The transition to phase synchronized states of neural networks with bursting dynamics may have nonstationary characteristics, as well as sensitivity to initial conditions. Here, we analyze the ...paradigmatic network composed of neurons of Rulkov to investigate dynamic properties of the transitions to phase synchronization displayed by networks under two different topologies of the connection matrices, namely, small-world and random ones. Our analyses of both connection architectures reveal that neural networks under small-world topology display higher sensibility to initial conditions, and contrarily to the random connection case, depict a nonstationary transition to phase synchronization through the presence of a two-state on–off intermittency. The analyses are based on the recurrence quantifier determinism calculated by using only the local (mean) field potential (LFP) of the network, an experimentally easy accessible data. The use of LFP data offers advantages in the quantification of the nonstationary dynamics at the transition to phase synchronized states, since the more traditional Kuramoto order parameter must be computed over the individual signals of the neurons.
•Small-world and random network topologies are studied.•Nonstationary transition to phase synchronization are observed.•Recurrence quantification analysis are employed to quantify nonstationary behavior.
A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related ...morbidity and tumor response.
One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 250-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median follow-up time was 20.2 months (range: 10-30 months). Toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate specific antigen (PSA) measurements.
Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade 1 or 2 late morbidity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normalization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients).
The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing complications to surrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalization with pretreatment PSA < or = 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging.
Objectives. To assess the effect of proton radiation on clinical and biochemical outcomes for early prostate cancer.
Methods. Three hundred nineteen patients with T1-T2b prostate cancer and initial ...prostate-specific antigen (PSA) levels 15.0 ng/mL or less received conformal radiation doses of 74 to 75 cobalt gray equivalent with protons alone or combined with photons. No patient had pre- or post-treatment hormonal therapy until disease progression was documented. Patients were evaluated for biochemical disease-free survival, PSA nadir, and toxicity; the mean and median follow-up period was 43 months.
Results. Overall 5-year clinical and biochemical disease-free survival rates were 97% and 88%, respectively. Initial PSA level, stage, and post-treatment PSA nadir were independent prognostic variables for biochemical disease-free survival: a PSA nadir 0.5 ng/mL or less was associated with a 5-year biochemical disease-free survival rate of 98%, versus 88% and 42% for nadirs 0.51 to 1.0 and greater than 1.0 ng/mL, respectively. No severe treatment-related morbidity was seen.
Conclusions. It appears that patients treated with conformal protons have 5-year biochemical disease-free survival rates comparable to those who undergo radical prostatectomy, and display no significant toxicity. A Phase III randomized dose-escalation trial is underway to define the optimum radiation dose for early-stage prostate cancer.
The influence of dosing interval on the human antibody response to anthrax vaccine adsorbed (AVA) was evaluated in two retrospective serological studies. In both studies, the interval between the ...first two doses was 2, 3 or 4 weeks. In the first study, banked sera were selected from 89 at-risk individuals at a mean time of 13 days after the second dose of vaccine. In the second study, banked sera were selected from 51 at-risk individuals at a mean time of 48 days following the first dose of AVA. In both studies, the geometric mean anti-protective antigen IgG antibody titer increased significantly as the interval between the two doses increased from 2 to 4 weeks (
p=0.0005–0.029). In the first study, the seroconversion rate also increased as the interval between the first two doses increased (
p=0.0034). A prospective, randomized study has been completed and is being analyzed to confirm these findings.
NeuLAND (New Large-Area Neutron Detector) is the next-generation neutron detector for the R3B (Reactions with Relativistic Radioactive Beams) experiment at FAIR (Facility for Antiproton and Ion ...Research). NeuLAND detects neutrons with energies from 100 to 1000 MeV, featuring a high detection efficiency, a high spatial and time resolution, and a large multi-neutron reconstruction efficiency. This is achieved by a highly granular design of organic scintillators: 3000 individual submodules with a size of 5 × 5 × 250 cm3 are arranged in 30 double planes with 100 submodules each, providing an active area of 250 × 250 cm2 and a total depth of 3 m. The spatial resolution due to the granularity together with a time resolution of σt≤ 150 ps ensures high-resolution capabilities. In conjunction with calorimetric properties, a multi-neutron reconstruction efficiency of 50% to 70% for four-neutron events will be achieved, depending on both the emission scenario and the boundary conditions allowed for the reconstruction method. We present in this paper the final design of the detector as well as results from test measurements and simulations on which this design is based.
Abstract Objectives The aim of this study was to investigate the individual and combined accuracy of dynamic computed tomography (CT) myocardial perfusion imaging (MPI) and computed tomography ...angiography (CTA) fractional flow reserve (FFR) for the identification of functionally relevant coronary artery disease (CAD). Background Coronary CTA has become an established diagnostic test for ruling out CAD, but it does not allow interpretation of the hemodynamic severity of stenotic lesions. Two recently introduced functional CT techniques are dynamic MPI and CTA FFR using computational fluid dynamics. Methods From 2 institutions, 74 patients (n = 62 men, mean age 61 years) planned for invasive angiography with invasive FFR measurement in 142 vessels underwent CTA imaging and dynamic CT MPI during adenosine vasodilation. A patient-specific myocardial blood flow index was calculated, normalized to remote myocardial global left ventricular blood flow. CTA FFR was computed using an on-site, clinician-operated application. Using binary regression, a single functional CT variable was created combining both CT MPI and CTA FFR. Finally, stepwise diagnostic work-up of CTA FFR with selective use of CT MPI was simulated. The diagnostic performance of CT MPI, CTA FFR, and CT MPI integrated with CTA FFR was evaluated using C statistics with invasive FFR, with a threshold of 0.80 as a reference. Results Sensitivity, specificity, and accuracy were 73% (95% confidence interval CI: 61% to 86%), 68% (95% CI: 56% to 80%), and 70% (95% CI: 62% to 79%) for CT MPI and 82% (95% CI: 72% to 92%), 60% (95% CI: 48% to 72%), and 70% (63% to 80%) for CTA FFR. For CT MPI integrated with CTA FFR, diagnostic accuracy was 79% (95% CI: 71% to 87%), with improvement of the area under the curve from 0.78 to 0.85 (p < 0.05). Accuracy of the stepwise approach was 77%. Conclusions CT MPI and CTA FFR both identify functionally significant CAD, with comparable accuracy. Diagnostic performance can be improved by combining the techniques. A stepwise approach, reserving CT MPI for intermediate CTA FFR results, also improves diagnostic performance while omitting nearly one-half of the population from CT MPI examinations.
Background. Binet A CLL, which includes most newly diagnosed cases, has considerable heterogeneous disease courses. Some patients can live for decades without requiring therapy, while others require ...therapy within months from diagnosis. Given the improved tolerability and efficacy of newer agents and combinations, it is important to identify patients with CLL who, despite initially presenting with early stage CLL, are at increased risk for accelerated progression to symptomatic disease. Such patients are candidates for early therapeutic intervention trials testing whether biomarker-triggered treatment rather than symptom-triggered treatment may improve overall outcome in CLL, as already documented in the myeloma setting. On these bases, a specific and robust time to progression predictive model is needed.
Aim. Develop of a model for prognostication of time-to-first treatment (TTFT) in Binet A CLL.
Methods. We performed an analysis using individual patient data from clinically and biologically annotated Binet A CLL cohorts initially managed with watch and wait, including institutional series, clinical trial series, and population series, accounting for a total of 2816 patients with a median follow-up ranging from 5 to 12 years. The adjusted association between exposure variables and TTFT was estimated by Cox regression. Backward elimination using likelihood ratio statistics with selection criterion p <.05 was used to derive the final model. We assigned a weighted risk score to each factor of the final model based on the regression parameters from the Cox regression analysis. The prognostic score was then defined as the sum of single-risk parameters. We identified different risk groups based on recursive partitioning. Discrimination capacity of the model was assessed through c-index.
Results. The training cohort included a single-institution series of 353 consecutive Binet A CLL from the University of Eastern Piedmont. Nineteen baseline markers were considered as covariates, including clinical (age, sex, palpable lymph nodes, palpable spleen), laboratory (haemoglobin, platelet and lymphocyte count, beta-2-microglobulin), cytogenetic del(17p), del(11q), trisomy 12, del(13q), and molecular (IGHV, ATM, MYD88, NOTCH1, SF3B1, TP53 mutations) variables. By multivariable analysis, only five variables were independently associated with TTFT and were used to build the prognostic score, namely: lymphocyte count >15 G/L (HR=2.5), palpable lymph nodes (HR=2.4), palpable spleen (HR=2.4), unmutated IGHV gene (HR=2.8) and trisomy 12 (HR=2.4). Using weighted grading, a score of 1 was assigned to each variable. A prognostic index was derived, separating three different groups: low- (score 0), intermediate- (score 1), and high-risk (score 2-5) with significantly different probability of need of therapy (4.5%, 11.9%, 52.8% at 4 years for the low- to high-risk group, respectively, c-index: 0.77; Fig. 1). The model was consistently confirmed in 6 validation series (Table 1), including: i) 1225 Binet A patients from the MDACC institutional cohort; ii) 332 patients from the Barcelona institutional cohort; iii) 283 patients from the O-CLL1 trial (NCT00917540); iv) 241 patients from the Brno institutional cohort; v) 205 patients from the Sapienza University institutional cohort; and vi) 177 patients from the SCAN population-based cohort.
Conclusion. The resulting model combines routine clinical and molecular variables in an easily applicable prognostic score for estimating risk for progression to active CLL requiring treatment among early stage CLL. This model was validated by international data sets of Binet A patients and can help design of clinical trials testing whether therapy initiation at an earlier stage than at manifestation of organ complications is beneficial for high-risk patients.
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Doubek:Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Consultancy. Mauro:janssen: Other: board member; abbvie: Other: board member. Zucca:Celltrion: Consultancy; AstraZeneca: Consultancy. Foà:CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding.
Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who ...were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.
We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.
Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment.
The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.
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