Reporting standard for describing first responder systems, smartphone alerting systems, and AED networks.

Standardized reporting of data is crucial for out-of-hospital cardiac arrest (OHCA) research. While the implementation of first responder systems dispatching volunteers to OHCA is encouraged, there is currently no uniform reporting standard for describing these systems. A steering committee established a literature search to identify experts in smartphone alerting systems. These international experts were invited to a conference held in Hinterzarten, Germany, with 40 researchers from 13 countries in attendance. Prior to the conference, participants submitted proposals for parameters to be included in the reporting standard. The conference comprised five workshops covering different aspects of smartphone alerting systems. Proposed parameters were discussed, clarified, and consensus was achieved using the Nominal Group Technique. Participants voted in a modified Delphi approach on including each category as a core or supplementary element in the reporting standard. Results were presented, and a writing group developed definitions for all categories and items, which were sent to participants for revision and final voting using LimeSurvey web-based software. The resulting reporting standard consists of 68 core items and 21 supplementary items grouped into five topics (first responder system, first responder network, technology/algorithm/strategies, reporting data, and automated external defibrillators (AED)). This proposed reporting standard generated by an expert opinion group fills the gap in describing first responder systems. Its adoption in future research will facilitate comparison of systems and research outcomes, enhancing the transfer of scientific findings to clinical practice.

Intracranial dural based marginal zone MALT-type B-cell lymphoma: a case - Based update and literature review.

OBJECTIVES: Dural based Marginal Zone MALT-type B-Cell Lymphoma (MZBCL) is an intracranial tumor that can mimicking meningioma both from a clinical and a radiological point of view. A standard treatment protocol is still lacking. Aim of the present work is to provide an update of the present literature regarding this rare neoplasia. PATIENTS AND METHODS: We report the case of a patient with a dural-based lesion mimicking a meningioma of the tentorium. After surgical treatment, the diagnosis was of MZBCL. A literature review is performed to highlight the typical characteristics of this rare intracranial lesion and to define the best therapeutic approach. RESULTS: Literature review included 38 articles describing 126 cases of intracranial dural-based MZBCL. No clinical trial has been found. Clinical and histopathological features are properly collected to provide a guide for future cases. Different treatment options have been attempted. Combination of surgery with adjuvant radiation therapy is the most used option. CONCLUSIONS: MZBCL should be considered in differential diagnosis for dural-based intracranial lesion. Surgery followed by radiation therapy is the most reported treatment. As a consequence of the rarity of this disease, of its indolent progression and of the lack of adequate follow-up, it is not possible to define it is the best treatment option.

Trans-sulcal versus trans-parenchymal approach in supratentorial cavernomas. A multicentric experience.

OBJECTIVES: Cavernous malformations (CM) are low-flow vascular lesions that can cause significant symptoms and neurological deficits. Different intraoperative surgical approaches have been developed. Aim of the present investigation is the comparison between the trans-sulcal approach (TS) and the trans-parenchymal neuronavigation-assisted approach (TPN) in a surgical series from two neurosurgical centers. The technique and clinical outcomes are discussed, with a specific focus on seizure outcome. PATIENTS AND METHODS: Clinical and radiological data from two neurosurgical centers ("A. Gemelli" Hospital in Rome and A.O.U. Città della Salute e della Scienza in Turin) were retrospectively reviewed in order to evaluate the different outcome of TS and TPN approach for cavernous malformation treatment. RESULTS: A total of 177 patients underwent surgical intervention for supratentorial CM, 130 patients with TPN approach and 47 with TS approach. TS approach was associated with higher rate of seizure in early post-operative period both in epileptic patients (p < 0,001) and in patients without history of seizures before surgery (p = 0,002). Moreover, length of incision (p < 0,001), area of craniotomy (p < 0,001) and corticectomy (p < 0,001) were bigger in TS than in TPN approach. Brain contusion (p < 0,001) and fluid collection (p < 0,001) were more likely to be discovered after TS approach. CONCLUSIONS: TPN is a valuable approach for resection of CM. Minor complications are significantly lower in TPN approach when compared with TS approach. In addition, it is associated with lower rate of early post-operative seizure and shorter length of stay.

Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy.

BACKGROUND: Left bundle branch block (LBBB) morphology is associated with improved outcome of cardiac resynchronisation therapy (CRT) and is an important criterion for patient selection. There are, however, multiple definitions for LBBB. Moreover, applying these definitions seems subjective. We investigated the inter- and intraobserver agreement in the determination of LBBB using available definitions, and clinicians' judgement of LBBB. METHODS: Observers were provided with 12­lead ECGs of 100 randomly selected CRT patients. Four observers judged the ECGs based on different LBBB-definitions (ESC, AHA/ACC/HRS, MADIT, and Strauss). Additionally, four implanting cardiologists scored the same 100 ECGs based on their clinical judgement. Observer agreement was summarized through the proportion of agreement (P) and kappa coefficient (k). RESULTS: Relative intra-observer agreement using different LBBB definitions, and within clinical judgement was moderate (range k 0.47-0.74 and k = 0.76 (0.14), respectively). The inter-observer agreement between observers using LBBB definitions as well as between clinical observers was minimal to weak (range k 0.19-0.44 and k = 0.35 (0.20), respectively). The probability of classifying an ECG as LBBB by available definitions varied considerably (range 0.20-0.76). The agreement between different definitions of LBBB ranged from good (P = 0.95 (0.07)) to weak (P = 0.40 (0.22)). Furthermore, correlation between the different LBBB definitions and clinical judgement was poor (range phi 0.30-0.55). CONCLUSION: Significant variation in the probability of classifying LBBB is present in using different definitions and clinical judgement. Considerable intra- and inter-observer variability adds to this variation. Interdefinition agreement varies significantly and correlation of clinical judgement with LBBB classification by definitions is modest at best.

A statistical shape model of the left ventricle from real-time 3D echocardiography and its application to myocardial segmentation of cardiac magnetic resonance images.

OBJECT: We present in this paper the application of a statistical shape model of the left ventricle (LV) built from transthoracic real time 3D echocardiography (3DE) to segment the LV endocardium and epicardium in cardiac magnetic resonance (CMR) images. MATERIAL AND METHODS: The LV model was built from a training database constituted by over 9000 surfaces obtained from retrospectively selected 3DE examination of 435 patients with various pathologies. Three-dimensional segmentation of the endocardium and the epicardium was obtained by processing CMR images acquired in 30 patients with a dedicated active shape modelling (ASM) algorithm using the proposed LV model. RESULTS: The segmentation results obtained with the proposed method were compared with those obtained by the manual reference technique; similarity was proven by computing: i) point to surface distance (<2 mm), ii) Dice similarity coefficient (>89%), iii) Hausdorff distance (∼5 mm). This was furthermore confirmed by equivalence testing, linear regression and Bland Altman analysis applied on derived clinical parameters, such as LV volumes and mass. CONCLUSIONS: This study showed the potential usefulness of the proposed inter-modal ASM approach featuring a 3DE-based LV model for the 3D segmentation of the LV myocardium in CMR images.

Fast uncertainty quantification of activation sequences in patient-specific cardiac electrophysiology meeting clinical time constraints.

We present a fast, patient-specific methodology for uncertainty quantification in electrophysiology, aimed at meeting the time constraints of clinical practitioners. We focus on computing the statistics of the activation map, given the uncertainties associated with the conductivity tensor modeling the fiber orientation in the heart. We use a fast parallel solution method implemented on a graphics processing unit for the eikonal approximation, in order to compute the activation map and to sample the random fiber field with correlation on the basis of geodesic distances. While this enables to perform uncertainty quantification studies with a manageable computational effort, the required time frame still exceeds clinically suitable time expectations. In order to reduce it further by 2 orders of magnitude, we rely on Bayesian multifidelity methods. In particular, we propose a low-fidelity model that is patient-specific and free from the additional training cost associated with reduced models. This is achieved by a sound physics-based simplification of the full eikonal model. The low-fidelity output is then corrected by the standard multifidelity framework. In practice, the complete procedure only requires approximately 100 new runs of our eikonal graphics processing unit solver for producing the sought estimates and their associated credible intervals, enabling a full online analysis in less than 5 minutes.

