Search

Abstract Background Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. Methods The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. Results Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. Conclusions We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Applying coatings of paraffins and other synthetic waxes is a common approach to impart hydrophobic properties to fibres and thus control their surface characteristics. Replacing these fossil-based products with alternatives derived from renewable resources can contribute to humankind’s transition to a sustainable bioeconomy. This study presents the coating of hemp fibres with waxes extracted from pine bark as an exemplar application. Two bio-based emulsifiers were used to prepare wax emulsions suitable for a dry blending process. The coatings on the fibres were characterised, quantified, and visualised using a combination of spectroscopic and microscopic techniques. Confocal fluorescence microscopy was an excellent tool to investigate the spatial distribution of the pine bark waxes on the fibre surfaces. While successful deposition was demonstrated for all tested formulations, coating homogeneity varied for different emulsifiers. Compounding the hemp fibres with a bio-based polyester resulted in the substantial improvement of the mechanical behaviour. However, the presence of a wax coating on the fibres did not lead to a significant change in mechanical properties compared to the controls with uncoated fibres. Optimising the composite chemistry or adjusting the processing conditions might improve the compatibility of the hemp fibres with the matrix material, resulting in enhanced mechanical performance.

We present a case of a 70-year-old male who was brought to the hospital with altered mental status and was found to have 2 serious complications of cocaine use which are Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) syndrome and mesenteric ischemia. CHANTER syndrome is a recently described constellation of radiologic and clinical findings and has a strong association with opiates, and/or other drugs of abuse, including cocaine. Even though CHANTER has many similarities with other ischemic, anoxic, and/or toxic injuries related to substance abuse such as clinical presentation and restricted diffusion on magnetic resonance imaging (MRI); the typical distribution of affected regions in the brain is helpful in differentiating from other injuries. With this study, we aim to emphasize the clues that separate CHANTER syndrome from other acute neurologic problems in the setting of substance use. Our case also suggests that the obstructive hydrocephalus, a known possible complication of CHANTER, is likely seen in the cases with severe and central cerebellar involvement. Additionally, it is not common to see complications in 2 different systems concurrently and a multisystemic approach is crucial to a patient with cocaine use to prevent missed life-threatening consequences throughout the various body systems.

Abstract Background Development of pleural effusion (PE) following CABG is common. Post-CABG PE are divided into early- (within 30 days of surgery) and delayed-onset (30 days–1 year) which are likely due to distinct pathological processes. Some experts suggest asbestos exposure may confer an independent risk for late-onset post-CABG PE, however no large studies have explored this potential association. Research question To explore possible association between asbestos exposure and post-CABG PE using routine data. Methods All patients who underwent CABG 01/04/2013–31/03/2018 were identified from the Hospital Episode Statistics (HES) Database. This England-wide population was evaluated for evidence of asbestos exposure, pleural plaques or asbestosis and a diagnosis of PE or PE-related procedure from 30 days to 1 year post-CABG. Patients with evidence of PE three months prior to CABG were excluded, as were patients with a new mesothelioma diagnosis. Results 68,150 patients were identified, of whom 1,003 (1%) were asbestos exposed and 2,377 (3%) developed late-onset PE. After adjusting for demographic data, Index of Multiple Deprivation and Charlson Co-morbidity Index, asbestos exposed patients had increased odds of PE diagnosis or related procedure such as thoracentesis or drainage (OR 1.35, 95% CI 1.03–1.76, p = 0.04). In those with evidence of PE requiring procedure alone, the adjusted OR was 1.66 (95% CI 1.14–2.40, p = 0.01). Additional subgroup analysis of the 518 patients coded for pleural plaques and asbestosis alone revealed an adjusted OR of post-CABG PE requiring a procedure of 2.16 (95% CI 1.38–3.37, p = 0.002). Interpretation This large-scale study demonstrates prior asbestos exposure is associated with modestly increased risk of post-CABG PE development. The risk association appears higher in patients with assigned clinical codes indicative of radiological evidence of asbestos exposure (pleural plaques or asbestosis). This association may fit with a possible inflammatory co-pathogenesis, with asbestos exposure ‘priming’ the pleura resulting in greater propensity for PE evolution following the physiological insult of CABG surgery. Further work, including prospective studies and clinicopathological correlation are suggested to explore this further.

