Pace mapping has been used to identify the site of origin of focal ventricular arrhythmias. The spatial resolution of pace mapping has not been adequately quantified using currently available ...three-dimensional mapping systems.
The purpose of this study was to determine the spatial resolution of pace mapping in patients with idiopathic ventricular tachycardia or premature ventricular contractions originating in the right ventricular outflow tract.
In 16 patients with idiopathic ventricular tachycardia/ectopy from the right ventricular outflow tract, comparisons and classifications of pace maps were performed by two observers (good pace map: match >10/12 leads; inadequate pace map: match < or =10/12 leads) and a customized MATLAB 6.0 program (assessing correlation coefficient and normalized root mean square of the difference (nRMSd) between test and template signals). With an electroanatomic mapping system, the correlation coefficient of each pace map was correlated with the distance between the pacing site and the effective ablation site. The endocardial area within the 10-ms activation isochrone was measured.
The ablation procedure was effective in all patients. Sites with good pace maps had a higher correlation coefficient and lower nRMSd than sites with inadequate pace maps (correlation coefficient: 0.96 +/- 0.03 vs 0.76 +/- 0.18, P <.0001; nRMSd: 0.41 +/- 0.16 vs 0.89 +/- 0.39, P <.0001). Using receiver operating characteristic curves, appropriate cutoff values were >0.94 for correlation coefficient (sensitivity 81%, specificity 89%) and < or =0.54 for nRMSd (sensitivity 76%, specificity 80%). Good pace maps were located a mean of 7.3 +/- 5.0 mm from the effective ablation site and had a mean activation time of -24 +/- 7 ms. However, in 3 (18%) of 16 patients, the best pace map was inadequate at the effective ablation site, with an endocardial activation time at these sites of -25 +/- 12 ms. Pace maps with correlation coefficient > or =0.94 were confined to an area of 1.8 +/- 0.6 cm2. The 10-ms isochrone measured 1.2 +/- 0.7 cm2.
The spatial resolution of a good pace map for targeting ventricular tachycardia/ectopy is 1.8 cm2 in the right ventricular outflow tract and therefore is inferior to the spatial resolution of activation mapping as assessed by isochronal activation. In approximately 20% of patients, pace mapping is unreliable in identifying the site of origin, possibly due a deeper site of origin and preferential conduction via fibers connecting the focus to the endocardial surface.
Summary Background Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated ...whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. Methods The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0–2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov , number NCT01650805. Findings Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight 80% of ten patients given ponatinib and five 38% of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five 3% of 154 vs one 1% of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 14% of 154 vs three 2% of 152 with imatinib), thrombocytopenia (19 12% of 154 vs ten 7% of 152 with imatinib), rash (ten 6% of 154 vs two 1% of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 8% of 152 vs five 3% of 154 with ponatinib) and thrombocytopenia (ten 7% of 152 vs 19 12% of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. Interpretation The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. Funding ARIAD Pharmaceuticals.
Lead sulfide (PbS) and cadmium sulfide (CdS) quantum dots (QDs) are prepared over mesoporous TiO2 films by a successive ionic layer adsorption and reaction (SILAR) process. These QDs are exploited as ...a sensitizer in solid‐state solar cells with 2,2′,7,7′‐tetrakis(N,N‐di‐p‐methoxyphenylamine)‐9,9′‐spirobifluorene (spiro‐OMeTAD) as a hole conductor. High‐resolution transmission electron microscopy (TEM) images reveal that PbS QDs of around 3 nm in size are distributed homogeneously over the TiO2 surface and are well separated from each other if prepared under common SILAR deposition conditions. The pore size of the TiO2 films and the deposition medium are found to be very critical in determining the overall performance of the solid‐state QD cells. By incorporating promising inorganic QDs (PbS) and an organic hole conductor spiro‐OMeTAD into the solid‐state cells, it is possible to attain an efficiency of over 1% for PbS‐sensitized solid‐state cells after some optimizations. The optimized deposition cycle of the SILAR process for PbS QDs has also been confirmed by transient spectroscopic studies on the hole generation of spiro‐OMeTAD. In addition, it is established that the PbS QD layer plays a role in mediating the interfacial recombination between the spiro‐OMeTAD+ cation and the TiO2 conduction band electron, and that the lifetime of these species can change by around 2 orders of magnitude by varying the number of SILAR cycles used. When a near infrared (NIR)‐absorbing zinc carboxyphthalocyanine dye (TT1) is added on top of the PbS‐sensitized electrode to obtain a panchromatic response, two signals from each component are observed, which results in an improved efficiency. In particular, when a CdS‐sensitized electrode is first prepared, and then co‐sensitized with a squarine dye (SQ1), the resulting color change is clearly an addition of each component and the overall efficiencies are also added in a more synergistic way than those in PbS/TT1‐modified cells because of favorable charge‐transfer energetics.
