3D tomography of cells in micro-channels

We combine confocal imaging, microfluidics and image analysis to record 3D-images of cells in flow. This enables us to recover the full 3D representation of several hundred living cells per minute. Whereas 3D confocal imaging has thus far been limited to steady specimen, we overcome this restriction and present a method to access the 3D shape of moving objects. The key of our principle is a tilted arrangement of the micro-channel with respect to the focal plane of the microscope. This forces cells to traverse the focal plane in an inclined manner. As a consequence, individual layers of passing cells are recorded which can then be assembled to obtain the volumetric representation. The full 3D information allows for a detailed comparisons with theoretical and numerical predictions unfeasible with e.g.\ 2D imaging. Our technique is exemplified by studying flowing red blood cells in a micro-channel reflecting the conditions prevailing in the microvasculature. We observe two very different types of shapes: `croissants' and `slippers'. Additionally, we perform 3D numerical simulations of our experiment to confirm the observations. Since 3D confocal imaging of cells in flow has not yet been realized, we see high potential in the field of flow cytometry where cell classification thus far mostly relies on 1D scattering and fluorescence signals

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE: Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE: To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS: Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES: Survival, stroke, and New York Heart Association functional class. RESULTS: Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE: In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis

Hybrid Erythrocyte Liposomes: Functionalized Red Blood Cell Membranes for Molecule Encapsulation

The modification of erythrocyte membrane properties provides a new tool towards improved drug delivery and biomedical applications. The fabrication of hybrid erythrocyte liposomes is presented by doping red blood cell membranes with synthetic lipid molecules of different classes (PC, PS, PG) and different degrees of saturation (14:0, 16:0-18:1). The respective solubility limits are determined, and material properties of the hybrid liposomes are studied by a combination of X-ray diffraction, epi-fluorescent microscopy, dynamic light scattering (DLS), Zeta potential, UV-vis spectroscopy, and Molecular Dynamics (MD) simulations. Membrane thickness and lipid orientation can be tuned through the addition of phosphatidylcholine lipids. The hybrid membranes can be fluorescently labelled by incorporating Texas-red DHPE, and their charge modified by incorporating phosphatidylserine and phosphatidylglycerol. By using fluorescein labeled dextran as an example, it is demonstrated that small molecules can be encapsulated into these hybrid liposomes

The risk-to-benefit ratio of transcatheter aortic valve implantation in specific patient cohorts: a single-centre experience

Transcatheter aortic valve implantation (TAVI) has recently developed into an acceptable alternative to conventional surgery in high-risk patients. However, information on the identification of patients gaining most benefit from this procedure is still limited. The aim of this study was to evaluate safety and efficacy of TAVI in different patient cohorts. Between August 2008 and December 2010, 180 high-risk patients underwent TAVI at our institution (97 transapical and 83 transfemoral approaches). Periprocedural complications as well as mortality and incidence of MACCE during follow-up were recorded. Mean age was 82 +/- A 5 years, and mean logistic EuroScore 27 +/- A 14%. In the total cohort, 30-day mortality was 8.9% and 12-month survival (according to Kaplan-Meier-analysis) 72%, with no significant differences between the two approaches. However, a significant difference in survival was obvious after stratification of patients according to logistic EuroScore mortality estimates. Survival proportions at 1 year were 62% in patients with logistic EuroScore > 40%, 71% in patients with EuroScore 20-40% and 80% in octogenarians with EuroScore < 20% (P = 0.009). Furthermore, the observed median event-free survival as an indicator for morbidity ranged between 315 days in the first, 442 days in the second and 710 days in the third group (P = 0.1). TAVI proved to be feasible with reproducible results. However, mortality and rehospitalization rates were considerably high in specific patient cohorts, suggesting that the risk-to-benefit ratio of TAVI should be validated individually. In the present study, octogenarians with logistic EuroScore < 20% could be identified as candidates apparently gaining high benefit from the procedure

The "smoker's paradox" in patients with acute coronary syndrome: a systematic review