Higher body mass index (BMI) is a risk factor for thrombosis. Platelets are essential for hemostasis but contribute to thrombosis when activated pathologically. We hypothesized that higher BMI leads to changes in platelet characteristics, thereby increasing thrombotic risk. The effect of BMI on platelet traits (measured by Sysmex) was explored in 33 388 UK blood donors (INTERVAL study). Linear regression showed that higher BMI was positively associated with greater plateletcrit (PCT), platelet count (PLT), immature platelet count (IPC), and side fluorescence (SFL, a measure of mRNA content used to derive IPC). Mendelian randomization (MR), applied to estimate a causal effect with BMI proxied by a genetic risk score, provided causal estimates for a positive effect of BMI on both SFL and IPC, but there was little evidence for a causal effect of BMI on PCT or PLT. Follow-up analyses explored the functional relevance of platelet characteristics in a pre-operative cardiac cohort (COPTIC). Linear regression provided observational evidence for a positive association between IPC and agonist-induced whole blood platelet aggregation. Results indicate that higher BMI raises the number of immature platelets, which is associated with greater whole blood platelet aggregation in a cardiac cohort. Higher IPC could therefore contribute to obesity-related thrombosis.

Background Access to specialised early intervention mental health services for children, including group counselling for parents/carers, is still a challenge in non-metropolitan areas of Australia. Aim To gain understanding of the acceptability of a school-based targeted parenting group program delivered via telehealth by exploring the experiences of parents/carers, clinicians and school staff, and asking what works, how, why and in what circumstances. Methods Caregivers, clinicians and school staff involved in the delivery of a mental health program via telehealth into primary schools in two rural Local Health Districts (LHDs) in southern New South Wales (NSW) were invited to participate in interviews and/or focus group discussions. Thematic analysis of the data was conducted with reference to realist theory. Findings We conducted semi-structured interviews with 12 caregivers, five semi-structured interviews and two focus group discussions with school staff from six participating schools, and three focus groups with seven clinicians who delivered the intervention. We found that the intervention and micro contexts interacted to influence acceptability by initiating or enhancing cohesion among caregivers, establishing channels of communication between caregivers and teachers, and connection between caregivers and clinicians despite geographic distance. Several adaptations were made to strengthen the therapeutic alliance between caregivers and clinicians. Conclusion Relationships crucial to the success of delivering psychological group counselling were established. Regional community contexts can facilitate acceptability of parenting group counselling delivered into schools via telehealth. Implementation of the program was flexible enough to allow clinicians to adjust their approach and materials to better suit the telehealth modality.

BackgroundMyocardial infarction induces elevation of progenitor cells in the circulation, a reparative response inhibited by type-2 diabetes.ObjectivesDetermine if myocardial infarct severity and diabetes interactively influence the migratory activity of CD34+/CXCR4+ progenitor cells and if the migratory test predicts cardiac outcomes.Materials and methodsA longitudinal study was conducted on patients with or without diabetes with a STEMI or NSTEMI. CD34+/CXCR4+ cells were measured in the peripheral blood using flow cytometry, and migratory activity was tested in vitro on cells isolated from samples collected on days 0 and 4 post-infarct. Cardiac function was assessed at three months using cardiac MRI.ResultsOf 1,149 patients screened, 71 (6.3%) were eligible and consented. Fifty had STEMI (16 with diabetes) and 21 NSTEMI (8 with diabetes). The proportion of CD34+/CXCR4+ cells within blood mononuclear cells was 1.96 times higher after STEMI compared with NSTEMI (GMR = 1.96, 95% CI 0.87, 4.37) and 1.55 times higher in patients with diabetes compared to patients without diabetes (GMR = 1.55, 95% CI 0.77, 3.13). In the latter, STEMI was associated with a 2.42-times higher proportion of migrated CD34 + /CXCR4 + cells compared with NSTEMI (GMR = 2.42, 95% CI 0.66, 8.81). In patients with diabetes, the association was the opposite, with a 55% reduction in the proportion of migrated CD34+/CXCR4+ cells. No statistically significant associations were observed between the frequency in peripheral blood or in vitro migration capacity of CD34+/CXCR4+ cells and MRI outcomes.ConclusionWe document the interaction between infarct and diabetes on the migratory activity of CD34+/CXCR4+ cells. The test did not predict functional outcomes in the studied cohort.

