Time-dependent Predictive Values of Prognostic Biomarkers with Failure Time Outcome.

In a prospective cohort study, information on clinical parameters, tests and molecular markers is often collected. Such information is useful to predict patient prognosis and to select patients for targeted therapy. We propose a new graphical approach, the positive predictive value (PPV) curve, to quantify the predictive accuracy of prognostic markers measured on a continuous scale with censored failure time outcome. The proposed method highlights the need to consider both predictive values and the marker distribution in the population when evaluating a marker, and it provides a common scale for comparing different markers. We consider both semiparametric and nonparametric based estimating procedures. In addition, we provide asymptotic distribution theory and resampling based procedures for making statistical inference. We illustrate our approach with numerical studies and datasets from the Seattle Heart Failure Study

Optimized pulses for the control of uncertain qubits

Constructing high-fidelity control fields that are robust to control, system, and/or surrounding environment uncertainties is a crucial objective for quantum information processing. Using the two-state Landau-Zener model for illustrative simulations of a controlled qubit, we generate optimal controls for \pi/2- and \pi-pulses, and investigate their inherent robustness to uncertainty in the magnitude of the drift Hamiltonian. Next, we construct a quantum-control protocol to improve system-drift robustness by combining environment-decoupling pulse criteria and optimal control theory for unitary operations. By perturbatively expanding the unitary time-evolution operator for an open quantum system, previous analysis of environment-decoupling control pulses has calculated explicit control-field criteria to suppress environment-induced errors up to (but not including) third order from \pi/2- and \pi-pulses. We systematically integrate this criteria with optimal control theory, incorporating an estimate of the uncertain parameter, to produce improvements in gate fidelity and robustness, demonstrated via a numerical example based on double quantum dot qubits. For the qubit model used in this work, post facto analysis of the resulting controls suggests that realistic control-field fluctuations and noise may contribute just as significantly to gate errors as system and environment fluctuations.Comment: 38 pages, 15 figures, RevTeX 4.1, minor modifications to the previous versio

Use of Risk Models to Predict Death in the Next Year Among Individual Ambulatory Patients With Heart Failure

Importance: The clinical practice guidelines for heart failure recommend the use of validated risk models to estimate prognosis. Understanding how well models identify individuals who will die in the next year informs decision making for advanced treatments and hospice. Objective: To quantify how risk models calculated in routine practice estimate more than 50% 1-year mortality among ambulatory patients with heart failure who die in the subsequent year. Design, Setting, and Participants: Ambulatory adults with heart failure from 3 integrated health systems were enrolled between 2005 and 2008. The probability of death was estimated using the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk calculator. Baseline covariates were collected from electronic health records. Missing covariates were imputed. Estimated mortality was compared with actual mortality at both population and individual levels. Main Outcomes and Measures: One-year mortality. Results: Among 10930 patients with heart failure, the median age was 77 years, and 48.0% of these patients were female. In the year after study enrollment, 1661 patients died (15.9% by life-table analysis). At the population level, 1-year predicted mortality among the cohort was 9.7% for the SHFM (C statistic of 0.66) and 17.5% for the MAGGIC risk calculator (C statistic of 0.69). At the individual level, the SHFM predicted a more than 50% probability of dying in the next year for 8 of the 1661 patients who died (sensitivity for 1-year death was 0.5%) and for 5 patients who lived at least a year (positive predictive value, 61.5%). The MAGGIC risk calculator predicted a more than 50% probability of dying in the next year for 52 of the 1661 patients who died (sensitivity, 3.1%) and for 63 patients who lived at least a year (positive predictive value, 45.2%). Conversely, the SHFM estimated that 8496 patients (77.8%) had a less than 15% probability of dying at 1 year, yet this lower-risk end of the score range captured nearly two-thirds of deaths (n = 997); similarly, the MAGGIC risk calculator estimated a probability of dying of less than 25% for the majority of patients who died at 1 year (n = 914). Conclusions and Relevance: Although heart failure risk models perform reasonably well at the population level, they do not reliably predict which individual patients will die in the next year

Treating symptoms and reversing remodelling: clinical and echocardiographic 1‐year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation

Aims- To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR). Methods and results- This was a pooled analysis of patients (n = 68) who, despite guideline-directed medical therapy had symptomatic heart failure (HF) with mild (n = 25) or moderate (n = 43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6-min walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At 1 year, New York Heart Association class status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units [95% confidence interval (CI) 3 to17; P < 0.01] and mean 6-min walk test distance increased by 34 m (95% CI 12 to 57; P < 0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of −7 mL (95% CI −11 to −3; P < 0.001), vena contracta −0.11 cm (95% CI −0.20 to −0.02; P < 0.05), and effective regurgitant orifice area −0.03 cm2 (95% CI −0.06 to −0.01; P < 0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank P = 0.22). Progression-free survival was 70% (82% in mild vs. 63% in moderate SMR; P = 0.16). Freedom from HF hospitalization was 73% (87% in mild SMR vs. 66% in moderate SMR; P = 0.07). Conclusion- Among patients with symptomatic HF and mild or moderate SMR on guideline-directed medical therapy, percutaneous mitral annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates

Public understandings of addiction: where do neurobiological explanations fit?

Developments in the field of neuroscience, according to its proponents, offer the prospect of an enhanced understanding and treatment of addicted persons. Consequently, its advocates consider that improving public understanding of addiction neuroscience is a desirable aim. Those critical of neuroscientific approaches, however, charge that it is a totalising, reductive perspective–one that ignores other known causes in favour of neurobiological explanations. Sociologist Nikolas Rose has argued that neuroscience, and its associated technologies, are coming to dominate cultural models to the extent that 'we' increasingly understand ourselves as 'neurochemical selves'. Drawing on 55 qualitative interviews conducted with members of the Australian public residing in the Greater Brisbane area, we challenge both the 'expectational discourses' of neuroscientists and the criticisms of its detractors. Members of the public accepted multiple perspectives on the causes of addiction, including some elements of neurobiological explanations. Their discussions of addiction drew upon a broad range of philosophical, sociological, anthropological, psychological and neurobiological vocabularies, suggesting that they synthesised newer technical understandings, such as that offered by neuroscience, with older ones. Holding conceptual models that acknowledge the complexity of addiction aetiology into which new information is incorporated suggests that the impact of neuroscientific discourse in directing the public's beliefs about addiction is likely to be more limited than proponents or opponents of neuroscience expect

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Update on clinical trials of kidney stone repositioning and preclinical results of stone breaking with one system

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary collecting system to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 15 of 16 kidneys (94%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 8 of 8 stones on post mortem dissection. A 1-week survival study with the BWL exposures and 10 specific-pathogen-free pigs, showed all findings were within normal limits on clinical pathology, hematology, and urinalysis. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective