UK perspective on the changing landscape of non-invasive cardiac testing.

Objective: To document UK rates of exercise treadmill testing, functional stress testing and CT coronary angiography (CTCA). Specific aims were to determine how rates have changed in the context of changing guideline recommendations within the UK and to identify regional inequalities in the utilisation of testing modalities. Secondary objectives were to compare these trends with national data on revascularisation. Methods: 159 acute National Health Service trusts were served Freedom of Information (FOI) requests to provide total numbers of CTCA and functional imaging tests for each financial year from 2011-2012 to 2016-2017. Results: The FOI requests yielded data from 88% of Trusts, increasing from 81.9% in 2011-2012% to 92.1% in 2016-2017. Exercise treadmill tests (ETTs) were performed by over 97% of Trusts. ETT was the most commonly performed diagnostic test in the UK across the study period despite declining by 8.4%. Utilisation of non-invasive stress imaging tests increased by 80.9% during the same period. Myocardial perfusion scintigraphy and stress echocardiography increased by 25.8% and 73.9%, respectively. The 268% increase in CTCA scans was yet greater. Trends in test utilisation during the study period showed important regional differences between devolved nations. Comparably, only small changes in rates of invasive coronary angiography and revascularisation have been reported during the study period. Conclusion: Non-invasive imaging in UK Trusts has increased substantially since 2010 with only a small decline in use of the ETT and minimal changes in rates of invasive coronary angiography and revascularisation in the same time period

traT gene sequences, serum resistance and pathogenicity-related factors in clinical isolates of Escherichia coli and other gram-negative bacteria

The R6-5 plasmid-specified outer membrane protein, TraT protein, has previously been shown to mediate resistance to bacterial killing by serum. Colony hybridization with a 700 bp DNA fragment carrying most of the traT gene was used to examine the prevalence of traT in Gram-negative bacteria, particularly strains of Escherichia coli, isolated from clinical specimens. traT was found in isolates of E. coli, Salmonella, Shigella and Klebsiella, but not in Pseudomonas, Aeromonas or Plesiomonas, nor in the few isolates of Enterobacter, Proteus, Acinetobacter, Citrobacter, Serratia or Yersinia that were examined. It was detected in a significantly higher proportion of the E. coli strains isolated from the blood of patients with bacteraemia/septicaemia or from faeces of patients with enteric infections (50-70%) than in that of strains isolated from normal faeces (20-40%). The incidence of traT in strains isolated from cases of urinary tract infections was variable. traT was found to be frequently associated with production of the K1 capsule and with the carriage of ColV plasmids, but not with the carriage of R plasmids, nor with serum resistance or the production of haemolysin

Identifying and accounting for the Coriolis Effect in satellite NO2 observations and emission estimates

Recent developments in atmospheric remote sensing from satellites have made it possible to resolve daily emission plumes from industrial point sources, around the globe. Wind rotation aggregation coupled with statistical fitting is commonly used to extract emission estimates from these observations. These methods are used here to investigate how the Coriolis Effect influences the trajectory of observed emission plumes, and to assess the impact of this influence on satellite derived emission estimates. Of the 17 industrial sites investigated, nine showed the expected curvature for the hemisphere they reside in. Five showed no or negligible curvature, and two showed opposing or unusual curvature. The sites which showed conflicting curvature all reside in topographically diverse regions, where strong meso-gamma scale (2&ndash;20 km) turbulence dominates over larger synoptic circulation patterns. For high curvature cases the assumption that the wind-rotated plume aggregate is symmetrically distributed across the downwind axis breaks down, which impairs the quality of statistical fitting procedures. Using NOx emissions from Matimba power station as a test case, not compensating for Coriolis curvature resulted in an10 underestimation of &sim; 9 % on average for years 2018 to 2021. This study is the first formal observation of the Coriolis Effect and its influence on satellite observed emission plumes, and highlight both the variability of emission calculation methods and the need for a standardised scheme for this data to act as evidence for regulators.</p

On the hierarchical classification of G Protein-Coupled Receptors

Motivation: G protein-coupled receptors (GPCRs) play an important role in many physiological systems by transducing an extracellular signal into an intracellular response. Over 50% of all marketed drugs are targeted towards a GPCR. There is considerable interest in developing an algorithm that could effectively predict the function of a GPCR from its primary sequence. Such an algorithm is useful not only in identifying novel GPCR sequences but in characterizing the interrelationships between known GPCRs. Results: An alignment-free approach to GPCR classification has been developed using techniques drawn from data mining and proteochemometrics. A dataset of over 8000 sequences was constructed to train the algorithm. This represents one of the largest GPCR datasets currently available. A predictive algorithm was developed based upon the simplest reasonable numerical representation of the protein's physicochemical properties. A selective top-down approach was developed, which used a hierarchical classifier to assign sequences to subdivisions within the GPCR hierarchy. The predictive performance of the algorithm was assessed against several standard data mining classifiers and further validated against Support Vector Machine-based GPCR prediction servers. The selective top-down approach achieves significantly higher accuracy than standard data mining methods in almost all cases

Prolonged dual anti-platelet therapy in stable coronary disease: a comparative observational study of benefits and harms in unselected versus trial populations

Objective: To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. Design: Observational population based cohort study. Setting: PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). Participants: 7238 patients who survived a year or more after acute myocardial infarction. Interventions: Prolonged dual antiplatelet therapy after acute myocardial infarction. Main outcome measures: Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. Results: 1676/7238 (23.1%) patients met trial inclusion and exclusion criteria (“target” population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER’s target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER’s target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. Conclusions: This novel use of primary-secondary care linked electronic health records allows characterisation of “healthy trial participant” effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction

Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes.

The PROGRESS series (www.progress-partnership.org) sets out a framework of four interlinked prognosis research themes and provides examples from several disease fields to show why evidence from prognosis research is crucial to inform all points in the translation of biomedical and health related research into better patient outcomes. Recommendations are made in each of the four papers to improve current research standards What is prognosis research? Prognosis research seeks to understand and improve future outcomes in people with a given disease or health condition. However, there is increasing evidence that prognosis research standards need to be improved Why is prognosis research important? More people now live with disease and conditions that impair health than at any other time in history; prognosis research provides crucial evidence for translating findings from the laboratory to humans, and from clinical research to clinical practice This first article introduces the framework of four interlinked prognosis research themes and then focuses on the first of the themes - fundamental prognosis research, studies that aim to describe and explain future outcomes in relation to current diagnostic and treatment practices, often in relation to quality of care Fundamental prognosis research provides evidence informing healthcare and public health policy, the design and interpretation of randomised trials, and the impact of diagnostic tests on future outcome. It can inform new definitions of disease, may identify unanticipated benefits or harms of interventions, and clarify where new interventions are required to improve prognosis

上野老台宛状（貴子退身の事は追々聞？云々）

BACKGROUND: Electronic health records (EHRs), when linked across primary and secondary care and curated for research use, have the potential to improve our understanding of care quality and outcomes. OBJECTIVE: To evaluate new opportunities arising from linked EHRs for improving quality of care and outcomes for patients at risk of or with coronary disease across the patient journey. DESIGN: Epidemiological cohort, health informatics, health economics and ethnographic approaches were used. SETTING: 230 NHS hospitals and 226 general practices in England and Wales. PARTICIPANTS: Up to 2 million initially healthy adults, 100,000 people with stable coronary artery disease (SCAD) and up to 300,000 patients with acute coronary syndrome. MAIN OUTCOME MEASURES: Quality of care, fatal and non-fatal cardiovascular disease (CVD) events. DATA PLATFORM AND METHODS: We created a novel research platform [ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER)] based on linkage of four major sources of EHR data in primary care and national registries. We carried out 33 complementary studies within the CALIBER framework. We developed a web-based clinical decision support system (CDSS) in hospital chest pain clinics. We established a novel consented prognostic clinical cohort of SCAD patients. RESULTS: CALIBER was successfully established as a valid research platform based on linked EHR data in nearly 2 million adults with > 600 EHR phenotypes implemented on the web portal (see https://caliberresearch.org/ portal). Despite national guidance, key opportunities for investigation and treatment were missed across the patient journey, resulting in a worse prognosis for patients in the UK compared with patients in health systems in other countries. Our novel, contemporary, high-resolution studies showed heterogeneous associations for CVD risk factors across CVDs. The CDSS did not alter the decision-making behaviour of clinicians in chest pain clinics. Prognostic models using real-world data validly discriminated risk of death and events, and were used in cost-effectiveness decision models. CONCLUSIONS: Emerging ‘big data’ opportunities arising from the linkage of records at different stages of a patient’s journey are vital to the generation of actionable insights into the diagnosis, risk stratification and cost-effective treatment of people at risk of, or with, CVD. FUTURE WORK: The vast majority of NHS data remain inaccessible to research and this hampers efforts to improve efficiency and quality of care and to drive innovation. We propose three priority directions for further research. First, there is an urgent need to ‘unlock’ more detailed data within hospitals for the scale of the UK’s 65 million population. Second, there is a need for scaled approaches to using EHRs to design and carry out trials, and interpret the implementation of trial results. Third, large-scale, disease agnostic genetic and biological collections linked to such EHRs are required in order to deliver precision medicine and to innovate discovery. STUDY REGISTRATION: CALIBER studies are registered as follows: study 2 – NCT01569139, study 4 – NCT02176174 and NCT01164371, study 5 – NCT01163513, studies 6 and 7 – NCT01804439, study 8 – NCT02285322, and studies 26–29 – NCT01162187. Optimising the Management of Angina is registered as Current Controlled Trials ISRCTN54381840. FUNDING: The National Institute for Health Research (NIHR) Programme Grants for Applied Research programme (RP-PG-0407-10314) (all 33 studies) and additional funding from the Wellcome Trust (study 1), Medical Research Council Partnership grant (study 3), Servier (study 16), NIHR Research Methods Fellowship funding (study 19) and NIHR Research for Patient Benefit (study 33)

