Publications

Objectives This study aimed to update the Logistic Clinical SYNTAX score to predict 3-year survival after percutaneous coronary intervention (PCI) and compare the performance with the SYNTAX score alone. Background The SYNTAX score is a well-established angiographic tool to predict long-term outcomes after PCI. The Logistic Clinical SYNTAX score, developed by combining clinical variables with the anatomic SYNTAX score, has been shown to perform better than the SYNTAX score alone in predicting 1-year outcomes after PCI. However, the ability of this score to predict long-term survival is unknown. Methods Patient-level data (N = 6,304, 399 deaths within 3 years) from 7 contemporary PCI trials were analyzed. We revised the overall risk and the predictor effects in the core model (SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction) using Cox regression analysis to predict mortality at 3 years. We also updated the extended model by combining the core model with additional independent predictors of 3-year mortality (i.e., diabetes mellitus, peripheral vascular disease, and body mass index). Results The revised Logistic Clinical SYNTAX models showed better discriminative ability than the anatomic SYNTAX score for the prediction of 3-year mortality after PCI (c-index: SYNTAX score, 0.61; core model, 0.71; and extended model, 0.73 in a cross-validation procedure). The extended model in particular performed better in differentiating low- and intermediate-risk groups. Conclusions Risk scores combining clinical characteristics with the anatomic SYNTAX score substantially better predict 3-year mortality than the SYNTAX score alone and should be used for long-term risk stratification of patients undergoing PCI.

<h3>Importance</h3> Women with acute myocardial infarction (MI) undergoing mechanical reperfusion remain at increased risk of adverse cardiac events and mortality compared with their male counterparts. Whether the benefits of new-generation drug-eluting stents (DES) are preserved in women with acute MI remains unclear. <h3>Objective</h3> To investigate the long-term safety and efficacy of new-generation DES vs early-generation DES in women with acute MI. <h3>Design, Setting, and Participants</h3> Collaborative, international, individual patient-level data of women enrolled in 26 randomized clinical trials of DES were analyzed between July and December 2016. Only women presenting with an acute coronary syndrome were included. Study population was categorized according to presentation with unstable angina (UA) vs acute MI. Acute MI included non–ST-segment elevation MI (NSTEMI) or ST-segment elevation MI (STEMI). <h3>Interventions</h3> Randomization to early- (sirolimus- or paclitaxel-eluting stents) vs new-generation (everolimus-, zotarolimus-, or biolimus-eluting stents) DES. <h3>Main Outcomes and Measures</h3> Composite of death, MI or target lesion revascularization, and definite or probable stent thrombosis at 3-year follow-up. <h3>Results</h3> Overall, the mean age of participants was 66.8 years. Of 11 577 women included in the pooled data set, 4373 (37.8%) had an acute coronary syndrome as clinical presentation. Of these 4373 women, 2176 (49.8%) presented with an acute MI. In women with acute MI, new-generation DES were associated with lower risk of death, MI or target lesion revascularization (14.9% vs 18.4%; absolute risk difference, −3.5%; number needed to treat [NNT], 29; adjusted hazard ratio, 0.78; 95% CI, 0.61-0.99), and definite or probable stent thrombosis (1.4% vs 4.0%; absolute risk difference, −2.6%; NNT, 46; adjusted hazard ratio, 0.36; 95% CI, 0.19-0.69) without evidence of interaction for both end points compared with women without acute MI (<i>P</i>for interaction = .59 and<i>P</i>for interaction = .31, respectively). A graded absolute benefit with use of new-generation DES was observed in the transition from UA, to NSTEMI, and to STEMI (for death, MI, or target lesion revascularization: UA, −0.5% [NNT, 222]; NSTEMI, −3.1% [NNT, 33]; STEMI, −4.0% [NNT, 25] and for definite or probable ST: UA, −0.4% [NNT, 278]; NSTEMI, −2.2% [NNT, 46]; STEMI, −4.0% [NNT, 25]). <h3>Conclusions and Relevance</h3> New-generation DES are associated with consistent and durable benefits over 3 years in women presenting with acute MI. The magnitude of these benefits appeared to be greater per increase in severity of acute coronary syndrome.

We report three cases of successful implantation of three different stents specially designed for bifurcation lesions, guided by intracoronary ultrasound. The BARD and AVE are true bifurcated stents for side-branch access and the NIR-Side Royal is a single modified NIR stent with an aperture to allow provisional bifurcation stenting. These designs introduce a new era in percutaneous management of coronary bifurcation lesions. Cathet. Cardiovasc. Intervent. 49:105–111, 2000. © 2000 Wiley-Liss, Inc.