Objective To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England.Design A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT).Data sources Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES).Setting Primary and secondary care.Participants Patients ≥18 years old with ACS undergoing emergency PCI.Interventions Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI).Main outcome measures Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE).Results In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only).Conclusions In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel.Trial registration number ISRCTN76607611.

ObjectiveThe aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.MethodsData from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.ResultsOf the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).ConclusionsThe mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

Objective To determine the benefits and harms of pre-admission interventions (prehabilitation) on postoperative outcomes in patients undergoing major elective surgery.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) (published or unpublished). We searched Medline, Embase, CENTRAL, DARE, HTA and NHS EED, The Cochrane Library, CINAHL, PsychINFO and ISI Web of Science (June 2020).Setting Secondary care.Participants Patients (≥18 years) undergoing major elective surgery (curative or palliative).Interventions Any intervention administered in the preoperative period with the aim of improving postoperative outcomes.Outcomes and measures Primary outcomes were 30-day mortality, hospital length of stay (LoS) and postoperative complications. Secondary outcomes included LoS in intensive care unit or high dependency unit, perioperative morbidity, hospital readmission, postoperative pain, heath-related quality of life, outcomes specific to the intervention, intervention-specific adverse events and resource use.Review methods Two authors independently extracted data from eligible RCTs and assessed risk of bias and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Random-effects meta-analyses were used to pool data across trials.Results 178 RCTs including eight types of intervention were included. Inspiratory muscle training (IMT), immunonutrition and multimodal interventions reduced hospital LoS (mean difference vs usual care: −1.81 days, 95% CI −2.31 to −1.31; −2.11 days, 95% CI −3.07 to −1.15; −1.67 days, 95% CI −2.31 to −1.03, respectively). Immunonutrition reduced infective complications (risk ratio (RR) 0.64 95% CI 0.40 to 1.01) and IMT, and exercise reduced postoperative pulmonary complications (RR 0.55, 95% CI 0.38 to 0.80, and RR 0.54, 95% CI 0.39 to 0.75, respectively). Smoking cessation interventions reduced wound infections (RR 0.28, 95% CI 0.12 to 0.64).Conclusions Some prehabilitation interventions may reduce postoperative LoS and complications but the quality of the evidence was low.PROSPERO registration number CRD42015019191.

Abstract Background We determined whether it is feasible to identify important changes in care management resulting from cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway from hospital episode data, in order to construct a composite primary outcome (hypothesised to reduce the risk of major adverse cardiac-related events, MACE) to compare patients exposed to CMR or not. Methods We used Hospital Episode Statistics (HES) and Patient Episode Database for Wales (PEDW) to identify clinical events that reflected important changes in management in the year following the index admission in five subgroups of patients who activated the PPCI pathway recruited as part of a feasibility cohort study (n = 1655 with HES/PEDW data). For all subgroups, we identified frequency of events and time to the first event for each change in management. Results We identified all clinical events (new diagnoses, additional diagnostic tests and procedures) except for medication prescriptions. Diagnostic tests were underestimated because most are carried out in outpatient clinics and outpatient datasets had missing procedure codes for 74% of patients (some tests done in hospital may also not be recorded). We successfully tabulated frequencies of events and distributions of times to first event for most changes in management by CMR status and in CMR / non CMR centres. Conclusions It is feasible to identify changes in care management between patients who have / do not have CMR within relevant patient subgroups. Further work to derive a weighting algorithm is required before attempting to combine the events in a composite endpoint.

The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.

