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1.  Quality of Life Benefits of Percutaneous Coronary Intervention for Chronic Occlusions 
We aimed to compare quality of life benefits of percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) with non-CTO PCI.
Data quantifying the benefits of PCI of CTO are inconsistent.
We leveraged a 10-center prospective PCI registry including Seattle Angina Questionnaire (SAQ) assessment at the time of PCI and in follow-up. We propensity matched attempted CTO PCIs with up to 10 non-CTO PCIs. The primary analysis compared changes between baseline and 6 months in SAQ Physical Limitation (PL), Quality of Life (QoL) and Angina Frequency (AF) scores as well as the Rose Dyspnea scores (RDS) and the EQ5D Visual Analogue Scale (VAS). Non-inferiority was assessed for quality of life changes between CTO and non-CTO PCI.
In 3,303 patients enrolled, 167 single-vessel CTOs were attempted; 147 (88%) were matched with 1,616 non-CTO PCI. Baseline PL (73.0 vs. 77.4, p=0.039) and VAS (66.4 vs. 70.8, p=0.005) scores were lower for CTO. There was no difference in AF, QoL or RDS scores. At 6-month follow-up, all SAQ scores improved (p<0.05 vs. baseline for all) and were equivalent for CTO and Non-CTO (p=NS for all). VAS scores remained lower for CTO, but improved in both groups (p<0.05 vs. baseline for both). Formal non-inferiority testing demonstrated that CTO PCI was not inferior to non-CTO PCI (p≤0.02 for all).
Symptoms, function, QoL and dyspnea improve to the same degree following CTO PCI as compared with non-CTO PCI. Symptom relief supports CTO PCI to improve patients’ quality of life.
PMCID: PMC4277434  PMID: 24259445
Coronary Occlusions; Angioplasty; Transluminal; Percutaneous Coronary
2.  Differentiation imbalance in single Oesophageal progenitor cells causes clonal immortalization and field change 
Nature cell biology  2014;16(6):615-622.
Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed ‘field change’1, 2. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signaling pathway. Notch is frequently subject to inactivating mutation in squamous cancers3-6. Quantitative analysis reveals that cell divisions which produce two differentiated daughters are absent in mutant progenitors. As a result mutant clones are no longer lost by differentiation and become functionally immortal. In addition, mutant cells promote the differentiation of neighbouring wild type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Furthermore, Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells.
PMCID: PMC4085550  PMID: 24814514
3.  The reliability of in-hospital diagnoses of diabetes mellitus in the setting of an acute myocardial infarction 
Incident diabetes mellitus (DM) is important to recognize in patients with acute myocardial infarction (AMI). To develop an efficient screening strategy, we explored the use of random plasma glucose (RPG) at admission and fasting plasma glucose (FPG) to select patients with AMI for glycosylated hemoglobin (HbA1c) testing.
Design, setting, andparticipants
Prospective registry of 1574 patients with AMI not taking glucose-lowering medication from 24 US hospitals. All patients had HbA1c measured at a core laboratory and admission RPG and ≥2 FPGs recorded during hospitalization. We examined potential combinations of RPG and FPG and compared these with HbA1c≥6.5%—considered the gold standard for DM diagnosis in these analyses.
An RPG>140 mg/dL or FPG≥126 mg/dL had high sensitivity for DM diagnosis. Combining these into a screening protocol (if admission RPG>140, check HbA1c; or if FPG≥126 on a subsequent day, check HbA1c) led to HbA1c testing in 50% of patients and identified 86% with incident DM (number needed to screen (NNS)=3.3 to identify 1 case of DM; vs NNS=5.6 with universal HbA1c screening). Alternatively, using an RPG>180 led to HbA1c testing in 40% of patients with AMI and identified 82% of DM (NNS=2.7).
We have established two potential selective screening methods for DM in the setting of AMI that could identify the vast majority of incident DM by targeted screening of 40–50% of patients with AMI with HbA1c testing. Using these methods may efficiently identify patients with AMI with DM so that appropriate education and treatment can be promptly initiated.
PMCID: PMC4242083  PMID: 25452878
Diagnosis; Myocardial Infarction; Glucose
4.  Insulin Resistance is Associated with Significant Clinical Atherosclerosis in Non-Diabetic Patients with Acute Myocardial Infarction 
Arteriosclerosis, thrombosis, and vascular biology  2013;33(9):10.1161/ATVBAHA.113.301585.
