborators, and from a postal survey sent to heads of academic departments of general practice and clinical chemistry and to researchers active or interested in the field worldwide. Questionnaires were also sent to 150 commercial organisations. Publications that met agreed definitions and reported original data were included in the systematic review. Of the 1057 publications identified, 102 (92 related to NPT, eight to CDDS, and two to EDI) were passed to the reviewers for appraisal of validity. The limited amount of published research relating to any particular NPT prohibited meta-analysis. Scoring systems to assess the validity of evaluations were also difficult to apply., Research Findings: A wide variety of NPT systems have been developed. In general, the quality of the methods reported in the literature was poor. The issue of patient convenience and acceptability has not been adequately addressed. No evaluations of alternative delivery systems met the review criteria. No studies have evaluated the telephone or fax machine as a means of reporting results. For EDI, the majority of papers were descriptive. EDI and alternative delivery systems are not a replacement for NPT when the provision of an immediate result might have an impact on the quality of care. EDI may have clinical and cost advantages over traditional means of communication, but this has not been evaluated. The advisory role of the laboratory can be supported by CDDS. The use of CDDS and NPT has not, however, been fully evaluated. Few economic analyses have been conducted, and most were simple cost analyses. There are insufficient data for conclusions to be drawn on the cost-effectiveness of NPT in primary care., Recommendations: FURTHER SYSTEMATIC REVIEWS: Subject-specific systematic reviews are required that include laboratory and secondary care studies, and consider the potential for altering current management and patient acceptability. Priority topics include: biochemistry profiles on desktop analysers; cholesterol testing; urinalysis for the diagnosis of urinary tract infection; anticoagulation control; NPTs for the identification of acute infection. (ABSTRACT TRUNCATED)

The use of research evidence depends on more than its quality. If one considers other factors that influence the use of evidence, the quantity of accessible evidence and initiatives ensuring a wider understanding of it must be equally important. In consequence, improving the quality of research evidence alone will not necessarily lead to its greater use.