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Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health and Care Research Oxford Biomedical Research Centre ECG patches (and respective monitoring data analysis) were granted free of charge by the manufacturer (iRhythm) Background Incidence of stroke could be reduced by detection of subclinical atrial fibrillation (AF) and appropriate anticoagulation. Opportunistic screening by pulse-taking or ECG is recommended by some international guidelines. In contrast, there is uncertainty regarding the benefits and harms of systematic screening across populations and/or using longer monitoring durations. Purpose To assess if screening using a one-off single-lead continuous non-invasive ECG patch worn for 14 days increases AF detection at 2.5 years compared to standard care, and whether this approach is cost-effective. Methods AMALFI is an ongoing mail-based open-label randomised controlled trial of remote AF screening in England. Streamlined design includes integration with national electronic health data and care pathways for participant identification, invitation, and management. The target population are individuals aged ≥65 years with CHA2DS2VASc score of ≥3 in men and ≥4 in women, and with no prior history of AF or allergy to latex. Participants in the intervention arm self-apply the ECG patch and return it for analysis after 14 days. AF findings (duration ≥30 seconds at any rate) are communicated to primary care physicians, with further clinical management at their discretion. Participants in the control arm receive usual care (which is expected to include opportunistic AF screening). The primary outcome is the proportion of participants with newly-detected AF recorded in primary care electronic health records in each group at 2.5 years after randomisation. Results From 2019 to 2022, AMALFI invited 22,188 people, of whom 5,040 (23%) were randomised. Baseline characteristics included age 77±6 years, 47% female, and median CHA2SD2VASc score 3 (Table 1). Of 2520 individuals randomised to the intervention, 2127 (84%) wore and returned the patch. Median wear time was 13.9 days and median proportion of time analysable was 98.8%. AF was present in 102 patch reports, representing 4.8% of reports received and 4% of the intervention arm (in line with a priori estimates for power calculations for the primary outcome); median AF burden was 11.3%. AF was present at commencement of recording in 40% of these reports, by the end of the first day in 58%, and by the end of the first week in 83% (Figure 1). Incidental findings included supraventricular tachycardia (in 90% of reports), non-sustained ventricular tachycardia (VT; in 32%), sustained VT (in 0.1%), Mobitz II/high-grade/3rd degree AV block (in 1.1%), and pauses >6s (in 0.3%). Conclusion AMALFI’s innovative design facilitated recruitment and demonstrates that a remote ECG patch-based AF screening strategy is feasible, resulting in a new diagnosis of AF in ~4% of individuals selected due to moderate-to-high clinical stroke risk. Longer term follow-up will provide data on the incremental value and cost-effectiveness of AF diagnosis by systematic screening compared to routine opportunistic detection.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly Background We recently demonstrated that in human atria, endomysial fibrosis causes conduction disturbances during atrial fibrillation (AF), while overall connective tissue content (over-all fibrosis) has no effect. Etiological and molecular determinants of endomysial fibrosis are largely unknown. Methods We quantified over-all and endomysial atrial fibrosis using staining with WGA in left (LA, n=95) and right (RA, n=76) atrial appendages sampled from a European cohort (CATCH ME) of patients undergoing cardiac surgery. The contributions of AF, heart failure (HF), sex, age, and 4 principal components accounting for confounding clinical characteristics to over-all and endomysial fibrosis were determined in a multivariate model. RNA sequencing was performed to explore biological pathways associated with the two types of fibrosis. Results Over-all and endomysial fibrosis were moderately correlated (LA: r=0.69, RA: 0.61, both p Conclusions Taken together, female sex, HF, and AF are the main drivers of fibrosis in human atria. However, endomysial fibrosis is independently associated with AF whereas over-all fibrosis is not. BMP10 is a specific marker of endomysial fibrosis. Our findings suggest that distinct mechanisms are involved in the development of over-all versus endomysial fibrosis in human atria and may provide an explanation for the recently reported predictive value of BMP10 biomarkers levels for AF recurrences after AF ablation and for stroke.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly Background Atrial cardiomyopathy is emerging as independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy and a reduction in capillary density are histological hallmarks of atrial cardiomyopathy. The contribution of etiological factors to atrial cardiomyopathy has not been robustly quantified. Purpose To quantify the relation between histological features of atrial cardiomyopathy and the clinical profile of patients. Methods We examined left (LA, n=91) and right (RA, n=75) atrial appendages sampled from a European cohort of patients undergoing cardiac surgery. Quantification of histological cardiomyopathy features was performed a recently developed and validated imaging analysis algorithm following myocardial triple staining with wheat germ agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex, age, and 4 principal components accounting for confounding clinical characteristics to over-all and endomysial fibrosis were determined in a multivariate model. K-means clustering of 6 atrial histological features was performed to identify different types of remodeling. Results LA samples showed less fibrosis (p Samples clustered into 2 distinct clusters. One cluster showed fibrotic cardiomyopathy, with more endomysial (p Conclusions Fibrotic cardiomyopathy is associated with female sex, persistent AF and heart failure while hypertrophic cardiomyopathy more often occurs in men. More research is needed to establish whether treatment of AF and heart failure prevents the development of atrial cardiomyopathy.