High overall conversion efficiencies are obtained from solid‐state solar cells sensitized with PbS and CdS quantum dots (QDs) using spiro‐OMeTAD as a hole‐conductor. Thorough optimization of important parameters leads to 1.46% efficiency at full‐sun intensity. A second organic dye sensitizer can be added over the QDs‐sensitized electrode and these cells have been tested as model systems of organic–inorganic hybrid sensitizer systems.
Abstract
The prevalence of obesity, measured by body mass index, has risen to unacceptable levels in both men and women in the United States and worldwide with resultant hazardous health ...implications. Genetic, environmental, and behavioral factors influence the development of obesity, and both the general public and health professionals stigmatize those who suffer from the disease. Obesity is associated with and contributes to a shortened life span, type 2 diabetes mellitus, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner-the more weight lost, the better the outcome. The phenotype of "medically healthy obesity" appears to be a transient state that progresses over time to an unhealthy phenotype, especially in children and adolescents. Weight loss is best achieved by reducing energy intake and increasing energy expenditure. Programs that are effective for weight loss include peer-reviewed and approved lifestyle modification programs, diets, commercial weight-loss programs, exercise programs, medications, and surgery. Over-the-counter herbal preparations that some patients use to treat obesity have limited, if any, data documenting their efficacy or safety, and there are few regulatory requirements. Weight regain is expected in all patients, especially when treatment is discontinued. When making treatment decisions, clinicians should consider body fat distribution and individual health risks in addition to body mass index.
This Scientific Statement critically reviews the definition of obesity, providing a list of assessment methods, obesity-related diseases, and prevention measures.
Background Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled ...corticosteroids. Objective To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks). Methods Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV1 and methacholine PC20 . After this, an additional 4-month trial evaluated asthma control. Results Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations ( r ≥ ± 0.6) were albuterol reversibility ( r = 0.83; P < .001), FEV1 /forced vital capacity ( r = −0.75; P < .001), and FEV1 % predicted ( r = −0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV1 improvement) and nonresponders (≤5%) determined the longer-term need for steroids. For the nonresponders, asthma control remained unchanged whether inhaled corticosteroids were continued or were substituted with a placebo ( P = .99). The good short-term responders maintained asthma control longer-term only if maintained on inhaled steroids ( P = .007). Conclusion The short-term response to inhaled corticosteroids with regard to FEV1 improvement predicts long-term asthma control. Clinical implications The decision to use long-term inhaled steroids could be based on a short-term trial. Different therapeutic strategies would need to be established for nonresponders.
Objective This report summarizes the 30-day and 12-month results of endovascular treatment using the Medtronic Vascular Talent Thoracic Stent Graft System (Medtronic Vascular, Santa Rosa, Calif) for ...patients with thoracic aortic aneurysms (TAA) who are considered candidates for open surgical repair. Methods The study was a prospective, nonrandomized, multicenter, pivotal trial conducted at 38 sites. Enrollment occurred between December 2003 and June 2005. Standard follow-up interval examinations were prescribed at 1 month, 6 months, 1 year, and annually thereafter. These endovascular results were compared with retrospective open surgical data from three centers of excellence. Results The Evaluation of the Medtronic Vascular Talent Thoracic Stent Graft System for the Treatment of Thoracic Aortic Aneurysms (VALOR) trial enrolled 195 patients, and 189 were identified as retrospective open surgical subjects. Compared with the open surgery group, the VALOR test group had similar age and sex distributions, but had a smaller TAA size. Patients received a mean number of 2.7 ± 1.3 stent graft components. The diameters of 25% of the proximal stent graft components implanted were <26 mm or >40 mm. Left subclavian artery revascularization was performed before the initial stent graft procedure in 5.2% of patients. Iliac conduits were used in 21.1% of patients. In 33.5% of patients, the bare spring segment of the most proximally implanted device was in zones 1 or 2 of the aortic arch. In 194 patients (99.5%), vessel access and stent graft deployment were successful at the intended site. The 30-day VALOR results included perioperative mortality, 2.1%; major adverse advents, 41%; incidence of paraplegia, 1.5%; paraparesis, 7.2%; and stroke, 3.6%. The 12-month VALOR results included all-cause mortality, 16.1%; aneurysm-related mortality, 3.1%; conversion to open surgery, 0.5%; target aneurysm rupture, 0.5%; stent graft migration >10 mm, 3.9%; endoleak (12.2%), stent graft patency, 100%; stable or decreasing aneurysm diameter, 91.5%; and loss of stent graft integrity, four patients. No deployment-related events or perforation of the aorta by a graft component occurred. The Talent Thoracic Stent Graft showed statistically superior performance with respect to acute procedural outcomes ( P < .001), 30-day major adverse events (41% vs 84.4%, P < .001), perioperative mortality (2% vs 8%, P < .01), and 12-month aneurysm-related mortality (3.1% vs 11.6%, P < .002) vs open surgery. Conclusions The pivotal VALOR 12-month trial results demonstrate that the Medtronic Talent Thoracic Stent Graft System is a safe and effective endovascular therapy as an alternative to open surgery in patients with TAA who were considered candidates for open surgical repair.