Secondary bacterial infection in COVID-19 patients is associated with increased mortality and disproportionately affects critically ill patients. This single-centre retrospective observational study investigates the comparative efficacy of change in procalcitonin (PCT) and other commonly available biomarkers in revealing or predicting microbiologically proven secondary infection in critical COVID-19 patients. Adult patients admitted to an intensive care unit (ICU) with confirmed SARS-CoV-2 infection between 9 March 2020 and 5 June 2020 were recruited to the study. For daily biomarker and secondary infection, laboratory-confirmed bloodstream infection (LCBI) and ventilator-associated pneumonia/tracheobronchitis (VAP/VAT) data were collected. We observed a PCT rise in 53 (81.5%) of the patients, a C-reactive protein (CRP) rise in 55 (84.6%) and a white blood cell count (WBC) rise in 61 (93.8%). Secondary infection was confirmed in 33 (50.8%) of the patients. A PCT rise was present in 97.0% of patients with at least one confirmed VAP/VAT and/or LCBI event. CRP and WBC rises occurred in 93.9% and 97.0% of patients with confirmed VAP/VAT and/or LCBI, respectively. Logistic regression analysis found that, when including all biomarkers in the same model, there was a significant association between PCT rise and the occurrence of LCBI and/or VAP/VAT (OR = 14.86 95%CI: 2.20, 342.53; p = 0.021). Conversely, no statistically significant relationship was found between either a CRP rise (p = 0.167) or a WBC rise (p = 0.855) and the occurrence of VAP/VAT and/or LCBI. These findings provide a promising insight into the usefulness of PCT measurement in predicting the emergence of secondary bacterial infection in ICU.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. Methods WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10–5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran–Mantel–Haenszel test to compare gene-level variant counts in cases vs controls. Results No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10–12), SOD1 (p = 8.9 × 10–9) and NEK1 (p = 1.1 × 10–9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10–3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). Conclusions While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

Scabies is a relatively common parasitic infection, which has sometimes been associated with the formation of granuloma annulare. We report the case of an 86-year-old female who developed a non-necrotizing granulomatous dermatitis after a scabies infestation. This case highlights the importance of considering scabies in the differential diagnosis when granulomatous dermatitis is noted histologically that cannot be explained by other causes.

American Indian tribes historically survived on hunting, gathering, and farming activities. As federal policy changed, reservations were estab­lished, which limited some of these hunting and gathering activities. Nevada is home to Washoe, Shoshone, and Paiute American Indians. There are 19 federally recognized American Indian tribes with 27 reservations and colonies geographically dispersed across the state of Nevada. Several of these reservations are near Nevada’s small, rural towns where access to fruits and vegetables is lim­ited. Often, the residents of small rural towns next to the reservation are unaware of the tribal cultural history. University of Nevada Cooperative Exten­sion created an elementary nutrition education pro­gram called Veggies for Kids, for use in reservation schools and off-reservation schools under the U.S. Department of Agriculture (USDA) Supplemental Nutrition Assistance Program–Education (SNAP-Ed). The Veggies for Kids program utilizes tradi­tional foods, tribal language, and gardening experi­ences as building blocks to introduce healthy eating and increase fruit and vegetable intake among ele­mentary students. For the 2017–2018 school year, pre- and post-test data were collected from 45 American Indian kindergarten students attending schools on reservations and 486 kindergarten stu­dents in off-reservation schools located next to a reservation. Methods of data analysis included descriptive statistics, paired sample t-tests, and nonparametric McNemar testing. Results from the kindergarten data showed an increase in test scores of students correctly identifying USDA’s MyPlate food groups, naming selected fruits and vegetables provided during the program, self-reporting water consumption, and selecting physical activity. Cumulative student test scores for all kindergarten data were statistically significant at p-value

Introduction‘Real world’ bleeding in patients exposed to different regimens of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) have a clinical and economic impact but have not been previously quantified.Methods and analysisWe will use linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations eligible for three ‘target trials’ in patient groups: percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); conservatively managed (medication only) acute coronary syndrome (ACS). Patients ≥18 years old will be eligible if, in CPRD records, they have: ≥1 year of data before the index event; no prescription for DAPT or anticoagulants in the preceding 3 months; a prescription for aspirin or DAPT within 2 months after discharge from the index event. The primary outcome will be any bleeding event (CPRD or HES) up to 12 months after the index event. We will estimate adjusted HR for time to first bleeding event comparing: aspirin and clopidogrel (reference) versus aspirin and prasugrel or aspirin and ticagrelor after PCI; and aspirin (reference) versus aspirin and clopidogrel after CABG and ACS. We will describe rates of bleeding in patients prescribed TT (DAPT plus an anticoagulant). Potential confounders will be identified systematically using literature review, semistructured interviews with clinicians and a short survey of clinicians. We will conduct sensitivity analyses addressing the robustness of results to the study’s main limitation—that we will not be able to identify the intervention group for patients whose bleeding event occurs before a DAPT prescription in CPRD.Ethics and disseminationThis protocol was approved by the Independent Scientific Advisory Committee for the UK Medicines and Healthcare Products Regulatory Agency Database Research (protocol 16_126R) and the South West Cornwall and Plymouth Research Ethics Committee (17/SW/0092). The findings will be presented in peer-reviewed journals, lay summaries and briefing papers to commissioners/other stakeholders.Trial registration number76607611; Pre-results.

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1β, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1β, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1β and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1β function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.

BACKGROUND:In patients with reperfused ST-elevation myocardial infarction (STEMI) both invasive and non-invasive assessments of microvascular dysfunction, the index of microcirculatory resistance (IMR), and microvascular obstruction (MVO) by cardiovascular magnetic resonance (CMR), independently predict poor long-term outcomes. AIMS:The aims of this study were to investigate whether an invasive parameter (IMR), assessed at the time of primary percutaneous intervention (PPCI), could predict the extent of MVO in proportion to infarct size (MVO index). METHODS:50 patients presenting with STEMI and TIMI flow ≤ I in the infarct related artery were prospectively recruited to the study, before undergoing PPCI. All patients underwent invasive IMR assessment at maximal hyperaemia using adenosine, and following stent insertion. CMR was performed on day 2 following STEMI, MVO was assessed both on first-pass rest perfusion (early MVO) and in the late gadolinium enhancement (LGE) images (late MVO) along with infarct size. The MVO index was calculated as the ratio of late MVO/infarct size. Differences between IMR quartiles and the MVO index were investigated. RESULTS:The median IMR was 38.5 (range 9 to 202). The median size of late MVO was 1.9% LV (range 0 to 21.0% LV). IMR predicted late MVO (p

Background: Anaemia, coagulopathic bleeding and transfusion are strongly associated with organ failure, sepsis and death following cardiac surgery. Objective: To evaluate the clinical effectiveness and cost-effectiveness of medical devices used as diagnostic and therapeutic tools for the management of anaemia and bleeding in cardiac surgery. Methods and results: Workstream 1 – in the COagulation and Platelet laboratory Testing in Cardiac surgery (COPTIC) study we demonstrated that risk assessment using baseline clinical factors predicted bleeding with a high degree of accuracy. The results from point-of-care (POC) platelet aggregometry or viscoelastometry tests or an expanded range of laboratory reference tests for coagulopathy did not improve predictive accuracy beyond that achieved with the clinical risk score alone. The routine use of POC tests was not cost-effective. A systematic review concluded that POC-based algorithms are not clinically effective. We developed two new clinical risk prediction scores for transfusion and bleeding that are available as e-calculators. Workstream 2 – in the PAtient-SPecific Oxygen monitoring to Reduce blood Transfusion during heart surgery (PASPORT) trial and a systematic review we demonstrated that personalised near-infrared spectroscopy-based algorithms for the optimisation of tissue oxygenation, or as indicators for red cell transfusion, were neither clinically effective nor cost-effective. Workstream 3 – in the REDWASH trial we failed to demonstrate a reduction in inflammation or organ injury in recipients of mechanically washed red cells compared with standard (unwashed) red cells. Limitations: Existing studies evaluating the predictive accuracy or effectiveness of POC tests of coagulopathy or near-infrared spectroscopy were at high risk of bias. Interventions that alter red cell transfusion exposure, a common surrogate outcome in most trials, were not found to be clinically effective. Conclusions: A systematic assessment of devices in clinical use as blood management adjuncts in cardiac surgery did not demonstrate clinical effectiveness or cost-effectiveness. The contribution of anaemia and coagulopathy to adverse clinical outcomes following cardiac surgery remains poorly understood. Further research to define the pathogenesis of these conditions may lead to more accurate diagnoses, more effective treatments and potentially improved clinical outcomes. Study registration: Current Controlled Trials ISRCTN20778544 (COPTIC study) and PROSPERO CRD42016033831 (systematic review) (workstream 1); Current Controlled Trials ISRCTN23557269 (PASPORT trial) and PROSPERO CRD4201502769 (systematic review) (workstream 2); and Current Controlled Trials ISRCTN27076315 (REDWASH trial) (workstream 3). Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 5, No. 17. See the NIHR Journals Library website for further project information.

In the original publication of this article [1], the author noted two corrections after publication.

Physician advocacy and leadership is increasingly recognized as an important part of our social responsibility. Frameworks, such as CanMEDS, have set out definitions of health advocacy and leadership for medical education. Despite calls for mandatory advocacy and leadership teaching and potential wellness benefits, presently medical curricula do not usually teach practical advocacy and leadership skills to learners. There is also a demonstrated disconnect between staff and resident perceptions of advocacy. Our group set out to create an innovative Advocacy and Leadership Curriculum (ALC) to fill this gap. A collaboration of over twenty medical students and professors from across Canada and the U.S worked over the past year to survey students, conduct curriculum mapping, examine current literature and practices in order to inform the creation of an ALC. A competency- and milestone-based ALC was created based on this data and reviewed by experts in medical education and/or physician advocacy. This ALC addresses three spheres of advocacy: the Patient level, the Institutional level, and the Population level (which includes the Community). A guiding principle of the ALC is to form positive working partnerships with communities and patients and to collaborate with other health professionals to advocate with, and on behalf of, patients. CanMEDS-based Learning Objectives, divided into theoretical, skills-based, and application-based categories, form the core of the program. The curriculum prepares learners for real-world advocacy through longitudinal projects, interdisciplinary work, and community-based service learning. Novel engagement of other professionals and physician advocates to act as advocacy preceptors is central to the curriculum. Innovative assessment techniques- such as advocacy simulations, longitudinal study of physician advocacy activity, and focus on attitudes and behaviour as well as knowledge and practical advocacy skills- are introduced. The ALC serves as an adaptable model for the training of socially responsible medical learners who are conversant in advocacy techniques and able to advocate with patients, within institutions, and with populations. Projects resulting from the ALC will improve medical school social accountability.

During the early 1970s, within a broader climate of social, political and institutional upheaval, students of architecture sought opportunities to redefine the architectural project beyond traditional education and practice. While these activities often involved highly speculative drawn and modelled projects, DIY structures or performance-based works, this paper examines instead the use of mobile architecture through a series of retrofitted bus projects from the period. Perhaps the most well-known example, the AD/AA/Polyark bus, was the outcome of collaboration between 'Architectural Design', the Architectural Association London and Cedric Price. In 1973, the same year the AD/AA/Polyark bus departed London, students at the University of Queensland, Australia, also embarked on tours of rural Queensland and New South Wales in their adapted double-decker bus, the Mobile Design Research Unit. The following year students at the University of Sydney undertook an eight-month tour of Australia as part of their own retrofitted bus project, the Australian Communications Capsule. While the AD/AA/Polyark project was an extension of the Architectural Association, both the Mobile Design Research Unit and the Australian Communications Capsule appear to have operated outside of any formal arrangement with the university. Through their mobility, the buses facilitated modes of interaction between architectural thinking and the broader community, while creating physical distance between these practices and their institutional connections. At stake was the question of architecture’s agency within its broader socio-political context. This paper describes a moment during the early to mid-1970s when mobility operated as a tool for alternative modes of architectural education and practice.

Lack of reproducibility is an ongoing problem in some areas of the biomedical sciences. Poor experimental design and a failure to engage with experienced statisticians at key stages in the design and analysis of experiments are two factors that contribute to this problem. The RIPOSTE (Reducing IrreProducibility in labOratory STudiEs) framework has been developed to support early and regular discussions between scientists and statisticians in order to improve the design, conduct and analysis of laboratory studies and, therefore, to reduce irreproducibility. This framework is intended for use during the early stages of a research project, when specific questions or hypotheses are proposed. The essential points within the framework are explained and illustrated using three examples (a medical equipment test, a macrophage study and a gene expression study). Sound study design minimises the possibility of bias being introduced into experiments and leads to higher quality research with more reproducible results.