Sensitivity analysis of ventricular activation and electrocardiogram in tailored models of heart-failure patients.

Cardiac resynchronization therapy is not effective in a variable proportion of heart failure patients. An accurate knowledge of each patient's electroanatomical features could be helpful to determine the most appropriate treatment. The goal of this study was to analyze and quantify the sensitivity of left ventricular (LV) activation and the electrocardiogram (ECG) to changes in 39 parameters used to tune realistic anatomical-electrophysiological models of the heart. Electrical activity in the ventricles was simulated using a reaction-diffusion equation. To simulate cellular electrophysiology, the Ten Tusscher-Panfilov 2006 model was used. Intracardiac electrograms and 12-lead ECGs were computed by solving the bidomain equation. Parameters showing the highest sensitivity values were similar in the six patients studied. QRS complex and LV activation times were modulated by the sodium current, the cell surface-to-volume ratio in the LV, and tissue conductivities. The T-wave was modulated by the calcium and rectifier-potassium currents, and the cell surface-to-volume ratio in both ventricles. We conclude that homogeneous changes in ionic currents entail similar effects in all ECG leads, whereas the effects of changes in tissue properties show larger inter-lead variability. The effects of parameter variations are highly consistent between patients and most of the model tuning could be performed with only ~10 parameters.

Retinal transduction profiles by high-capacity viral vectors.

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, the limited cargo capacity of AAV prevents their use for therapy of those inherited retinopathies (IRs) due to mutations in large (>5 kb) genes. Viral vectors derived from adenovirus (Ad), lentivirus (LV) and herpes virus (HV) can package large DNA sequences, but do not target efficiently retinal photoreceptors (PRs) where the majority of genes responsible for IRs are expressed. Here, we have evaluated the mouse retinal transduction profiles of vectors derived from 16 different Ad serotypes, 7 LV pseudotypes and from a bovine HV. Most of the vectors tested transduced efficiently the retinal pigment epithelium. We found that LV-GP64 tends to transduce more PRs than the canonical LV-VSVG, albeit this was restricted to a narrow region. We observed more extensive PR transduction with HdAd1, 2 and 5/F35++ than with LV, although none of them outperformed the canonical HdAd5 or matched the extension of PR transduction achieved with AAV2/8.

Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors.

Gene therapy with adeno-associated viral (AAV) vectors is limited by AAV cargo capacity that prevents their application to the inherited retinal diseases (IRDs), such as Stargardt disease (STGD) or Usher syndrome type IB (USH1B), which are due to mutations in genes larger than 5 kb. Trans-splicing or hybrid dual AAV vectors have been successfully exploited to reconstitute large gene expression in the mouse retina. Here, we tested them in the large cone-enriched pig retina that closely mimics the human retina. We found that dual AAV trans-splicing and hybrid vectors transduce pig photoreceptors, the major cell targets for treatment of IRDs, to levels that were about two- to threefold lower than those obtained with a single AAV vector of normal size. This efficiency is significantly higher than that in mice, and is potentially due to the high levels of dual AAV co-transduction we observe in pigs. We also show that subretinal delivery in pigs of dual AAV trans-splicing and hybrid vectors successfully reconstitute, albeit at variable levels, the expression of the large genes ABCA4 and MYO7A mutated in STGD and USH1B, respectively. Our data support the potential of dual AAV vectors for large gene reconstitution in the cone-enriched pig retina that is a relevant preclinical model.

Novel adeno-associated viral vectors for retinal gene therapy.