The prevalence of insulin resistance (IR) is increasing worldwide due to increasing age, obesity, and physical inactivity. Emerging evidence supports a direct pro-atherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a ‘real-world’ clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in non-diabetic individuals.
Approach and Results
We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 non-diabetic patients surviving acute myocardial infarction. Patients were divided into quartiles based on the homeostasis model assessment grading of IR (HOMA-IR), and associations between IR and multivessel coronary artery disease (MVD), defined as ≥2 arteries with ≥70% stenosis (or ≥50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% non-white. The crude prevalence of MVD was 37.8%, 42.3%, 47.2%, and 48.0% for HOMA-IR quartiles 1, 2, 3, and 4 respectively (ptrend =0.009). In multivariable modeling, compared with quartile 1, both quartile 3 [RR (95% CI) = 1.31 (1.07-1.60)] and quartile 4 [1.29 (1.03-1.60)] were independently associated with MVD. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (LDL-C, HDL-C, triglyceride, HbA1c, and hs-CRP).
We demonstrate an independent association between IR and MVD in non-diabetic post-MI patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of insulin resistance independent of glucose control and other components of the metabolic syndrome.
PMCID: PMC3855677  PMID: 23868937
Atherosclerosis; Insulin resistance
5.  Physical Disability, Anxiety and Depression in People with MS: An Internet-Based Survey via the UK MS Register 
PLoS ONE  2014;9(8):e104604.
People with Multiple Sclerosis are known to have a relatively high prevalence of both anxiety and depression. Studies of the relationship between physical disability and mental health in people with MS have reported mixed results, showing the need for further work.
Between May 2011 and April 2012, 4516 people completed the MSIS-29 (v.1) and HADS scales via the dedicated internet site of the UK MS Register within a 7 day time window. These responses were linked with basic demographic and descriptive data and analysed in SPSS (v.20).
The proportions of people experiencing anxiety or depression increased with physical disability such that 38.0% of respondents with low, and 66.7% with high disability reported at least mild anxiety, and 17.1% of people with low, and 71.7% with high disability experienced at least mild depression. The multiple regression model explained 18.4% of the variance in anxiety with MSIS-29-PHYS score being the strongest predictor of anxiety. The model for depression explained 37.8% of the variance with MSIS-29-PHYS score being the strongest predictor. Some of the other variables included showed negative associations with anxiety and depression, indicating that the influence of physical disability on mental wellbeing could be underestimated.
This study indicates that there is a positive relationship between physical disability and anxiety and depression, that physical disability impacts on anxiety and depression to differing extents, and that the effects vary with gender, age, disease course and disease duration. We have shown that physical disability is a predictor of anxiety and depression, and that other factors may mask the extent of this effect. Whether the causes of anxiety and depression are reactive, organic or a combination, it is essential that mental wellbeing is given due attention in caring for people with MS so that all their health needs can be met.
PMCID: PMC4143231  PMID: 25153835
6.  Derivation and Validation of a Risk Standardization Model for Benchmarking Hospital Performance for Health-Related Quality of Life Outcomes after Acute Myocardial Infarction 
Circulation  2013;129(3):313-320.
Before outcomes-based measures of quality can be used to compare and improve care, they must be risk-standardized to account for variations in patient characteristics. Despite the importance of health-related quality of life (HRQL) outcomes among patients with acute myocardial infarction (AMI), no risk-standardized models have been developed.
Methods and Results
We assessed disease-specific HRQL using the Seattle Angina Questionnaire at baseline and 1 year later in 2693 unselected AMI patients from 24 hospitals enrolled in the TRIUMPH registry. Using 57 candidate sociodemographic, economic, and clinical variables present on admission, we developed a parsimonious, hierarchical linear regression model to predict HRQL. Eleven variables were independently associated with poor HRQL after AMI, including younger age, prior CABG, depressive symptoms, and financial difficulties (R2=20%). The model demonstrated excellent internal calibration and reasonable calibration in an independent sample of 1890 AMI patients in a separate registry, although the model slightly over-predicted HRQL scores in the higher deciles. Among the 24 TRIUMPH hospitals, 1-year unadjusted HRQL scores ranged from 67–89. After risk-standardization, HRQL scores variability narrowed substantially (range=79–83), and the group of hospital performance (bottom 20%/middle 60%/top 20%) changed in 14 of the 24 hospitals (58% reclassification with risk-standardization).