Summary Background The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to ...assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. Methods This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov , number NCT01302041. Findings 67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2–98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Interpretation Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer. Funding Astellas Pharma Inc, Medivation Inc.
Summary Background Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban ...reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6–12 months. Methods In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT02293395. Findings Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239–354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients 5%; 80 participants 5% of 1519 vs 74 participants 5% of 1518; HR 1·09 95% CI 0·80–1·50; p=0·5840). Interpretation A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. Funding Janssen Research & Development and Bayer AG.
Abstract Background Context Watertight dural repair is crucial for both incidental durotomy and closure after intradural surgery. Purpose To describe a perfusion-based cadaveric simulation model with ...cerebrospinal-fluid (CSF) reconstitution and to compare spine dural repair techniques. Study Design/Setting Fresh Tissue Dissection Laboratory. Sample Size 8 fresh human cadavers. Outcome Measures A watertight closure was achieved when pressurized saline up to 40 mm Hg did not cause further CSF leakage beyond the suture lines. Methods Fresh human cadaveric specimens underwent cannulation of the intradural cervical spine for intrathecal reconstitution of the CSF system. The cervicothoracic dura was then exposed from C7-T12 via laminectomy. The entire dura was then opened in 6 cadavers (ALLSPINE) and closed with 6-0 Prolene (n=3) or 4-0 Nurolon (n=3) and pressurized with saline via a perfusion system to 60 mm Hg to check for leakage. In 2 cadavers (INCISION), 6 separate 2 cm incisions were made and closed with either 6-0 Prolene or 4-0 Nurolon and then pressurized. A hydrogel sealant was then added and the closure was pressurized again to check for further leakage. Results Spinal laminectomy with repair of intentional durotomy was successfully performed in 8 cadavers. The operative microscope was used in all cases, and the model provided a realistic experience of spinal durotomy repair. For ALLSPINE cadavers (mean 240 mm dura/cadaver repaired), mean pressure thresholds for CSF leakage was observed at 66.7 (± 2.9) mm Hg in the 6-0 Prolene group and at 43.3 (± 14.4) mm Hg in the 4-0 Nurolon group (p >0.05). For INCISION cadavers, mean pressure thresholds for CSF leakage without hydrogel sealant were significantly higher in 6-0 Prolene group than the 4-0 Nurolon group (6-0 Prolene: 80.0 ± 4.5 mm Hg vs. 4-0 Nurolon: 32.5 ± 2.7 mm Hg; p < 0.01). Mean pressure thresholds for CSF leakage with the hydrogel sealants were not significantly different (6-0 Prolene: 100.0 ± 0.0 mm Hg vs. 4-0 Nurolon: 70.0 ± 33.1 mm Hg). The use of a hydrogel sealant significantly increased the pressure thresholds for possible CSF leakage in both the 6-0 Prolene group (p = 0.01) and the 4-0 Nurolon group (p < 0.01) when compared to mean pressures without the hydrogel sealant. Conclusions We described the feasibility of utilizing a novel cadaveric model for both the study and training of watertight dural closure techniques. 6-0 Prolene was observed to be superior to 4-0 Nurolon for watertight dural closure without a hydrogel sealant. The use of a hydrogel sealant significantly improved watertight dural closures for both 6-0 Prolene and 4-0 Nurolon groups in the cadaveric model.
Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown ...gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology.
In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots.
The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817–0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of −0·48 cm3 (−0·37 to −0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751–0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1–5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1–5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282–2·387, p=0·0004) and model C-index (0·667, 0·622–0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314–2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626–0·711).
Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration.
Deutsche Forschungsgemeinschaft.
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