BackgroundAtrial cardiomyopathy (AtCM) is emerging as an independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are histological hallmarks of atCM. However, the contribution of various etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been robustly quantified. We aimed to evaluate the association between histological features of atCM and the clinical phenotype.MethodsWe examined left (LA, n=95) and right (RA, n=76) atrial appendages sampled from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed using the JavaCyte algorithm, following staining with agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex and age to histological characteristics were determined in a multivariate model. K-means clustering of 6 histological features was performed to identify different types of atCM.ResultsIn both LA and RA, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41µm,p=0.01; RA:+0.89±0.43µm,p=0.032), whereas total extracellular matrix (ECM) content was unchanged in AF. Men had larger cardiomyocytes (LA:+1.87±0.72μm,p=0.012), while women had a higher degree of endomysial fibrosis (LA:+0.99±0.51µm,p=0.048). Heart failure patients showed more endomysial fibrosis (LA:+1.79±0.41µm,pConclusionsAtCM phenotypes vary with patient characteristics. Fibrotic atCM is associated with female sex, persistent AF and heart failure, while hypertrophic features are more common in men.

BackgroundIn patients undergoing cardiac surgery perioperative statin therapy has been associated with an unexpected increase in postoperative plasma creatinine. Here we investigated mechanisms and predictors of acute kidney injury (AKI) in 1922 patients enrolled in the Statin Therapy in Cardiac Surgery (STICS) randomized placebo-controlled trial of perioperative rosuvastatin (20 mg once daily).MethodsAKI was defined according to international guidelines (KDIGO) using plasma creatinine, and also by cystatin C. Potentially mechanistically relevant plasma/serum biomarkers of muscle injury, inflammation, and kidney injury were investigated, including total creatine kinase (CK), growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), procalcitonin (PCT), placental growth factor (PLGF), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL).ResultsAt 48 hours post-surgery, the incidence of AKI was greater in the rosuvastatin group than in the placebo group when defined by a rise in creatinine (24.7% vs 19.3%, p=0.005) or cystatin C (9.2% vs 5.1%, p10x and >40x the baseline level (30.9% versus 26.5%, p=0.032, and 2.1% versus 0.7%, p=0.016, respectively), whereas postoperative concentrations of GDF-15, IL-6, PCT, PLGF, and NGAL were similar between groups. In multivariable analyses, insulin treatment, baseline KIM-1, combined coronary artery bypass grafting (CABG) and aortic valve replacement (AVR) surgery, and allocation to rosuvastatin were all independently associated with AKI as defined by creatinine or cystatin C. Odds ratios for rosuvastatin compared to placebo for both creatinine- and cystatin C-defined AKI were not materially altered by further adjustment for post-randomization increases in CK.ConclusionsPerioperative rosuvastatin initiation increased the absolute risk of AKI after cardiac surgery by 4-5%, whether defined by creatinine or cystatin C, and led to higher post-operative KIM-1, suggesting a deleterious effect on renal function, possibly mediated by proximal tubular injury. Insulin treatment, baseline KIM-1, combined CABG/AVR surgery, and allocation to rosuvastatin were all independently associated with AKI by any definition.

Introduction Epicardial adipose tissue (EAT) is a visceral fat deposit within the pericardial sac which surrounds the heart myocardium and coronary arteries. The automated quantification of EAT volume is possible from routine CCTA scans via a deep-learning approach. The use of automated EAT quantification for the assessment of atrial fibrillation (AF) risk in the post-operative period, and longer-term, has not been previously investigated. Purpose To apply a deep-learning approach for automated segmentation of EAT from routine CCTA scans to assess the immediate post-operative and long-term risk of AF conveyed by EAT. Methods A deep-learning automated EAT segmentation tool using a 3D Residual-U-Net neural network architecture for 3D volumetric segmentation of CCTA data was created and trained on over 2800 consecutive CCTA performed as part of clinical care in patients with stable chest pain from 2015 onwards within the European arm of the Oxford Risk Factors And Non Invasive Imaging (ORFAN) Study. External validation in 817patients demonstrated excellent correlation between machine and human expert (CCC = 0.972). The prognostic value of deep-learning derived EAT volume was assessed in the AdipoRedOx Study (n=253; UK patients undergoing cardiac surgery) against both immediate in-hospital outcomes and longer-term outcomes from UK-wide NHS data, with adjustment for AF risk factors. Results There were 97 cases of new-onset AF in the immediate post-operative period (38.3%). EAT volume was found to be an independent predictor of post-operative AF regardless of body mass index. Utilising the median EAT volume as the cut point, the adjusted hazard ratio (HR [95% CI]) for risk of new-onset post-operative AF in-hospital was 1.56 [1.09–3.85], p Over a median follow-up period of 89 months there were 48 unique cases (19%) of confirmed AF found in nation-wide NHS hospital episode statistics data for the AdipoRedOx cohort. EAT volume was found to be a significant independent predictor of long-term AF. Utilising the median EAT volume as the cut point, the adjusted HR for risk of new-onset long-term AF following cardiac surgery was 1.25 [1.08–3.17], p Conclusions Automatically segmented EAT volume measured using a deep learning network predicts risk of both short-term new onset AF following cardiac surgery, and long-term risk of AF in the 7 years following the surgery independently of BMI and AF risk factors. This suggests that EAT is a potent mediator of AF risk in the post cardiac surgery setting. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation - TG/19/2/34831EU Commission - 965286

Introduction In patients undergoing cardiac surgery, perioperative statin therapy does not prevent atrial fibrillation or myocardial injury, but results in increased creatinine levels after surgery. Here we investigated the incidence of acute kidney injury (AKI) in 1922 patients scheduled for elective cardiac surgery who were randomized to perioperative rosuvastatin (20 mg once daily) or placebo in the Statin Therapy In Cardiac Surgery (STICS) trial. Methods AKI post-surgery was defined according to international guidelines using plasma creatinine. Biomarkers related to kidney function, muscle injury and inflammation were investigated, including cystatin C, total creatine kinase (CK), troponin I, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), procalcitonin, and placental growth factor (PGF). Results At 48 hours post-surgery, AKI was significantly more common in patients allocated to rosuvastatin compared to placebo when defined by creatinine (24.7% vs 19.3%; OR 1.37 [95% CI 1.10–1.70]; p=0.005; Figure 1A) or by cystatin C (9.2% vs 5.1%; OR 1.86 [95% CI 1.29–2.67]; p10x and >40x baseline level were also more frequent in rosuvastatin-allocated patients compared to placebo (30.9% vs 26.5%, p=0.02, and 2.1% vs 0.7%, p=0.02, respectively; Figure 1C). Post-operative concentrations of troponin I, GDF-15, IL-6, procalcitonin, and PGF were similar between the groups (Table 1). Conclusions Perioperative rosuvastatin initiation increased the absolute risk of AKI after cardiac surgery by 4–5%. Rosuvastatin also led to greater elevations in post-operative creatine kinase, but did not affect other biomarkers of tissue injury, inflammation, and myocardial injury. Further research is needed to delineate the underlying mechanism of AKI with perioperative rosuvastatin. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Background Atrial fibrillation (AF) is associated with embolic stroke, but risk scores such as CHA2DS2-VASc perform only modestly (C statistics 0.6–0.7). Meanwhile, up to 25% of embolic strokes in patients without AF have no identifiable cause, and occult left atrial (LA) thromboembolism may be a relevant mechanism in such cases. Purpose We hypothesised that imaging of left atrial blood flow could improve embolic risk prediction in patients with and without AF. We used 4D flow magnetic resonance imaging (MRI) to identify a biomarker that is: (a) independently associated with embolic brain infarction by brain MRI, (b) able to stratify blood flow characteristics both during AF and in sinus rhythm (SR), and (c) reproducible. Methods We recruited 3 patient cohorts to respectively address each aim. Firstly, to assess the association between LA flow parameters and embolic brain infarcts, we recruited cohort A, consisting of 134 patients (41% female; age 70±9 years) with a history of ischaemic stroke (N=44) or no history of stroke but with CHA2DS2VASc score ≥1 (N=90). Next, the sensitivity of 4D flow parameters to rhythm change was assessed in cohort B: 37 patients with persistent AF studied before and after cardioversion, whose results were compared with those of 23 healthy controls in SR [CHA2DS2-VASc = 0.0 (0.0–0.0)]. Finally, scan-rescan coefficients of variation (CV) and interval-scan CV at 30 days were determined in Cohort C (86 subjects; 64 in SR, 22 in AF). Brain MRI was used to identify large non-cortical or cortical brain infarcts (LNCCI) – i.e. infarcts likely to be embolic in origin. Results At least one LNCCI was present in 39 of 134 patients in cohort A. Lower LA vorticity was significantly associated with higher risk of prevalent LNCCIs (Figure 1), after adjustment for AF, age, and CHA2DS2VASc score [OR=2.10 (95% CI 1.12–3.92) per SD, P=0.02]. This association remained significant after further adjustment for other cardiac parameters (all P LA vorticity was sensitive to rhythm change, improving significantly in patients in cohort B in SR at ≥4 weeks after cardioversion (CV) of persistent AF (Figure 2A, paired P Finally, reproducibility studies in cohort C showed that LA vorticity had a same-day scan-rescan CV of 7% without significant differences between SR and AF subjects (P>0.05), and also showed no significant temporal variability on interval scanning (P>0.05). Conclusions LA vorticity is reproducible, sensitive to changes in heart rhythm, and independently associated with embolic brain infarcts, suggesting a promising imaging biomarker of cardioembolism in SR and AF. LA blood flow imaging could improve stroke prediction and the personalisation of decisions about anticoagulation, regardless of heart rhythm. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Oxford BRC, BHF

