There is a growing demand to collect patients' experiences of their health status (their symptoms, function, and quality of life) in clinical trials, quality assessment initiatives, and in routine ...clinical care. In heart failure, the 23-item, disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) has been shown to be valid, reliable, sensitive to clinical change, and prognostic of both clinical events and costs. However, its use has been limited, in part, by its length. We sought to develop a shortened version of the instrument that maintains the psychometric properties of the full KCCQ.
Using data from 3 clinical studies incorporating 4168 patients, we derived and validated a 12-item KCCQ, the KCCQ-12, to capture symptom frequency, physical and social limitations, and quality of life impairment as a result of heart failure, as well as an overall summary score. The KCCQ-12 scores had high correlations with the original scales (>0.93 for all scales in all clinical settings), high test–retest reliability (>0.76 for all domains), high responsiveness (16–31 point improvements after discharge from hospitalization; standardized response mean =0.61–1.12), and comparable prognostic significance and interpretation of clinically important differences as compared with the full KCCQ.
The KCCQ-12 is a shorter version of the original 23-item instrument that should be more feasible to implement while preserving the psychometric properties of the full instrument.
To improve the patient-centeredness of care, patient-reported outcomes have been increasingly used to quantify patients' symptoms, function, and quality of life. In heart failure, the Kansas City ...Cardiomyopathy Questionnaire (KCCQ) has been qualified by the U.S. Food and Drug Administration as a Clinical Outcome Assessment and recommended as a performance measure for quantifying the quality of care. By systematically asking the same questions reproducibly over time, the KCCQ can validly and sensitively capture the impact of heart failure on patients' lives and is strongly associated with clinical events over time. This review describes how to interpret the KCCQ, how it should be analyzed in clinical trials to maximize the interpretability of results, and how it can be used in clinical practice and population health. By providing a deeper understanding of the KCCQ, it is hoped that its use can further improve the patient-centeredness of heart failure care.
Abstract Background A series of models have been developed to identify patients at high risk for poor outcomes after transcatheter aortic valve replacement (TAVR) to help guide treatment choices, ...offer patients realistic expectations of long-term outcomes, and support decision making. Objectives This study examined the performance of the previously developed TAVR Poor Outcome risk models in an external dataset and explored the incremental contribution of geriatric domains to model performance. Methods Poor outcome after TAVR was defined as death, poor quality of life (QOL), or decline in QOL, as assessed using the Kansas City Cardiomyopathy Questionnaire. We tested 4 TAVR Poor Outcome risk models: 6-month and 1-year full and clinical (reduced) models. We examined each model’s discrimination and calibration in the CoreValve trial dataset, and then tested the incremental contribution of frailty and disability markers to the model’s discrimination using the incremental discrimination index. Results Among 2,830 patients who underwent TAVR in the CoreValve US Pivotal Extreme and High Risk trials and associated continued access registries, 31.2% experienced a poor outcome at 6 months following TAVR (death, 17.6%; very poor QOL, 11.6%; QOL decline, 2.0%) and 50.8% experienced a poor outcome at 1 year (death, 30.2%; poor QOL, 19.6%; QOL, decline 1.0%). The models demonstrated similar discrimination as in the Placement of Aortic Transcatheter Valves Trial cohorts (c-indexes, 0.637 to 0.665) and excellent calibration. Adding frailty as a syndrome increased the c-indexes by 0.000 to 0.004 (incremental discrimination index, p < 0.01 for all except the 1-year clinical model), with the most important individual components being disability and unintentional weight loss. Conclusions Although discrimination of the TAVR Poor Outcome risk models was generally moderate, calibration was excellent among patients with different risk profiles and treated with a different TAVR device. These findings demonstrated the value of these models for individualizing outcome predictions in high-risk patients undergoing TAVR.
Clinical trials and national performance measures increasingly mandate reporting patients' perspectives of their health status: their symptoms, function, and quality of life. Although the Seattle ...Angina Questionnaire (SAQ) is a validated disease-specific health status instrument for coronary artery disease (CAD) with high test-retest reliability, predictive power, and responsiveness, its use in routine clinical practice has been limited, in part, by its length (19 items).