In this predictive model for HRQL after AMI, we identified risk factors, including economic and psychological characteristics, associated with HRQL outcomes. Adjusting for these factors substantially altered the rankings of hospitals as compared with unadjusted comparisons. Using this model to compare risk-standardized HRQL outcomes across hospitals may identify processes of care that maximize this important patient-centered outcome.
PMCID: PMC4103693  PMID: 24163068
quality of life; myocardial infarction; risk factors
7.  BST-2/Tetherin-mediated restriction of Chikungunya (CHIKV) VLP budding is counteracted by CHIKV non-structural protein 1 (nsP1) 
Virology  2013;438(1):37-49.
Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted by Aedes mosquitoes. Infection with CHIKV elicits a type I interferon response that facilities virus clearance, probably through the action of down-stream effectors such as antiviral IFN-stimulated genes (ISGs). Bone marrow stromal antigen 2 (BST-2) is an ISG shown to restrict HIV-1 replication by preventing the infection of bystander cells by tethering progeny virions on the surface of infected cells. Here we show that enrichment of cell surface BST-2 results in retention of CHIKV virus like particles (VLPs) on the cell membrane. BST-2 was found to co-localize with CHIKV structural protein E1 in the context of VLPs without any noticeable effect on BST-2 level. However, CHIKV nonstructural protein 1 (nsP1) overcomes BST-2-mediated VLPs tethering by down-regulating BST-2 expression.. We conclude that BST-2 tethers CHIKV VLPs on the host cell plasma membrane and identify CHIKV nsP1 as a novel BST-2 antagonist.
PMCID: PMC4086190  PMID: 23411007
BST-2; CHIKV; E1; nonstructural protein; nsP1; SEM; tetherin; VLP
8.  Hospital Variation in Survival Trends for In‐hospital Cardiac Arrest 
During the past decade, survival after in‐hospital cardiac arrest has improved markedly. It remains unknown whether the improvement in survival has occurred uniformly at all hospitals or was driven by large improvements at only a few hospitals.
Methods and Results
We identified 93 342 adults with an in‐hospital cardiac arrest at 231 hospitals in the Get With The Guidelines®‐Resuscitation registry during 2000–2010. Using hierarchical regression models, we evaluated hospital‐level trends in survival to discharge. Mean age was 66 years, 59% were men, and 21% were black. Between 2000 and 2010, there was a significant decrease in age, prevalence of heart failure and myocardial infarction, and cardiac arrests due to shockable rhythms (P<0.001 for all) and an increase in prevalence of sepsis, respiratory insufficiency, renal insufficiency, intensive care unit location, and mechanical ventilation before arrest (P<0.001 for all). After adjustment for temporal trends in baseline characteristics, hospital rates of in‐hospital cardiac arrest survival improved by 7% per year (odds ratio [OR] 1.07, 95% CI 1.06 to 1.08, P<0.001). Improvement in survival varied markedly and ranged from 3% in the bottom hospital quartile to 11% in the top hospital quartile. Compared with minor teaching hospitals (OR 1.04, 95% CI 1.02 to 1.06), hospital rate of survival improvement was greater at major teaching (OR 1.08, 95% CI 1.06 to 1.10) and nonteaching hospitals (OR 1.07, 95% CI 1.05 to 1.09, P value for interaction=0.03).
Although in‐hospital cardiac arrest survival has improved during the past decade, the magnitude of improvement varied across hospitals. Future studies are needed to identify hospital processes that have led to the largest improvement in survival.
PMCID: PMC4309112  PMID: 24922627
cardiac arrest; cardiopulmonary resuscitation; health services research; survival
9.  BST-2/tetherin is overexpressed in mammary gland and tumor tissues in MMTV-induced mammary cancer 
Virology  2013;444(0):124-139.
BST-2 restricts MMTV replication, but once infection has established, MMTV modulates BST-2 levels. MMTV-directed BST-2 modulation is tissue-specific and dependent on infection and neoplastic transformation status of cells. In the lymphoid compartment of infected mice, BST-2 expression is first upregulated and then significantly downregulated regardless of absence or presence of mammary tumors. However, in mammary gland tissues, upregulation of BST-2 expression is dependent on the presence of mammary tumors and tumor tissues themselves have high BST-2 levels. Elevated BST-2 expression in these tissues is not attributable to IFN since levels of IFNα and IFNγ negatively correlate with BST-2. Importantly, soluble factors released by tumor cells suppress IFNα and IFNγ but induce BST-2. These data suggest that overexpression of BST-2 in carcinoma tissues could not be attributed to IFNs but to a yet to be determined factor that upregulates BST-2 once oncogenesis is initiated.
PMCID: PMC4026021  PMID: 23806386
BST-2; tumor; cancer; epithelial cells; mammary gland; transformation; tetherin; human breast cancer; mouse mammary tumor virus; PI3K; AKT; MIP1α; CCL3
10.  Predictive validity of a new integrated selection process for medical school admission 
BMC Medical Education  2014;14:86.
This paper is an evaluation of an integrated selection process utilising previous academic achievement [Universities Admission Index (UAI)], a skills test [Undergraduate Medicine and Health Sciences Admission Test (UMAT)], and a structured interview, introduced (in its entirety) in 2004 as part of curriculum reform of the undergraduate Medicine Program at the University of New South Wales (UNSW), Australia. Demographic measures of gender, country of birth, educational background and rurality are considered.
Admission scores and program outcomes of 318 students enrolled in 2004 and 2005 were studied. Regression analyses were undertaken to determine whether selection scores predicted overall, knowledge-based and clinical-based learning outcomes after controlling for demographics.
UAI attained the highest values in predicting overall and knowledge-based outcomes. The communication dimension of the interview achieved similar predictive values as UAI for clinical-based outcomes, although predictive values were relatively low. The UMAT did not predict any performance outcome. Female gender, European/European-derived country of birth and non-rurality were significant predictors independent of UAI scores.
Results indicate promising validity for an integrated selection process introduced for the Medicine Program at UNSW, with UAI and interview predictive of learning outcomes. Although not predictive, UMAT may have other useful roles in an integrated selection process. Further longitudinal research is proposed to monitor and improve the validity of the integrated student selection process.
PMCID: PMC3999457  PMID: 24755325
Student selection; Predictive validity; Predicting; Performance; Demographics
11.  Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial 
BMJ Open  2014;4(2):e004886.
Perioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).
Methods and analysis
After receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.
Ethics and dissemination
The authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.
Clinical Trial Registration Number
PMCID: PMC3939660  PMID: 24568963
Surgery; Epidemiology
12.  Improving the transition from medical school to internship – evaluation of a preparation for internship course 
BMC Medical Education  2014;14:23.
This study evaluates the impact of a new 'Preparation for Internship’ (PRINT) course, which was developed to facilitate the transition of University of New South Wales (UNSW) medical graduates from Medical School to Internship.
During a period of major curricular reform, the 2007 (old program) and 2009 (new program) cohorts of UNSW final year students completed the Clinical Capability Questionnaire (CCQ) prior to and after undertaking the PRINT course. Clinical supervisors’ ratings and self-ratings of UNSW 2009 medical graduates were obtained from the Hospital-based Prevocational Progress Review Form.
Prior to PRINT, students from both cohorts perceived they had good clinical skills, with lower ratings for capability in procedural skills, operational management, and administrative tasks. After completing PRINT, students from both cohorts perceived significant improvement in their capability in procedural skills, operational management, and administrative tasks. Although PRINT also improved student-perceived capability in confidence, interpersonal skills and collaboration in both cohorts, curriculum reform to a new outcomes-based program was far more influential in improving self-perceptions in these facets of preparedness for hospital practice than PRINT.
The PRINT course was most effective in improving students’ perceptions of their capability in procedural skills, operational management and administrative tasks, indicating that student-to-intern transition courses should be clinically orientated, address relevant skills, use experiential learning, and focus on practical tasks. Other aspects that are important in preparation of medical students for hospital practice cannot be addressed in a PRINT course, but major improvements are achievable by program-wide curriculum reform.
PMCID: PMC3913947  PMID: 24485072
Undergraduate medical education; Transition to internship; Outcome based curriculum; Clinical skills
13.  Comparison of Clinical Interpretation with Visual Assessment and Quantitative Coronary Angiography in Patients Undergoing Percutaneous Coronary Intervention in Contemporary Practice: The Assessing Angiography (A2) Project 
Circulation  2013;127(17):1793-1800.
Studies conducted decades ago described substantial disagreement and errors in physicians’ angiographic interpretation of coronary stenosis severity. Despite the potential implications of such findings, no large-scale efforts to measure or improve clinical interpretation were subsequently made.
Methods & Results
We compared clinical interpretation of stenosis severity in coronary lesions with an independent assessment using quantitative coronary angiography (QCA) in 175 randomly selected patients undergoing elective percutaneous coronary intervention (PCI) at 7 U.S. hospitals in 2011. To assess agreement, we calculated mean difference in percent diameter stenosis between clinical interpretation and QCA and a Cohen’s weighted kappa statistic. Of 216 treated lesions, median percent diameter stenosis was 80.0% (Q1 and Q3, 80.0 and 90.0%) with 213 (98.6%) assessed as ≥70%. Mean difference in percent diameter stenosis between clinical interpretation and QCA was +8.2 ± 8.4%, reflecting an average higher percent diameter stenosis by clinical interpretation (P<0.001). A weighted kappa of 0.27 (95% CI, 0.18 to 0.36) was found between the 2 measurements. Of 213 lesions considered ≥70% by clinical interpretation, 56 (26.3%) were <70% by QCA though none was <50%. Differences between the 2 measurements were largest for intermediate lesions by QCA (50 to <70%) with variation existing across sites.
Physicians tended to assess coronary lesions treated with PCI as more severe than measurements by QCA. Almost all treated lesions were ≥70% by clinical interpretation, while approximately a quarter were <70% by QCA. These findings suggest opportunities to improve clinical interpretation of coronary angiography.
PMCID: PMC3908681  PMID: 23470859
Health policy and outcomes research; Quality improvement; Coronary angiography; Percutaneous coronary intervention; Quantitative coronary angiography
14.  InterProScan 5: genome-scale protein function classification 
Bioinformatics  2014;30(9):1236-1240.
Motivation: Robust large-scale sequence analysis is a major challenge in modern genomic science, where biologists are frequently trying to characterize many millions of sequences. Here, we describe a new Java-based architecture for the widely used protein function prediction software package InterProScan. Developments include improvements and additions to the outputs of the software and the complete reimplementation of the software framework, resulting in a flexible and stable system that is able to use both multiprocessor machines and/or conventional clusters to achieve scalable distributed data analysis. InterProScan is freely available for download from the EMBl-EBI FTP site and the open source code is hosted at Google Code.
Availability and implementation: InterProScan is distributed via FTP at and the source code is available from
Contact: or or
PMCID: PMC3998142  PMID: 24451626
15.  Correction: The Later Stone Age Calvaria from Iwo Eleru, Nigeria: Morphology and Chronology 
PLoS ONE  2013;8(11):10.1371/annotation/887b6c18-6c37-44d2-8a50-2760bc9ad5d6.
PMCID: PMC3820804  PMID: 24244233
16.  EBI metagenomics—a new resource for the analysis and archiving of metagenomic data 
Nucleic Acids Research  2013;42(Database issue):D600-D606.
Metagenomics is a relatively recently established but rapidly expanding field that uses high-throughput next-generation sequencing technologies to characterize the microbial communities inhabiting different ecosystems (including oceans, lakes, soil, tundra, plants and body sites). Metagenomics brings with it a number of challenges, including the management, analysis, storage and sharing of data. In response to these challenges, we have developed a new metagenomics resource ( that allows users to easily submit raw nucleotide reads for functional and taxonomic analysis by a state-of-the-art pipeline, and have them automatically stored (together with descriptive, standards-compliant metadata) in the European Nucleotide Archive.
PMCID: PMC3965009  PMID: 24165880
17.  The difficult airway with recommendations for management – Part 1 – Difficult tracheal intubation encountered in an unconscious/induced patient 
Canadian Journal of Anaesthesia  2013;60(11):1089-1118.
Previously active in the mid-1990s, the Canadian Airway Focus Group (CAFG) studied the unanticipated difficult airway and made recommendations on management in a 1998 publication. The CAFG has since reconvened to examine more recent scientific literature on airway management. The Focus Group’s mandate for this article was to arrive at updated practice recommendations for management of the unconscious/induced patient in whom difficult or failed tracheal intubation is encountered.