Vectors derived from adeno-associated virus (AAV) are currently the most promising vehicles for therapeutic gene delivery to the retina. Recently, subretinal administration of AAV2 has been demonstrated to be safe and effective in patients with a rare form of inherited childhood blindness, suggesting that AAV-mediated retinal gene therapy may be successfully extended to other blinding conditions. This is further supported by the great versatility of AAV as a vector platform as there are a large number of AAV variants and many of these have unique transduction characteristics useful for targeting different cell types in the retina including glia, epithelium and many types of neurons. Naturally occurring, rationally designed or in vitro evolved AAV vectors are currently being utilized to transduce several different cell types in the retina and to treat a variety of animal models of retinal disease. The continuous and creative development of AAV vectors provides opportunities to overcome existing challenges in retinal gene therapy such as efficient transfer of genes exceeding AAV's cargo capacity, or the targeting of specific cells within the retina or transduction of photoreceptors following routinely used intravitreal injections. Such developments should ultimately advance the treatment of a wide range of blinding retinal conditions.

AAV-mediated photoreceptor transduction of the pig cone-enriched retina.

Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases.

Electronic cardiac medicine: present and future opportunities.

The second half of the 20th century witnessed a revolution in electronic medicine similar to that in pharmacology in the decades before. The advent of the implantable pacemaker, implantable cardioverter-defibrillators, cardiac resynchronisation therapies, insertable loop recorders and more, have improved diagnoses and reduced mortality and morbidity in millions of patients suffering from cardiac disease. The possibility to monitor patients continually without need for frequent office visits has the potential to reduce follow-up burden on physicians, facilitate increased use of home-based care and further improve the safety for patients. This review summarises the role of cardiac device therapies today and some of the developments which we can hope for in the nearest future.

Estimates of lifetime attributable risk of cancer after a single radiation exposure from 64-slice computed tomographic coronary angiography.

AIMS: To estimate the life attributable risk (LAR) of cancer incidence over a wide range of dose radiation exposure and a large spectrum of possible diagnostic computed tomographic coronary angiography (CTCA) scenarios. METHODS: This study included 561 consecutive patients who underwent a successful prospective ECG-gating CTCA protocol (low-dose group) 64-slice CTCA and 188 patients who underwent retrospective ECG-gating CTCA with ECG-triggered dose modulation CTCA (high-dose group). LAR was computed, given the organ equivalent dose, for all cancers in both sexes. LAR was tabulated for each decile of dose-length product by 10-year age classes, separately for each sex. RESULTS: Estimates of LAR of any cancer for an exposure at age < or =40 year were lower in males than in females for any given quantile. At age >/ or =50 years, LAR was similar between sexes only at the lowest exposure doses, whereas at higher dosage, it was, in general, higher for women. At the median age of this case series (62 years) and for a radiation exposure ranging from 1.33 to 3.81 mSv, LAR was 1 in 4329 (or 23.1 per 10(5) persons exposed) and 1 in 4629 (or 21.6 per 10(5) persons) in men and women, respectively. For an exposure ranging from 10.34 to 18.97 mSv at the same median age, the LAR of cancer incidence was 1 in 1336 (or 74.8 per 10(5) persons) in men and doubled (1 in 614 or 162.8 per 10(5) persons) in women. CONCLUSIONS: This study provided an estimate of the LAR of cancer in middle-aged patients of both sexes after a single diagnostic CTCA, providing an easy-to-read table.

Development and validation of a clinical index to predict survival after cardiac resynchronisation therapy.

OBJECTIVE: To develop and validate a prognostic risk index of cardiovascular mortality after cardiac resynchronisation therapy (CRT). DESIGN: Prospective cohort study. SETTING: District general hospital. PATIENTS: 148 patients with heart failure (mean age 66.7 (SD 10.4) years), New York Heart Association class III or IV, LVEF <35%) who underwent CRT. INTERVENTIONS: CRT device implantation. MAIN OUTCOME MEASURES: Value of a composite index in predicting cardiovascular mortality, validated internally by bootstrapping. The predictive value of the index was compared to factors that are known to predict mortality in patients with heart failure. RESULTS: All patients underwent assessment of 16 prognostic risk factors, including cardiovascular magnetic resonance (CMR) measures of myocardial scarring (gadolinium-hyperenhancement) and dyssynchrony, before implantation. Clinical events were assessed after a median follow-up of 913 (interquartile range 967) days. At follow-up, 37/148 (25%) of patients died from cardiovascular causes. In Cox proportional hazards analyses, (DSC) Dyssynchrony, posterolateral Scar location (both p<0.0001) and Creatinine (p = 0.0046) emerged as independent predictors of cardiovascular mortality. The DSC index, derived from these variables combined, emerged as a powerful predictor of cardiovascular mortality. Compared to patients with a DSC <3, cardiovascular mortality in patients in the intermediate DSC index (3-5; HR: 11.1 (95% confidence interval (CI) 3.00 to 41.1), p = 0.0003) and high DSC index (> or =5; HR: 30.5 (95% CI 9.15 to 101.8), p<0.0001) were higher. Bootstrap validation confirmed excellent calibration and internal validity of the prediction model. CONCLUSION: The DSC index, derived from a standard CMR scan and plasma creatinine before implantation, is a powerful predictor of cardiovascular mortality after CRT.