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 Background Risk factors for atrial fibrillation (AF), such as ageing, heart failure and AF itself, enhance AF propensity partly by inducing atrial fibrosis. Atrial endomysial fibrosis, a type of reactive fibrosis occurring between cardiomyocytes, impairs transverse conduction in rapid atrial pacing animal models. The factors underlying transcriptional regulation of endomysial fibrosis are largely unknown. Objective To examine the contributions of age, sex, AF and heart failure to the development of endomysial fibrosis in the context of concurrent pathologies. To study genome-wide transcriptional changes associated with endomysial fibrosis in human left and right atrial appendage biopsies (LAA, n=95; RAA, n=76). Methods An algorithm for automated quantification of endomysial fibrosis following staining with wheat germ agglutinin (WGA) was employed. Linear mixed models were constructed to determine endomysial fibrosis quantity as a function of AF, heart failure, sex, age and four principal components that accounted for potential confounding effects of other clinical characteristics. RNA sequencing was used to study expression changes in the atrial transcriptome associated with endomysial fibrosis. Results Sex, persistent AF, heart failure and age were independently associated with endomysial fibrosis. We identified hundreds (LAA: 386, RAA: 311) of RNA transcripts associated with endomysial fibrosis. None of these associations were independent from the clinical phenotypes. However, explorative gene set enrichment analysis identified association of endomysial fibrosis with gene sets involved in extracellular matrix organization, immune response, cell motility, developmental processes, cardiac muscle contraction and proteostasis in LAA while in RAA only gene sets regulating contractile function were enriched. Conclusion Besides AF, female sex, age and heart failure are associated with endomysial fibrosis in the atria. While abundance of none of the differential genes were independently associated with endomysial fibrosis, gene set enrichment analysis suggests an involvement of extracellular matrix organization, immune response, cell motility, developmental processes and cardiac muscle contraction in endomysial fibrosis.

Biological age is a better measure of functional capacity than chronological age.1 One of the measures of biological age is telomere length. Telomeres are nucleoprotein complexes that protect chromosome ends from damage. The DNA component of telomeres progressively shortens as biological age increases and thus acts as a read out for ‘miles on the biological clock’. 2 Telomere length progressively shortens as biological age increases. Within health care, ageing is almost exclusively described in terms of chronological age. Recent studies explored using biological age to stratify patients and predict outcomes.3 This project acts as a pilot study to investigate whether biological age is related to intensive care unit (ICU) outcomes and whether ICU patients age biologically at an accelerated rate. This project used blood samples from a previous study where patients underwent cardiac surgery and were admitted to the ICU. Blood samples were obtained before surgery and on days 1, 2, and 3 after surgery. The database contained the following physiological parameters: haemoglobin, urea, creatinine, RIFLE score, length of ICU stay, and whether renal replacement therapy was required. Information on co-morbidities and medication was also provided. DNA was isolated using a Maxwell machine and telomere length determined via quantitative PCR. One hundred and fifty-five blood samples from 46 patients underwent analysis. Telomere length did not differ significantly over the 4 days (P=0.662). No relationship was found between telomere length and any physiological parameter, co-morbidity, or medication. There was a trend towards significance with RIFLE score at day 3 increasing as telomere length decreased, although this was not statistically significant (P=0.09). No relationship between telomere length and the available physiological parameters, comorbidities, or medication was found. Telomere length did not vary during ICU stay. This study was limited by its small sample size. Future studies would benefit from a larger sample size; in addition, blood samples could also be obtained at 6 months after discharge to allow gradual alterations in biological age to be determined. Recent studies give evidence that telomere length is a weak biomarker of ageing,3 and that more meaningful data might be obtained using superior markers, such as CDKN2A expression or expression levels of non-coding RNAs.3

The present study focuses on the comparison of the tribological performance of three hydrogenated amorphous carbon (a-C:H) coatings, PA-CVD deposited on the Ti–6Al–4V alloy: (i) in standard deposition conditions, (ii) in conditions allowing a higher penetration in holes and cavities, and (iii) in standard deposition conditions, with a PVD-CrN interlayer. The topography and microstructure of the coatings were characterized and the intrinsic hardness, reduced modulus and practical adhesion were determined. The dry sliding friction and wear behaviour of the coated alloy was studied by a slider-on-cylinder tribometer, at room temperature and in laboratory air, under the same sliding speed (0.3 m/s) and distance (1000 m), in the load range 5–90 N. The counterfacing material was the SAE52100-EN100Cr6 bearing steel. A critical load, which corresponds to the end of coating life, was identified for each a-C:H coated system. Below the critical load, all the coatings were effective in significantly reducing wear by comparison to the uncoated alloy. However, the highest critical load (both in dry sliding and in scratch tests) was measured for the coating with the CrN interlayer, thus confirming the key role of interlayers in improving load support by the substrate. The modification of deposition conditions for achieving higher penetration of the a-C:H coating, allows to obtain a very hard and stiff film with relatively low adhesion, which shows low friction and wear values under low applied loads but fails prematurely at high applied load.

Aim: There is evidence towards superiority of stapled closure of loop ileostomy after low rectal anastomosis compared to hand suture in terms of operative time and bowel obstruction rate. The aim of this study is to compare the 30-day outcomes of the two techniques for ileostomy closure after ileal pouch-anal anastomosis (IPAA). Method: Consecutive patients undergoing ileostomy closure after IPAA between 2011–2106 were retrospectively included. Patients’ characteristics and perioperative outcomes were compared. Results: Hand-sewn suture and stapled anastomosis were performed in 280 (84.3%) and 52 (15.7%) patients. The two groups had comparable demographic characteristics. The median operative time was the same between groups (90 min). The incidence of Clavien-Dindo grade I (6.4% vs. 9.6%), II (4.3% vs. 1.9%) and IIIb (1.4% vs. 3.8%), the median days to flatus (2 vs. 2.5, P 0.3) and the length of hospital stay (6 days in both, P 0.9) were similar between groups. A slightly higher although non-significant rate of bowel obstruction was observed in the stapled group (3.8% vs. 2.5%, P 0.6). Conclusion: The loop ileostomy after IPAA should be closed according to the surgeon’s preference using indifferently the hand-sewn or the stapled technique, as the expected outcomes are similar.

Active pixel sensors (APS) technology offers performance competitive with charge-coupled device technology, and it offers advantages in on-chip functionality, system power reduction, cost, and miniaturization. In this paper, we present the design and characterization of a fast CMOS APS imager for high-speed laser detections, which can replace streak cameras. It produces intensity information as a function of one spatial dimension and time (I=f(x,t)) from a pixel array with two spatial dimensions. The time information is obtained for the first prototype camera by delaying successively the integration phase for each pixel of the same row. The different noise sources of the APS sensors, such as shot noise due to the photo sensor, thermal noise, and flicker noise due to the readout transistors, and the photon shot noise are presented in order to determine the fundamental limits of the image sensor. The first prototype fast MOS imager (FAMOSI) consists of 64/spl times/64 active pixels. The simulation and experimental results show that a conversion gain of 6.73/spl plusmn/0.25 /spl mu/ V/e/sup -/ has been obtained with a noise level of 87/spl plusmn/3 e/sup -/ rms. The power consumption of the chip is 25 mW at 50 frames/s. The time resolution is 0.8 ns for this new concept camera.

A novel Monolithic Active Pixel Sensor (MAPS) for charged particle tracking made in a standard CMOS technology is proposed. The sensor is a photodiode, which is readily available in a CMOS technology. The diode has a special structure, which allows the high detection efficiency required for tracking applications. The partially depleted thin epitaxial silicon layer is used as a sensitive detector volume. Semiconductor device simulation, using either ToSCA based or 3-D ISE-TCAD software packages shows that the charge collection is efficient, reasonably fast (order of 100 ns), and the charge spreading limited to a few pixels only. A first prototype has been designed, fabricated and tested. It is made of four arrays each containing 64×64 pixels, with a readout pitch of 20 μm in both directions. The device is fabricated using standard submicron 0.6 μm CMOS process, which features twin-tub implanted in a p-type epitaxial layer, a characteristic common to many modern CMOS VLSI processes. Extensive tests made with soft X-ray source ( 55 Fe) and minimum ionising particles (15 GeV/ c pions) fully demonstrate the predicted performances, with the individual pixel noise (ENC) below 20 electrons and the Signal-to-Noise ratio for both 5.9 keV X-rays and Minimum Ionising Particles (MIP) of the order of 30. This novel device opens new perspectives in high-precision vertex detectors in Particle Physics experiments, as well as in other application, like low-energy beta particle imaging, visible light single photon imaging (using the Hybrid Photon Detector approach) and high-precision slow neutron imaging.

In this paper, we present design and characterisation of a fast CMOS APS (active pixel sensor) imager for high-speed laser detection, which can replace streak cameras. It produces the intensity information as a function of one spatial dimension and time (I=f (x, t)) from a two spatial dimensions frame. The time information is obtained for the first prototype camera by delaying successively the integration phase for each pixel of the same row. The different noise sources of the APS sensors; such as shot noise due to the photo sensor, thermal noise and flicker noise due to the readout transistors, and the photon shot noise, are presented in order to determine the fundamental limits of the image sensor. The first prototype FAMOSI (fast MOS imager) consists of 64/spl times/64 active pixels. The simulation and experimental results show that a conversion gain of 6.73/spl plusmn/0.25 /spl mu/V/e has been obtained with a noise level of 87/spl plusmn/ 3 electrons rms. The power consumption of the chip is 25 mW at 50 frames/sec. The time resolution is 0.8 ns for this new concept of camera.

A new electrical simulation model for photogate active pixel sensor in CMOS imagers is proposed. Review of three conventional models is done and shows lack of accuracy. Therefore photoelectric mechanisms and charges transfer of photogate pixel are analysed and lead to the definition of a Verilog-A description model. This model is then simulated into the Cadence design tool environment and simulation results show great improvements in simulation accuracy of the proposed model versus others ones.

We designed a camera based on a fast CMOS APS imager for high speed optical detection which produces images simi-larly as a streak camera. This imager produces the intensity information I as function of one spatial dimension and time (I=f(x,t)) from one frame with two spatial dimensions. The time sweeping is obtained by delaying successively the integration phase for each pixel of the same row. For the first FAMOSI (Fast MOs Imager) prototype the start of in-tegration is given by the camera itself. This signal is injected to a laser trigger. This laser emits a 10 nanoseconds light pulse onto the sensor. The temporal evolution of the light pulse is then resolved by the camera with a resolution of 800 ps. In single shot, the maximum dynamic of the camera is estimated to 64 dB and is limited by the readout noise. We decide to work in accumulation mode in order to increase the signal to noise ratio of the camera. But the high laser trigger (about 20 ns rms) does not allow accumulation of several optical events without a large spreading. The camera has been modified in order to be triggered by an external signal delivered by a trigger unit. In this new configuration the laser emit pulses at a repetition rate of 50 Hz. A photodiode detect a part of the laser pulse and generate the trigger signal for FAMOSI. The laser pulse is delayed with an optical fibre before being directed to the camera. The trigger jitter obtained is then less than 100 ps and allows accumulation without significant loss of the temporal resolution. With accumulation the readout noise is attenuated by a √N factor. Then with N = 1000 accumulations, the dynamics approach 93 dB. This allows the camera to work similarly as a synchroscan streak camera and then to observe weak signal.

CMOS active pixel sensors (APS) have performances competitive with charge-coupled device (CCD) technology, and offer advantages in on-chip functionality, system power reduction, cost and miniaturization. In this paper, we present characterization of a fast CMOS APS used in an imager for high-speed laser detections, which can replace the streak cameras. It produces the intensity information in function of one spatial dimension and time [I = f(x,t)] from one frame in two spatial dimensions. The time information is obtained for the first prototype camera to delay successively the integration phase in each pixel of the same row. The different noise sources of the APS sensors such as shot noise due to the photo sensor, the thermal noise and flicker noise due to the readout transistors and the photon shot noise are presented to determine the fundamental limits on image sensor. The first prototype FAMOSI (FAst MOS Imager) is composed of 64 x 64 active pixels. The simulation and experimental results show that a conversion gain of 6.73 ± 0.25 μV/e - has been obtained with a noise level of 87 ± 3e - rms. The power consumption of the chip is 25 mW at 50 images/sec.

CMOS active pixel sensors (APS) have performances competitive with CCD technology, and offer advantages in on-chip functionality, system power reduction, cost and miniaturisation. We present design of a fast CMOS APS imager for high speed laser detections which can replace the streak cameras. This imager is composed of 64/spl times/64 active pixels. The simulation and experimental results show that a gain of 7.3 /spl mu//spl nu//e/sup -/ has been obtained with a noise level of 106 e rms. The power consumption of the chip is 30 mW at 50 images/sec.

In this paper, the results of the first temporal resolution imager CMOS for high-speed laser pulse characterisation are presented. This new imager can replace the conventional streak camera using a charge-coupled device (CCD) sensor for some applications. It produces the intensity information in function of time and one spatial dimension (Iph = f (x, t)). The time information is obtained for the prototype to delay successively the integration phase in each pixel of the same row. The different noise sources for an APS sensor such as the shot noise due to the photo sensor, the flicker noise and the thermal noise due to the transistors are studied to determine the fundamental limits on image sensor. The prototype imager named FAMOSI (FAst MOS Imager) consists of an array of 64 x 64 active pixel sensors that are integrated in AMS 0.6 μm CMOS technology. Each pixel size is 13 μm × 13 μm and has a fill factor of 28%. At 50 frames/s, theoretical and experimental results show a total noise of 95± 4 electrons, a fixed pattern noise of 2% (saturation voltage is 760 mV), a dynamic range of 64 dB and a power consumption of 25 mW. The conversion gain is 6.73 ± 0.25 μV/electrons and the time resolution is 0.8 ns.

Women with Turner's syndrome (TS) have a threefold increase in mortality, primarily as a result of their cardiovascular complications. Recently, the risk of fatal aortic dissection has come to light as a major cause of mortality in women with TS. The aim of this study was to assess the prevalence of aortic root dilatation in a group of women with TS and to investigate the factors contributing to its development. Thirty-eight women with TS attending a dedicated adult Turner clinic were examined clinically and by M-mode and two-dimensional echocardiography on at least one occasion. Aortic root dilatation was defined as an aortic root diameter greater than the 95th centile for body surface area. Fasting serum lipid concentrations were measured in all women. Additionally, 18 subjects underwent noninvasive assessment of central arterial stiffness using applanation tonometry. Fifty percent of subjects were hypertensive and a similar number had an abnormal echocardiogram. A bicuspid aortic valve was present in 33% of subjects, 16 women (42%) had ascending aortic root dilatation. This was associated with a bicuspid aortic valve in four women and hypertension in 11. Two women had isolated aortic root dilatation. Aortic root diameter was significantly associated with systolic blood pressure (r = 0.5, P = 0.003) and left ventricular thickness (r = 0.5, P = 0.02). There was no association with serum lipids or arterial compliance. Structural cardiac abnormalities are present in up to 50% of women with Turner's syndrome. Aortic root dilatation is a significant risk in women with Turner's syndrome and is closely dependent on blood pressure. Aortic root dilatation does not appear to be related to atherosclerosis and is more likely to be due to a mesenchymal defect. Regular surveillance of the aortic root diameter is essential in all women with Turner's syndrome and hypertension should be treated aggressively when present in order to minimize the risk of potentially fatal aortic dissection.

Rationale Nitric oxide production in the heart is involved in the regulation of ion channels activity, myocardial perfusion and thrombogenesis. Atrial fibrillation (AF) has been associated with reduced myocardial nitric oxide (NO) bioavailability; however, the mechanisms and the consequences of this phenomenon remain to be elucidated. Methods and Results We evaluated the activity, protein content, and localization of constitutive NO synthases (NOS) in atrial tissue from 62 patients with permanent AF and 148 controls in normal sinus rhythm (SR), and in goats after 2 weeks (2W-AF, n=15) or 6 months (6M-AF, n=10) of pacing-induced AF ( vs. sham surgery & SR, n=14). NOS activity was uncoupled in right atrial (RA) tissue from AF patients and 6M-AF goats, both of which also exhibited an ipsilateral reduction in the NOS cofactor tetrahydrobiopterin (BH4) and an increase in arginase activity (HPLC). Although ex vivo BH4 and arginine supplementation reversed NOS uncoupling, atrial NOS activity remained profoundly suppressed in AF due to a progressive decrease in the “neuronal” isoform of NOS (nNOS) in atrial cardiomyocytes (by 65% in 2W-AF, 86% in 6M-AF goats and 62% in patients with AF). Atrial nNOS mRNA expression (qRT-PCR) did not differ between AF and SR; however, nNOS ubiquitination was increased in AF. Atrial nNOS protein content was partially restored by inhibition of proteasomal activity with MG132 but not by inhibiting the autophagy-lysosomal pathway with bafilomycin A1 or by pre-treatment with BH4. nNOS signalling and protein stability in the cardiac muscle depends on the enzyme9s anchoring to the dystrophin-syntrophin complex at the sarcolemmal membrane. In the fibrillating atrial myocardium we observed a significant reduction in dystrophin (by 56%) and its associated proteins, 1α syntrophin and caveolin-3; by contrast no difference in the dystrophin complex was observed in the atrial myocardium of nNOS -/- mice. Immunoprecipitation showed co-localisation of nNOS with dystrophin in SR, but not in AF. To assess whether loss of nNOS and reduced NO bioavailability played a role in the AF-induced atrial electrical remodelling; we evaluated the effect of nNOS inhibition or gene deletion in human and murine atrial myocytes. In RA myocytes from patients in SR (but not in patients with AF), nNOS inhibition shortened the action potential duration (APD) by 40%, and decreased the rate dependent-adaptation of APD (both of which are a hallmark of AF-induced electrical remodelling). These findings were recapitulated in murine right atrial myocytes in the presence of nNOS gene deletion or inhibition. In mice, nNOS gene deletion was sufficient to induce a 2-fold increase in the likelihood of developing AF in response to electrical stimulation. Conclusions - These data indicate that dystrophin-dependent loss of myocardial nNOS in AF is sufficient to produce an atrial electrical substrate that increases both inducibility and maintenance of this arrhythmia. Therapeutic strategies aimed at preserving or restoring the dystrophin complex may have a profound effect on NO bioavailability and the electrical substrate of AF.

Xanthine oxidase (XO) is a major source of reactive oxygen species in the cardiovascular system. Enhanced XO activity in the failing myocardium has been associated with a reduction in inotropy; however, whether this association is causal remains to be established. To test this hypothesis, the effect of XO inhibition (oxypurinol, 100 μmol/l and allopurinol, 100 μmol/l) or activation (xanthine, 100 or 500 μmol/l) on cell shortening (3 Hz, 35°) was evaluated in left ventricular (LV) myocytes isolated from C56BL/6–129j mice. Similarly, LV superoxide production in the absence and presence of inhibitors of XO, NADPH oxidases (apocynin, 100 μmol/l) or nitric oxide synthases (LNAME, 1 μmol/l) was measured by lucigenin (5 μmol/l)-enhanced chemiluminescence. Oxypurinol and allopurinol significantly suppressed basal superoxide production and cell shortening (by about 20%), whereas xanthine caused a dose-dependent increase in cell shortening and superoxide production. In contrast, apocynin had no effect on superoxide release or cell shortening. Taken together, our findings indicate that superoxide production by XO exerts a tonic positive inotropic effect on murine LV myocytes, suggesting that the increase in XO activity in heart failure may be, at least in part, adaptive.

No abstract available.

Regarding primary mediastinal large B-cell lymphoma (PMLBCL), there are several controversial topics that warrant further investigation: the superiority of third-generation regimens, the impact of rituximab, the use of involved field radiotherapy (RT) and the assessment of clinical response by positron emission tomography (PET). We report our experience on 74 PMLBCL patients treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and rituximab: an observational retrospective single-centre study was conducted on patients diagnosed and treated between February 2002 and July 2011. All patients were evaluated by computed tomography scan and PET scan; after the final PET evaluation, PET-negative patients were observed, whereas PET-positive patients underwent mediastinal RT. Sixty-one (82.4\%) patients achieved a complete response after the MACOP-B plus rituximab regimen; 68.9\% presented a positive final PET and were treated with local RT, whereas 31.1\% had a negative PET. Five patients relapsed within 12 months. At 10 years, overall survival was 82\%, progression-free survival was 87.6\% and disease-free survival (DFS) was 90.5\% (median follow-up 4 years). No statistically significant differences were observed in DFS between the patients treated also with RT (PET positive) and patients only observed (PET negative): 90.7\% vs 90\% (p = 0.85), respectively. In our experience, adding rituximab does not change the final results in terms of complete response and DFS utilizing third-generation regimen. Furthermore, the introduction of the PET-guided RT approach leads to a patient-tailored treatment, which preserves the outcome and, at the same time, allows reducing the use of RT. Copyright © 2014 John Wiley & Sons, Ltd.

Il presente saggio, frutto di una ricerca empirica triennale finanziata dalla Commissione europea nell'ambito del V FP (Progetto YOYO), analizza il potenziale delle attività sportive, sopratttutto di quelle estetico-espressive, quale innesco motivazionale nel recupero di giovani in situazione di svantaggio. La motivazione intrinseca, legata al piacere di svolgere una determinata attività, nel caso qui preso in esame la danza, ha dimostrato la propria efficacia di diffusione ad altri ambiti della vita del soggetto, in questo caso alla frequenza e ai successi scolastici, soprattutto se accompagnata da figure adulte autorevoli in grado di incanalarla verso forme più profonde di riflessività esistenziale. Body, movement and sport activities have traditionally been less valued than cognitive abilities in the educational system, a fact that still permeates the design of school system, but an encouraging sign in favour of acknowledge of the educative purpose of movement and sport activities comes from the two other contexts of learning: The non-formal and the informal. Nowadays they are integrating the formal context (school), which is not more able to cover for the need of social integration of the new generations and economic competitiveness as a result of the advent of the Knowledge Society, the global context of technology and the internationalisation of commerce. This chapter is based on the research project YOYO - Youth Policy and Participation. Potentials of participation and informal learning in young people's transitions to the labour market. A comparative analysis in ten European regions - funded by the European Commission under the 5° Framework Programme RTD, Human Potential - Key Action "Improving the Socio-economic Knowledge Base" (Duration July 2001 - July 2004). It was carried on by EGRIS: a research network consisting of partners in Denmark, Germany, Great Britain, Ireland, Italy, the Netherlands, Portugal and Spain, whose main activity is to investigate the changing structures and processes of social integration in the context of new trajectories between youth and adulthood as well as the consequences for education and welfare. One of the most important finding of this research regards the role of movement as motivational factor, e.g. motivational change. Young people, who due to their disadvantaged background, have experienced demotivation at school or in the formal training schemes and are therefore at risk of disengaging, can be remotivated by actions that succeed in giving them a feeling of self-efficacy with regard to subjective needs and interests, as happens in the Portuguese case study project Batoto Yeto in which the intrinsic quality of movement (dance) is used to instil in the participants a feeling of self-efficacy also in terms of the more extrinsic aspects of life like training or work. In fact, their passion for dance and music triggers their motivation to study and to overcome their difficulties.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.