Objectives. The purpose of this study was to examine the proliferative capacity and extracellular matrix synthesis of human coronary plaque cells in vitro. Background. Common to both primary atherosclerosis and restenosis are vascular smooth muscle cell proliferation and production of extracellular matrix proteins. The applicability to humans of experimental animal models of these processes has been questioned. Methods. Primary atherosclerotic and restenotic lesions were excised by percutaneous directional coronary atherectomy in 93 patients. Smooth muscle cells were cultivated by an explant technique and identified by their morphology in culture, ultrastructural features under electron microscopy and immunostaining using monoclonal antibodies to smooth muscle cell alpha-actin. Proliferation in secondary culture was assessed with growth curves and the synthesis of collagen and sulfated glycosaminoglycans by the incorporation of 3H-proline and 35S-sulfate, respectively. These studies were also performed in cells derived from human umbilical artery media. Results. Success rates for primary (45%) and secondary (12%) culture of coronary cells were not influenced by clinical variables or lesion category. Primary culture success was improved by the presence of organized thrombus in the plaque and in relation to increased maximal cell density of the atherectomy specimen. Restenotic cells displayed more rapid growth than did cells of primary atherosclerotic origin, which grew in a manner similar to that of umbilical artery cells. Mean calculated population-doubling for the three cell groups were 52 h (95% confidence interval [CI] 48 to 58 h), 71 h (95% CI 62 to 83 h) and 74 h (95% CI 65 to 84 h), respectively. Restenotic and primary atherosclerotic cells did not differ in the synthesis of collagen ([mean ± SEM] 0.034 ± 0.004 vs. 0.033 ± 0.004 nmol isotope· μg protein−1, p = NS) or sulfated glycosaminoglycans (11.47 ± 1.07 vs. 15.37 ± 3.10 nmol isotope· μg protein−1, p = NS), but the coronary cells synthesized significantly more collagen and sulfated glycosaminoglycans than did umbilical artery cells (0.019 ± 0.004 and 5.43 ± 1.00 nmol isotope· μg protein−1, respectively, both p < 0.05). Conclusions. These data indicate that increased smooth muscle cell proliferation contributes to coronary restenosis in humans and support the concept that the extracellular matrix synthesis of adult smooth muscle cells is important to lesion formation.

Objective Endotoxin and cytokines have been reported to have both stimulatory and inhibitory effects on endothelial cell-derived nitric oxide release. This discrepancy may be explained by differential regulation of the endothelial and inducible types of nitric oxide synthase gene expression. This study aimed to investigate the differential effect of lipopolysaccharide treatment in vivo on the three isoforms (endothelial, brain-type, and inducible) of nitric oxide synthase gene expression in the rat. Design Prospective, controlled, animal trial. Setting Experimental laboratory of a postgraduate medical research institution. Subjects Normal, anesthetized rats. Interventions Animals were treated with lipopolysaccharide (15 mg/kg ip), saline (1 mL/kg ip), or lipopolysaccharide plus dexamethasone (3 mg/kg ip, 50 mins before lipopolysaccharide administration) in vivo 4 hrs before experimentation. Measurements and Main Results The expression of endothelial, brain-type, and inducible nitric oxide synthase mRNAs was quantified by Northern blot analysis using bovine, rat, and mouse cDNA probes, respectively. An endothelial nitric oxide synthase mRNA was detected at 4.3 kilobase in the heart, lung, and aorta, and a 10-kilobase brain-type nitric oxide synthase mRNA was detected in the brain. The endothelial and brain-type signals were strong in tissues from animals treated with saline, but were reduced by three- to four-fold in tissues from lipopolysaccharide-treated rats as estimated by optical density ratio. The 4.4-kilobase inducible nitric oxide synthase mRNA detected using the murine cDNA probe was absent or negligible in the heart, lung, and brain from saline-treated rats, but was markedly increased in the same tissues from lipopolysaccharide-treated animals. Dexamethasone significantly inhibited lipopolysaccharide-induced inducible nitric oxide synthase mRNA expression, but had no effect on the down-regulation of endothelial and brain nitric oxide synthase mRNAs. Conclusions Rats treated with lipopolysaccharide in vivo display down-regulation of endothelial nitric oxide mRNA in the heart, lung, and aorta, and brain-type nitric oxide synthase mRNA in the brain. There was a parallel up-regulation of inducible nitric oxide synthase mRNA in all tissues except in the aorta. Dexamethasone prevents the induction of inducible nitric oxide synthase mRNA, but has no effect on the down-regulation of endothelial and brain-type nitric oxide synthase mRNAs induced by lipopolysaccharide. Thus, endotoxin regulates constitutive and inducible nitric oxide synthase mRNA differentially. (Crit Care Med 1996; 24:1219-1225)

Five per cent of asthmatics remain symptomatic despite high-dose treatment. The aim of the study was to investigate how often such difficult-to-treat asthma is due to intractable asthma, misdiagnosis, non-adherence with therapy, or psychiatric problems. Difficult asthma was defined as persistence of symptoms despite treatment at step 4 of British guidelines or requirement for long-term oral glucocorticoids (step 5). One-hundred patients with a respiratory physician diagnosis of asthma were investigated in a single tertiary respiratory unit in an open and descriptive study. Twelve of the patients studied did not have asthma and a further seven had additional diagnoses. Of the remainder, 55 had an asthma diagnosis confirmed by demonstration of reversible airflow narrowing or peak flow variability, whilst 20 did not. Noncompliance with prednisolone therapy was more frequent in the 55 with confirmed asthma (nine of 18 prescribed oral prednisolone at a dose of ≥15 mg·day −1 ) and was not detected in the “unconfirmed asthma” group. There were no other significant differences between these groups. A major psychiatric component was detected in 10 patients. Systematic evaluation of difficult asthma is useful as it can identify alternative or additional diagnoses, psychiatric illness or nonconcordance with therapy in a substantial proportion of cases (32% in the present series).