<p>Abstract</p> <p>Background</p> <p>Smokers have been shown to have lower mortality after acute coronary syndrome than non-smokers. This has been attributed to the younger age, lower co-morbidity, more aggressive treatment and lower risk profile of the smoker. Some studies, however, have used multivariate analyses to show a residual survival benefit for smokers; that is, the "smoker's paradox". The aim of this study was, therefore, to perform a systematic review of the literature and evidence surrounding the existence of the "smoker's paradox".</p> <p>Methods</p> <p>Relevant studies published by September 2010 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1963) and the Cochrane Central Register of Controlled Trials, with a combination of text words and subject headings used. English-language original articles were included if they presented data on hospitalised patients with defined acute coronary syndrome, reported at least in-hospital mortality, had a clear definition of smoking status (including ex-smokers), presented crude and adjusted mortality data with effect estimates, and had a study sample of > 100 smokers and > 100 non-smokers. Two investigators independently reviewed all titles and abstracts in order to identify potentially relevant articles, with any discrepancies resolved by repeated review and discussion.</p> <p>Results</p> <p>A total of 978 citations were identified, with 18 citations from 17 studies included thereafter. Six studies (one observational study, three registries and two randomised controlled trials on thrombolytic treatment) observed a "smoker's paradox". Between the 1980s and 1990s these studies enrolled patients with acute myocardial infarction (AMI) according to criteria similar to the World Health Organisation criteria from 1979. Among the remaining 11 studies not supporting the existence of the paradox, five studies represented patients undergoing contemporary management.</p> <p>Conclusion</p> <p>The "smoker's paradox" was observed in some studies of AMI patients in the pre-thrombolytic and thrombolytic era, whereas no studies of a contemporary population with acute coronary syndrome have found evidence for such a paradox.</p

Quantum dynamics of molecules in 4He nano-droplets: Microscopic Superfluidity

High resolution spectroscopy of doped molecules in 4He nano-droplets and clusters gives a signature of superfluidity in microscopic system, termed as microscopic superfluidity. Ro-vibrational spectrum of 4HeN-M clusters is studied with the help of some important observations, revealed from experiments (viz., localised and orderly arrangement of 4He atoms, although, being free to move in the order of their locations; individual 4He atoms can not be tagged as normal/ superfluid, etc.) and other factors (e.g., consideration that the 4He atoms which happen to fall in the plane of rotation of a molecule, render a equipotential ring and thus, do not take part in rotation; etc.) which effect the rotational and vibrational spectrum of the system. This helps us in successfully explaining the experimental findings which state that the rotational spectrum of clusters have sharp peaks (indicating that the molecule rotates like a free rotor) and moment of inertia and vibrational frequency shift have a non-trivial dependence on N

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients : a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients’ clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward’s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients’ prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P &lt;.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27–3.62; HR 3.42, 95%CI 2.72–4.31; HR 2.79, 95%CI 2.32–3.35), and Cluster 1 (HR 1.88, 95%CI 1.48–2.38; HR 2.50, 95%CI 1.98–3.15; HR 2.09, 95%CI 1.74–2.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p&nbsp;&lt;.001. Over 24&nbsp;months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10&nbsp;ml/min/1.73&nbsp;m2 decrease), that was most notable in patients with eGFR &lt;30&nbsp;ml/min/1.73&nbsp;m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90&nbsp;ml/min/1.73&nbsp;m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

DNA damage in obesity: Initiator, promoter and predictor of cancer

Epidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity leads to a physiological imbalance in the regulation of adipose tissue and its normal functioning, resulting in hyperglycaemia, dyslipidaemia and inflammation. These states promote the generation of oxidative stress, which is exacerbated in obesity by a decline in anti-oxidant defence systems. Oxidative stress can have a marked impact on DNA, producing mutagenic lesions that could prove carcinogenic. Here we review the current evidence for genomic instability, sustained DNA damage and accelerated genome ageing in obesity. We explore the notion of genotoxicity, ensuing from systemic oxidative stress, as a key oncogenic factor in obesity. Finally, we advocate for early, pre-malignant assessment of genome integrity and stability to inform surveillance strategies and interventions

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients