Plasticity and learning in a network of coupled phase oscillators

A generalized Kuramoto model of coupled phase oscillators with slowly varying coupling matrix is studied. The dynamics of the coupling coefficients is driven by the phase difference of pairs of oscillators in such a way that the coupling strengthens for synchronized oscillators and weakens for non-synchronized pairs. The system possesses a family of stable solutions corresponding to synchronized clusters of different sizes. A particular cluster can be formed by applying external driving at a given frequency to a group of oscillators. Once established, the synchronized state is robust against noise and small variations in natural frequencies. The phase differences between oscillators within the synchronized cluster can be used for information storage and retrieval.Comment: 10 page

Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease

Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”, Napoli, December 5th-8th 2013

The fourth “Melanoma Bridge Meeting” took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent research in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, like BRAF and MEK inhibitors, as well as other signaling pathways inhibitors, are being tested in metastatic melanoma either as monotherapy or in combination, and have yielded promising results. Improved survival rates have also been observed with immune therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in melanoma as well. This meeting’s specific focus was on advances in targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. Significant consideration was given to issues surrounding the development of novel therapeutic targets as further study of patterns of resistance to both immunologic and targeted drugs are paramount to future drug development to guide existing and future therapies. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD.

RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease. EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOME: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH: We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m2, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m2 decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]). LIMITATIONS: Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting. CONCLUSIONS: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction

Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study

To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.Cross-sectional.Chronic Renal Insufficiency Cohort Study.Eight hundred twenty-five adults aged 55 and older with CKD.Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m 2 ) was estimated using the four-variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score ≤1 standard deviations from the mean).Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains ( P <.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1–3.9), naming (AOR=1.9, 95% CI=1.0–3.3), attention (AOR=2.4, 95% CI=1.3–4.5), executive function (AOR=2.5, 95% CI=1.9–4.4), and delayed memory (AOR=1.5, 95% CI=0.9–2.6) but not on category fluency (AOR=1.1, 95% CI=0.6–2.0) than those with mild to moderate CKD (eGFR 45–59).In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78647/1/j.1532-5415.2009.02670.x.pd

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction:The VICTORIA Biomarker Substudy

Background: Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. Methods and Results: High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. Conclusions: hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.</p