A Task Force supported by the European Respiratory Society was set up in 1997 in order to address the major issues relevant to difficult/therapy-resistant asthma.Although the group of patients involved is small in comparison to the high numbers of patients with asthma, these patients consume a significant proportion of medical resources in terms of both time and money [1].The major issues facing the Task Force were how to define "difficult asthma", how the patient with difficult asthma should be evaluated, the pathophysiological mechanisms underlying difficult asthma and the treatments available.The Task Force also concerned itself with defining the areas of research necessary to bring about a greater understanding of the causes of difficult asthma and novel treatments.The document resulting from this Task Force represents a consensus of different opinions, which will form the basis for further research. Formulating the definitionA large number of terms are used by clinicians when referring to asthmatic patients who have "difficult to treat" disease: difficult acute, difficult chronic, chronic severe, acute severe, therapy-resistant, difficult to control, corticosteroid-resistant or corticosteroid-dependent, symptomatic, life-threatening, and fatal.An encompassing inclusive rather than exclusive definition was sought and the use of the term "difficult/therapy-resistant asthma" was adopted to include all such cases of asthma of all age groups.Since wheezing disorders in preschool children are poorly characterized, this report specifically excludes children below the age of 5 yrs.Response to therapy is included in this concept and will have research implications.It was accepted that the definition needed to be inclusive, although losing some precision, but it was also recognized that its

Background: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods: We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results: 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion: Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.Trial Registration: ClinicalTrials.gov number, NCT04416399Funding: Oxford NIHR Biomedical Research Centre and AstraZenecaDeclaration of Interests: Dr. Ramakrishnan reports grants and non-financial support from Oxford Respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work; . Dr. Nicolau has nothing to disclose. Mrs Langford has nothing to disclose. Mr. Mahdi has nothing to disclose. Mrs Helen Jeffers reports personal fees from AstraZeneca, outside the submitted work; . Miss Mwasuku has nothing to disclose. Mrs Krassowska has nothing to disclose. Dr Fox has nothing to disclose. Dr Binnian has nothing to disclose. Dr Glover has nothing to disclose. Dr Bright has nothing to disclose. Dr. Butler reports grants from National Institute for Health Research (NIHR), Roche Molecular Diagnostics, Janssen Pharmaceuticals, and various public funding bodies for research related to diagnostics and infections. He has revcied personal fees from Pfizer INC, Roche Diagnostics, and Janssen Pharmaceuticals, outside the submitted work. Dr. Cane has nothing to disclose. Mr. Halner has nothing to disclose. Dr. Matthews has nothing to disclose. Dr. Donnelly reports grants from AstraZeneca, from Boehringer-Ingelheim, outside the submitted work; . Dr. Simpson has nothing to disclose. Dr Baker has nothing to disclose. Dr. Fadai has nothing to disclose. Dr. Peterson reports personal fees from AstraZeneca, outside the submitted work; . Mr. Bengtsson reports personal fees from AstraZeneca, outside the submitted work; Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study; Dr. Russell reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study; . Dr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work; .Ethics Approval Statement: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.The ethical approval number is 20/HRA/2531.

Polytetrafluoroethylene-covered stents (PCS) were recently proposed as a new modality mainly for the treatment of saphenous vein graft lesions, but restenosis occurring principally at the edges restricted their clinical use in the management of coronary aneurysms and perforations.To investigate the safety and effectiveness of the overlapping implantation of drug-eluting stents (DES) with PCS in clinical scenarios where the latter are indicated.Since April 2002, when DES were introduced in clinical practice, 14 consecutive patients were -treated with overlapping implantation of PCS with DES in 3 centres. Seven patients were treated for coronary aneurysms, 5 for coronary perforations and 2 for branch occlusion. The incidence of any major adverse cardiac events defined as death, myocardial infarction (MI), and target vessel revascularisation (TVR) was retrospectively evaluated. A control angiography was available in 13 patients, and quantitative coronary angiography was performed before and after the intervention and at follow-up to evaluate restenosis rate and late loss.At a mean clinical follow-up of 21.9 months there were no deaths or MI's, while one patient with occlusive restenosis underwent successful TVR (7.7%). At angiographic follow-up (mean: 9.7 months) there was one patient with restenosis (7.7%), who had a total occlusion. After excluding the patient with the occlusive restenosis mean diameter stenosis was 22.4+/-11.7% and late loss was 0.18+/-0.35 mm at follow-up. No early or late stent thrombosis occurred.Overlapping implantation of PCS with DES seems to be a safe and effective therapeutic modality demonstrating a low incidence of clinical and angiographic restenosis.