Isolation and evaluation of novel adeno-associated virus sequences from porcine tissues.

High antigenic compatibility and low toxicity is associated with xenograft transplantation of porcine tissues in immunodeficient human recipients. We hypothesized that adeno-associated viruses (AAVs) of porcine origin could be highly compatible to human tissues and thus of good efficiency and low toxicity for in vivo gene transfer. Porcine tissues were screened by PCR for the presence of AAV using primers designed to bind conserved regions and amplify variable regions of an alignment of several AAV sequences available on GenBank. We isolated new AAV capsid sequences from porcine tissues and successfully generated a recombinant AAV2/po1 vector by transfection. The AAV2/po1 vector was not cross-neutralized by antisera generated against all other commonly used AAVs (serotype 1, 2, 3, 4, 5, 7 and 8) indicating a distinct antigenic profile. Preexisting immunity to AAVpo1 could not be detected in the human sera evaluated. In mice, AAV2/po1 particles expressing beta-galactosidase or green fluorescent protein demonstrated high transduction efficiency in muscle fibers and the retina after intramuscular or intraocular administration. Biodistribution experiments following systemic administration showed efficient gene transfer exclusively in muscle fibers. Novel AAVs derived from porcine tissues may contribute to the generation of new preventive or curative clinical modalities acceptable for human use.

Relation between coronary atherosclerotic plaques and traditional risk factors in people with no history of cardiovascular disease undergoing multi-detector computed coronary angiography.

AIMS: To prospectively investigate the prevalence of coronary artery plaques (CAP) as detected by computed tomography-based angiography in a large number of consecutive individuals with no history of coronary artery disease (CAD) or acute coronary syndrome; to evaluate whether traditional risk factors are related to prevalence of CAP and to the expected 10-year risk of first major or fatal cardiovascular event (CVE). DESIGN: Prospective, single-centre, cross-sectional study. SETTING: The division of Cardiology at Fondazione Cardiocentro Ticino Lugano, Switzerland. METHODS: We prospectively included 920 consecutive individuals with no history of CAD who underwent computed tomography coronary angiography (CTCA). Risk estimation of fatal and non-fatal CVE was assessed using Global Assessment Risk (GAR) and Systematic Coronary Risk Evaluation (SCORE), respectively. Logistic regression was used to assess the association of risk factors with the prevalence of CAP. RESULTS: CAP was found in 459 (49.9%) individuals. Older age, higher body mass index, male gender, diabetes, hypertension and dyslipidaemia all increased the likelihood of the CAP burden at univariable analysis (p<0.001). At the multivariable analysis older age, male gender, hypertension and diabetes independently increased the likelihood of CAP burden (p<0.001). An increase in likelihood of CAP was observed in the presence of one, two and three or more risk factors and with an increasing value of GAR and SCORE. Notably, about 18% of subjects with CAP did not report any traditional risk factors and among individuals without CAPs, 12% had three or more risk factors. CONCLUSIONS: A direct relation between the prevalence of CAP, number of risk factors and the related 10-year risk of CVE was found. 18% of subjects without risk factors had CAP. In these individuals CTCA may help in further optimising the risk reduction strategies on an individual basis.