Association of Clinical Factors and Therapeutic Strategies With Improvements in Survival Following Non-ST-Elevation Myocardial Infarction, 2003-2013.

Importance: International studies report a decline in mortality following non–ST-elevation myocardial infarction (NSTEMI). Whether this is due to lower baseline risk or increased utilization of guideline-indicated treatments is unknown. Objective: To determine whether changes in characteristics of patients with NSTEMI are associated with improvements in outcomes. Design, Setting, and Participants: Data on patients with NSTEMI in 247 hospitals in England and Wales were obtained from the Myocardial Ischaemia National Audit Project between January 1, 2003, and June 30, 2013 (final follow-up, December 31, 2013). Exposures: Baseline demographics, clinical risk (GRACE risk score), and pharmacological and invasive coronary treatments. Main Outcomes and Measures: Adjusted all-cause 180-day postdischarge mortality time trends estimated using flexible parametric survival modeling. Results: Among 389 057 patients with NSTEMI (median age, 72.7 years [IQR, 61.7-81.2 years]; 63.1% men), there were 113 586 deaths (29.2%). From 2003-2004 to 2012-2013, proportions with intermediate to high GRACE risk decreased (87.2% vs 82.0%); proportions with lowest risk increased (4.2% vs 7.6%; P= .01 for trend). The prevalence of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, previous invasive coronary strategy, and current or ex-smoking status increased (all P < .001). Unadjusted all-cause mortality rates at 180 days decreased from 10.8% to 7.6% (unadjusted hazard ratio [HR], 0.968 [95% CI, 0.966-0.971]; difference in absolute mortality rate per 100 patients [AMR/100], −1.81 [95% CI, −1.95 to −1.67]). These findings were not substantially changed when adjusted additively by baseline GRACE risk score (HR, 0.975 [95% CI, 0.972-0.977]; AMR/100, −0.18 [95% CI, −0.21 to −0.16]), sex and socioeconomic status (HR, 0.975 [95% CI, 0.973-0.978]; difference in AMR/100, −0.24 [95% CI, −0.27 to −0.21]), comorbidities (HR, 0.973 [95% CI, 0.970-0.976]; difference in AMR/100, −0.44 [95% CI, −0.49 to −0.39]), and pharmacological therapies (HR, 0.972 [95% CI, 0.964-0.980]; difference in AMR/100, −0.53 [95% CI, −0.70 to −0.36]). However, the direction of association was reversed after further adjustment for use of an invasive coronary strategy (HR, 1.02 [95% CI, 1.01-1.03]; difference in AMR/100, 0.59 [95% CI, 0.33-0.86]), which was associated with a relative decrease in mortality of 46.1% (95% CI, 38.9%-52.0%). Conclusions and Relevance: Among patients hospitalized with NSTEMI in England and Wales, improvements in all-cause mortality were observed between 2003 and 2013. This was significantly associated with use of an invasive coronary strategy and not entirely related to a decline in baseline clinical risk or increased use of pharmacological therapies