Nineteen clinicians with backgrounds in anesthesia, emergency medicine, and intensive care joined this iteration of the CAFG. Each member was assigned topics and conducted reviews of Medline, EMBASE, and Cochrane databases. Results were presented and discussed during multiple teleconferences and two face-to-face meetings. When appropriate, evidence- or consensus-based recommendations were made together with assigned levels of evidence modelled after previously published criteria.
The clinician must be aware of the potential for harm to the patient that can occur with multiple attempts at tracheal intubation. This likelihood can be minimized by moving early from an unsuccessful primary intubation technique to an alternative “Plan B” technique if oxygenation by face mask or ventilation using a supraglottic device is non-problematic. Irrespective of the technique(s) used, failure to achieve successful tracheal intubation in a maximum of three attempts defines failed tracheal intubation and signals the need to engage an exit strategy. Failure to oxygenate by face mask or supraglottic device ventilation occurring in conjunction with failed tracheal intubation defines a failed oxygenation, “cannot intubate, cannot oxygenate” situation. Cricothyrotomy must then be undertaken without delay, although if not already tried, an expedited and concurrent attempt can be made to place a supraglottic device.
PMCID: PMC3825644  PMID: 24132407
18.  The difficult airway with recommendations for management – Part 2 – The anticipated difficult airway 
Canadian Journal of Anaesthesia  2013;60(11):1119-1138.
Appropriate planning is crucial to avoid morbidity and mortality when difficulty is anticipated with airway management. Many guidelines developed by national societies have focused on management of difficulty encountered in the unconscious patient; however, little guidance appears in the literature on how best to approach the patient with an anticipated difficult airway.
To review this and other subjects, the Canadian Airway Focus Group (CAFG) was re-formed. With representation from anesthesiology, emergency medicine, and critical care, CAFG members were assigned topics for review. As literature reviews were completed, results were presented and discussed during teleconferences and two face-to-face meetings. When appropriate, evidence- or consensus-based recommendations were made, and levels of evidence were assigned.
Principal findings
Previously published predictors of difficult direct laryngoscopy are widely known. More recent studies report predictors of difficult face mask ventilation, video laryngoscopy, use of a supraglottic device, and cricothyrotomy. All are important facets of a complete airway evaluation and must be considered when difficulty is anticipated with airway management. Many studies now document the increasing patient morbidity that occurs with multiple attempts at tracheal intubation. Therefore, when difficulty is anticipated, tracheal intubation after induction of general anesthesia should be considered only when success with the chosen device(s) can be predicted in a maximum of three attempts. Concomitant predicted difficulty using oxygenation by face mask or supraglottic device ventilation as a fallback makes an awake approach advisable. Contextual issues, such as patient cooperation, availability of additional skilled help, and the clinician’s experience, must also be considered in deciding the appropriate strategy.
With an appropriate airway evaluation and consideration of relevant contextual issues, a rational decision can be made on whether an awake approach to tracheal intubation will maximize patient safety or if airway management can safely proceed after induction of general anesthesia. With predicted difficulty, close attention should be paid to details of implementing the chosen approach. This should include having a plan in case of the failure of tracheal intubation or patient oxygenation.
PMCID: PMC3825645  PMID: 24132408
19.  IFNα and LPS up-regulate APOBEC3 (A3) mRNA through different signaling pathways 
APOBEC3 (A3) proteins are virus restriction factors that provide intrinsic immunity against infections by viruses like HIV-1 and MMTV. A3 proteins are inducible by inflammatory stimuli such as LPS and IFNα via mechanisms that are not yet fully defined. Using genetic and pharmacological studies on C57BL/6 mice and cells, we show that IFNα and LPS induce A3 via different pathways independent of each other. IFNα positively regulates mA3 mRNA expression through IFNαR•PKC•STAT1 and negatively regulates mA3 mRNA expression via IFNαR•MAPKs signaling pathways. Interestingly, LPS shows some variation in its regulatory behavior. While LPS mediated positive regulation of mA3 mRNA occurs through TLR4•TRIF•IRF3•PKC, it negatively modulates mA3 mRNA via TLR4•MyD88•MAPK signaling pathways. Additional studies on human PBMCs reveal that PKC differentially regulates IFNα and LPS induction of human A3A, A3F, and A3G mRNA expression. In summary, we have identified important signaling targets downstream of IFNαR and TLR4 that mediate A3 mRNA induction by both LPS and IFNα. Our results provide new insights into the signaling targets that could be manipulated to enhance intracellular store of A3 and potentially enhance A3 anti-viral function in the host.
PMCID: PMC3531240  PMID: 22972924
APOBEC3; interferon alpha; interferon beta; interferon alpha receptor; interferon regulatory factor 3; lipopolysaccharide; myeloid differentiation primary response gene (88); TIR-domain-containing adapter-inducing interferon-β; protein kinase C delta; Toll-like receptor 4; MAPK; ERK; JNK; P38
20.  Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis 
PeerJ  2013;1:e114.
Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established.
Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures.
Data Sources. A systematic review of the medical literature using Medline (1946–Week 4, 2012), EMBASE (1980–Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied.
Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included.
Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data.
Data Synthesis. All pooled analyses used the random effects model.
Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I2 = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I2 = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group.
Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs.
Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo.
PMCID: PMC3740140  PMID: 23940830
Systematic review; Meta-analysis; Lacosamide; Partial-onset seizures; Epilepsy; Antiepileptic drugs; Randomized controlled trials
21.  Body Mass Index and Mortality in Acute Myocardial Infarction Patients 
The American journal of medicine  2012;125(8):796-803.
Previous studies have described an “obesity paradox” with heart failure, whereby higher body mass index (BMI) is associated with lower mortality. However, little is known about the impact of obesity on survival after acute myocardial infarction.
Data from 2 registries of patients hospitalized in the United States with acute myocardial infarction between 2003–04 (PREMIER) and 2005–08 (TRIUMPH) were used to examine the association of BMI with mortality. Patients (n=6359) were categorized into BMI groups (kg/m2) using baseline measurements. Two sets of analyses were performed using Cox proportional hazards regression with fractional polynomials to model BMI as categorical and continuous variables. To assess the independent association of BMI with mortality, analyses were repeated adjusting for 7 domains of patient and clinical characteristics.
Median BMI was 28.6. BMI was inversely associated with crude 1-year mortality (normal, 9.2%; overweight, 6.1%; obese, 4.7%; morbidly obese; 4.6%; p<0.001), which persisted after multivariable adjustment. When BMI was examined as a continuous variable, the hazards curve declined with increasing BMI and then increased above a BMI of 40. Compared with patients with a BMI of 18.5, patients with higher BMIs had a 20% to 68% lower mortality at 1 year. No interactions between age (p=0.37), gender (p=0.87) or diabetes mellitus (p=0.55) were observed.
There appears to be an “obesity paradox” among acute myocardial infarction patients such that higher BMI is associated with lower mortality, an effect that was not modified by patient characteristics and was comparable across age, gender, and diabetes subgroups.
PMCID: PMC3408565  PMID: 22483510
body mass index; mortality; myocardial infarction; fractional polynomials; obesity paradox
22.  Changes in Social Support within the Early Recovery Period and Outcomes After Acute Myocardial Infarction 
To examine changes in social support during early recovery after acute myocardial infarction (AMI) and determine whether these changes influence outcomes within the first year.
Among 1951 AMI patients enrolled in a 19-center prospective study, we examined changes in social support between baseline (index hospitalization) and 1 month post-AMI to longitudinally assess their association with health status and depressive symptoms within the first year. We further examined whether 1-month support predicted outcomes independent of baseline support. Hierarchical repeated-measures regression evaluated associations, adjusting for site, baseline outcome level, baseline depressive symptoms, sociodemographic characteristics, and clinical factors.
During the first month of recovery, 5.6% of patients had persistently low support, 6.4% had worsened support, 8.1% had improved support, and 80.0% had persistently high support. In risk-adjusted analyses, patients with worsened support (versus persistently high) had greater risk of angina (relative risk=1.46), lower disease-specific quality of life (β=−7.44), lower general mental functioning (β=−4.82), and more depressive symptoms (β=1.94) (all p≤0.01). Conversely, patients with improved support (versus persistently low) had better outcomes, including higher disease-specific quality of life (β=6.78), higher general mental functioning (β=4.09), and fewer depressive symptoms (β=−1.48) (all p≤0.002). In separate analyses, low support at 1 month was significantly associated with poorer outcomes, independent of baseline support level (all p≤0.002).
Changes in social support during early AMI recovery were not uncommon and were important for predicting outcomes. Intervening on low support during early recovery may provide a means of improving outcomes.