In order to understand the implications of agriculture on the environment, ecosystem health must be measured. Observing the presence of a biological indicator within an ecosystem is one such method. In this study, male euglossine bees were observed using as attractant cineole 1:8, at adjacent organic (La Paz) and conventional (La Carena) coffee farms near the Northern Barranca River, San Ramón, Alajuela, Costa Rica. Simultaneous data collections were conducted on both farms in April 2004 (late-dry season) and June 2004 (early-rainy season) and combined with the findings of August 2004 (mid-rainy season). These observations show that orchid bees are a viable bio-indicator of organic farm health on a seasonal basis. In the dry season there was no significant difference in orchid bee abundance between the two farms. There is a strong tendency for more bees during the rainy season, suggesting that orchid bee abundance is linked to seasonality and forest access. Rev. Biol. Trop. 54 (4): 1189-1195. Epub 2006 Dec. 15Con el propósito de entender las implicaciones de la agricultura orgánica (en comparación con la tradicional) para el "estado de salud ambiental", usamos aceite de eucalipto (1:8-cineole), para monitorear la abundancia de machos de abejas de las orquídeas (euglosinas) como posibles bioindicadores. Comparamos una finca de café orgánico (La Paz) y una tradicional (La Carena), cerca del Río Barranca en San Ramón de Alajuela, Costa Rica. Las tomas simultáneas de datos fueron realizadas en ambas fincas en abril del 2004 (a finales de la estación seca), en junio del 2004 (a principios de la estación lluviosa) y en agosto del 2004 (a mediados de la estación lluviosa). Estas abejas pueden ser bioindicadores viables de la salud de las fincas orgánicas de café (en comparación con las tradicionales) durante la estación lluviosa. Durante la estación seca no se mostró una diferencia significativa en la abundancia de las abejas de orquídeas, entre una y otra finca. Hubo un número significativo de euglosinas en las fincas orgánicas durante la estación lluviosa; sugiriendo que el aumento está vinculado con la estacionalidad y el acceso al bosque en su hábitat natural

Objective: To examine smoking habits before and during pregnancy, as well as factors associated with smoking cessation, in three European settings. Methods: Women seeking antenatal care in Ashford (UK), Minorca and Barcelona (Spain) were recruited to the Asthma Multicenter Infant Cohort Study (AMICS). Questionnaires inquiring into the smoking habits of each woman and her partner, demographic data, occupation, educational level, number of previous children, breast feeding, alcohol intake, and history of asthma and of other allergic diseases were completed during pregnancy and in the first year after delivery. Results: A total of 1 572 pregnant women were included in the three cohorts. Smoking prior to pregnancy was more common in Barcelona (46.2%) than in Minorca (39.8%) or Ashford (31.6%). Cessation rates during pregnancy also differed: 18% of women in Ashford, 20.4% in Minorca and 31.9% in Barcelona were still smoking during the first trimester. In a multivariate regression model, the factors showing a significant (negative) association with smoking cessation during pregnancy were having older children, having a partner who smoked and starting smoking at a young age. Conclusions: Baseline smoking habits and changes in smoking habits during pregnancy significantly differed between the three communities studied. Women pregnant with their first child, those who had started smoking at a later age and those whose partners were non-smokers were more likely to stop smoking when pregnant.Objetivo: Describir el hábito tabáquico antes y durante el embarazo y los factores asociados con su cese con relación al embarazo en distintos entornos europeos. Métodos: Se ha incluido en el estudio a las mujeres captadas durante el embarazo para participar en el estudio AMICS (Asthma Multicentre Infant Cohort Study) en Ashford (Reino Unido), Barcelona y Menorca (España). Se administró un cuestionario durante el embarazo y otro durante el primer año posparto, que incluía los siguientes aspectos: hábito tabáquico de la mujer y de su compañero, datos demográficos, ocupación, nivel de estudios, número de hijos previos, lactancia materna, consumo de alcohol e historia de asma y otras enfermedades alérgicas. Resultados: Entre las 3 cohortes se incluyó a un total de 1.572 mujeres. Antes del embarazo, el porcentaje de mujeres fumadoras fue mayor en Barcelona (46,2%) que en Menorca (39,8%) o Ashford (31,6%). Las tasas de abandono del hábito tabáquico en relación con el embarazo también variaron en cada cohorte, de manera que durante el primer trimestre de embarazo continuaron fumando el 18% en Ashford, el 20,4% en Menorca y el 31,9% en Barcelona. En un modelo de regresión múltiple, tener hijos previos, que el compañero sea fumador y haber empezado a fumar más joven muestran una asociación (negativa) con la probabilidad de abandonar el tabaco en relación con el embarazo. Conclusiones: El consumo de tabaco antes y durante el embarazo muestra importantes diferencias en las 3 comunidades estudiadas. Las mujeres en su primer embarazo, que empezaron a fumar más tardíamente y cuyo compañero no fuma son las que con mayor frecuencia abandonan el tabaco al quedarse embarazadas.