Using data from 10 408 patients with CAD from 5 multicenter registries, we derived and validated a shortened version of the SAQ (SAQ-7) among patients presenting with stable CAD, undergoing percutaneous coronary intervention, and after acute myocardial infarction. We examined the psychometric properties of the SAQ-7 as compared with the full SAQ. Seven items from the Physical Limitation, Angina Frequency, and Quality of Life domains were identified for the SAQ-7, with high levels of concordance (0.88-1.00) with each original SAQ domain. The SAQ-7 demonstrated good construct validity (compared with Canadian Cardiovascular Society class for angina), with a correlation of 0.62 and 0.38 for patients with stable CAD and undergoing percutaneous coronary intervention, respectively. It was highly reproducible in patients with stable CAD (intraclass correlation, ≥0.78) and exhibited excellent responsiveness in patients after percutaneous coronary intervention (≥18 points in each SAQ domain). Finally, the SAQ-7 was predictive of 1-year mortality and readmission.
To increase the feasibility of measuring patient-reported outcomes in patients with CAD, we developed and validated a shortened 7-item SAQ instrument for use in clinical trials and routine care.
The Fermi γ-ray source 1FGL J1417.7-4407 (J1417) is a compact X-ray binary with a neutron star primary and a red giant companion in a ∼5.4 days orbit. This initial conclusion, based on optical and ...X-ray data, was confirmed when a 2.66 ms radio pulsar was found at the same location (and with the same orbital properties) as the optical/X-ray source. However, these initial studies found conflicting evidence about the accretion state and other properties of the binary. We present new optical, radio, and X-ray observations of J1417 that allow us to better understand this unusual system. We show that one of the main pieces of evidence previously put forward for an accretion disk-the complex morphology of the persistent H emission line-can be better explained by the presence of a strong, magnetically driven stellar wind from the secondary and its interaction with the pulsar wind. The radio spectral index derived from VLA/ATCA observations is broadly consistent with that expected from a millisecond pulsar, further disfavoring an accretion disk scenario. X-ray observations show evidence for a double-peaked orbital light curve, similar to that observed in some redback millisecond pulsar binaries and likely due to an intrabinary shock. Refined optical light-curve fitting gives a distance of 3.1 0.6 kpc, confirmed by a Gaia DR2 parallax measurement. At this distance the X-ray luminosity of J1417 is ( ) ×1033 erg s−1, which is more luminous than all known redback systems in the rotational-powered pulsar state, perhaps due to the wind from the giant companion. The unusual phenomenology of this system and its differing evolutionary path from redback millisecond pulsar binaries points to a new eclipsing pulsar "spider" subclass that is a possible progenitor of normal field millisecond pulsar binaries.
The question of whether it is possible to automate the scientific process is of both great theoretical interest and increasing practical importance because, in many scientific areas, data are being ...generated much faster than they can be effectively analysed. We describe a physically implemented robotic system that applies techniques from artificial intelligence to carry out cycles of scientific experimentation. The system automatically originates hypotheses to explain observations, devises experiments to test these hypotheses, physically runs the experiments using a laboratory robot, interprets the results to falsify hypotheses inconsistent with the data, and then repeats the cycle. Here we apply the system to the determination of gene function using deletion mutants of yeast (Saccharomyces cerevisiae) and auxotrophic growth experiments. We built and tested a detailed logical model (involving genes, proteins and metabolites) of the aromatic amino acid synthesis pathway. In biological experiments that automatically reconstruct parts of this model, we show that an intelligent experiment selection strategy is competitive with human performance and significantly outperforms, with a cost decrease of 3-fold and 100-fold (respectively), both cheapest and random-experiment selection.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CONTEXT Clinical practice guidelines recommend maintaining serum potassium levels between 4.0 and 5.0 mEq/L in patients with acute myocardial infarction (AMI). These guidelines are based on small ...studies that associated low potassium levels with ventricular arrhythmias in the pre−β-blocker and prereperfusion era. Current studies examining the relationship between potassium levels and mortality in AMI patients are lacking. OBJECTIVE To determine the relationship between serum potassium levels and in-hospital mortality in AMI patients in the era of β-blocker and reperfusion therapy. DESIGN, SETTING, AND PATIENTS Retrospective cohort study using the Cerner Health Facts database, which included 38 689 patients with biomarker-confirmed AMI, admitted to 67 US hospitals between January 1, 2000, and December 31, 2008. All patients had in-hospital serum potassium measurements and were categorized by mean postadmission serum potassium level (<3.0, 3.0-<3.5, 3.5-<4.0, 4.0-<4.5, 4.5-<5.0, 5.0-<5.5, and ≥5.5 mEq/L). Hierarchical logistic regression was used to determine the association between potassium levels and outcomes after adjusting for patient- and hospital-level factors. MAIN OUTCOME MEASURES All-cause in-hospital mortality and the composite of ventricular fibrillation or cardiac arrest. RESULTS There was a U-shaped relationship between mean postadmission serum potassium level and in-hospital mortality that persisted after multivariable adjustment. Compared with the reference group of 3.5 to less than 4.0 mEq/L (mortality rate, 4.8%; 95% CI, 4.4%-5.2%), mortality was comparable for mean postadmission potassium of 4.0 to less than 4.5 mEq/L (5.0%; 95% CI, 4.7%-5.3%), multivariable-adjusted odds ratio (OR), 1.19 (95% CI, 1.04-1.36). Mortality was twice as great for potassium of 4.5 to less than 5.0 mEq/L (10.0%; 95% CI, 9.1%-10.9%; multivariable-adjusted OR, 1.99; 95% CI, 1.68-2.36), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. In contrast, rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater. CONCLUSION Among inpatients with AMI, the lowest mortality was observed in those with postadmission serum potassium levels between 3.5 and <4.5 mEq/L compared with those who had higher or lower potassium levels.
Chronic stress in patients with cardiovascular disease (CVD), including peripheral artery disease (PAD), is independently associated worse outcomes. A model that can reliably identify factors ...associated with risk of chronic stress in patients with CVD is needed. In a prospective myocardial infarction (MI) registry (TRIUMPH), we constructed a logistic regression model using 27 patient demographic, socioeconomic, and clinical factors, adjusting for site, to identify predictors of chronic stress over 1 year. Stress at baseline and at 1-, 6- and 12-month follow-up was measured using the 4-item Perceived Stress Scale (PSS-4) range 0-16, scores greater than or equal to6 depicting high stress. Chronic stress was defined as at least 2 follow-up PSS-4 scores greater than or equal to6. We identified and validated this final model in another prospective registry of patients with symptomatic PAD, the PORTRAIT study. Our derivation cohort consisted of 4,340 patients with MI (mean age 59.1 ± 12.3 years, 33% females, 30% non-white), of whom 30% had chronic stress at follow-up. Of the 27 factors examined, female sex, current smoking, socioeconomic status, and economic burden due to medical care were positively associated with chronic stress, and ENRICHD Social Support Instrument (ESSI) score and age were inversely related to chronic stress. In the validation cohort of 797 PAD patients (mean age 68.6±9.7 years, 42% females, 28% non-white, 18% chronic stress) the c-statistic for the model was 0.77 and calibration was excellent. We can reliably identify factors that are independently associated with risk of chronic stress in patients with CVD. As chronic stress is associated with worse outcomes in this population, our work identifies potential targets for interventions to as well as the patients that could benefit from these.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the ISCHEMIA trial, patients with stable ischemic heart disease were randomly assigned to invasive or conservative treatment. As reported separately, the invasive strategy did not reduce clinical ...events. Improvements in health status were slightly greater with the invasive strategy, reflecting minimal effects in asymptomatic patients and larger effects in patients with angina symptoms at baseline.
For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D
receptors. Drug development of non-D
compounds, seeking to avoid the limiting side ...effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D
(anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D
-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D
receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT
receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D
signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D
receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D
receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT
receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.
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