PMCID: PMC3374926  PMID: 22691557
depression; health status; myocardial infarction; prognosis; quality of life; social support
23.  Adrenergic-pathway Gene Variants Influence β-Blocker-related Outcomes after Acute Coronary Syndrome in a Race-specific Manner 
Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for US healthcare. Genetic polymorphisms in the adrenergic pathway appear to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor-blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown.
BB after ACS is a measure of quality care, but the effectiveness across racial groups, is less clear.
A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African Americans) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors.
The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion (D) carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (HR 0.46; CI 0.21, 0.99; p=0.047; race-by-genotype interaction p= 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (HR for RG vs. GG =2.10; CI 1.14, 3.86; RR vs. GG =2.65; CI 1.38, 5.08; p=0.013; race-by-genotype interaction p=0.096).
Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasian and African Americans may illuminate opportunities to improve BB therapy in these groups.
PMCID: PMC3678950  PMID: 22703928
24.  How People with Multiple Sclerosis Rate Their Quality of Life: An EQ-5D Survey via the UK MS Register 
PLoS ONE  2013;8(6):e65640.
The EQ-5D is a widely-used, standardised, quality of life measure producing health profiles, indices and states. The aims of this study were to assess the role of various factors in how people with Multiple Sclerosis rate their quality of life, based on responses to the EQ-5D received via the web portal of the UK MS Register.
The 4516 responses to the EQ-5D (between May 2011 and April 2012) were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in SPSS (v.20).
The mean health state for people with MS was 59.73 (SD 22.4, median 61), compared to the UK population mean of 82.48 (which is approximately 1SD above the cohort mean). The characteristics of respondents with high health states (at or above +1SD) were: better health profiles (most predictive dimension: Usual Activities), higher health indices, younger age, shorter durations of MS, female gender, relapsing-remitting MS, higher educational attainment and being in paid employment (all p-values<0.001). Conversely, the characteristics of respondents with low health states (at or below -1SD) were: poorer health profiles (most predictive dimension: Mobility), lower health indices, older age, longer durations of MS, male gender, progressive MS, lower educational attainment and having an employment status of sick/disabled (p = 0.0014 for age, all other p-values<0.001). Particular living arrangements were not associated with either the high or low health status groups.
This large-scale study has enabled in-depth analyses on how people with MS rate their quality of life, and it provides new knowledge on the various factors that contribute to their self-assessed health status. These findings demonstrate the impact of MS on quality of life, and they can be used to inform care provision and further research, to work towards enhancing the quality of life of people with MS.
PMCID: PMC3679154  PMID: 23776516
25.  Effect of Living Alone on Patient Outcomes after Hospitalization for Acute Myocardial Infarction 
The American journal of cardiology  2011;108(7):943-948.
Considerable attention has been devoted to the effect of social support on patient outcomes after acute myocardial infarction (AMI). However, little is known about the relation between patient living arrangements and outcomes. Thus, we used data from PREMIER, a registry of patients hospitalized with AMI at 19 US centers between 2003-04, to assess the association of living alone with post-AMI outcomes. Outcome measures included 4-year mortality, 1-year readmission, and 1-year health status, using the Seattle Angina Questionnaire (SAQ) and Short Form-12 physical health component (SF-12 PCS) scales. Patients who lived alone had higher crude 4-year mortality (21.8% vs. 14.5%, P<0.001), but comparable rates of 1-year readmission (41.6% vs. 38.3%, p=0.79). Living alone was associated with lower unadjusted quality of life (mean SAQ −2.40 (95% confidence interval [CI] −4.44, −0.35), p=0.02), but had no impact on SF-12 PCS (−0.45 (95% CI −1.65, 0.76), p=0.47) compared with patients who did not live alone. After multivariable adjustment, patients who lived alone had a comparable risk of mortality (hazard ratio [HR] 1.35, 95% CI: 0.94-1.93) and readmission (HR 0.99, 95% CI: 0.76-1.28) as patients who lived with others. Mean quality of life scores remained lower among patients who lived alone (SAQ −2.91 (95% CI −5.56, −0.26), p=0.03). Living alone may be associated with poorer angina-related quality of life one year post-MI, but is not associated with mortality, readmission, or other health status measures after adjusting for other patient and treatment characteristics.
PMCID: PMC3670597  PMID: 21798499
Living alone; acute myocardial infarction; social support

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