Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia.

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes.

A tool to assess nontechnical skills of perfusionists in the cardiac operating room.

OBJECTIVES: This study aimed to develop the Perfusionists' Intraoperative Non-Technical Skills tool, specifically to the perfusionists' context, and test its inter-rater reliability. METHODS: An expert panel was convened to review existing surgical nontechnical skills taxonomies and develop the Perfusionists' Intraoperative Non-Technical Skills tool. During a workshop held at a national meeting, perfusionists completed the Perfusionists' Intraoperative Non-Technical Skills ratings after watching 4 videos displaying simulated cardiac operations. Two videos showed "good performance," and 2 videos showed "poor performance." Inter-rater reliability analysis was performed and intraclass correlation coefficient was reported. RESULTS: The final version of the Perfusionists' Intraoperative Non-Technical Skills taxonomy contains 4 behavioral categories (decision making, situation awareness, task management and leadership, teamwork and communication) with 4 behavioral elements each. Categories and elements are rated using an 8-point Likert scale ranging from 0.5 to 4.0. A total of 60 perfusionist raters were included and the comparison between rating distribution on "poor performance" and "good performance" videos yielded a statistically significant difference between groups, with a P value less than .001. A similar difference was found in all behavioral categories and elements. Reliability analysis showed moderate inter-rater reliability across overall ratings (intraclass correlation coefficient, 0.735; 95% confidence interval, 0.674-0.796; P < .001). Similar inter-rater reliability was found when raters were stratified by experience level. CONCLUSIONS: The Perfusionists' Intraoperative Non-Technical Skills tool presented moderate inter-rater reliability among perfusionists with varied levels of experience. This tool can be used to train and assess perfusionists in relevant nontechnical skills, with the potential to enhance safety and improve surgical outcomes.

Can the Minimum Protamine Dose to Neutralize Heparin at the Completion of Cardiopulmonary Bypass be Significantly Lower than the Conventional Practice?

Systemic anticoagulation with heparin during cardiopulmonary bypass (CPB) should be neutralized by protamine administration to restore normal hemostasis. However, protamine has potentially serious side effects and excessive protamine can cause increased postoperative bleeding. Thus, our goal is to appropriately dose protamine at the completion of CPB to neutralize heparin so that neither residual heparin nor excessive protamine is present. We performed a retrospective study of 216 patients who underwent cardiac surgery to search for a safe minimum protamine dose (PD) when measuring heparin concentration (HC). In addition, we developed a formula to determine PD using total heparin dose (THD) and CPB time without measuring HC. When protamine-to-heparin ratio (P-to-H) is set at 1 mg protamine to 100 international unit (IU) heparin in HMS Plus Hemostasis Management System (HMS), we determined that 75% of the calculated total PD is a safe minimum PD to sufficiently neutralize circulating heparin after CPB. On average, this translates into either .37 mg protamine/100 IU heparin of THD or .54 mg/100 IU of the first heparin bolus. The formula we developed to calculate PD without measuring HC can provide a PD that strongly agrees with the safe minimum PD when measuring HC. The safe minimum PD to neutralize circulating heparin after CPB can be significantly lower than conventional dosing practices. Reduction of PD may decrease the risk of postoperative bleeding and protamine-related adverse events. Based on our data, we decreased P-to-H in HMS to examine whether it is possible to reduce PD further than the safe minimum PD determined in this study.

Biomechanical regulation of breast cancer metastasis and progression.

Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

Factors associated with errors in the heparin dose response test: recommendations to improve individualized heparin management in cardiopulmonary bypass.

BACKGROUND: A critical aspect of cardiopulmonary bypass (CPB) is to achieve full anticoagulation to prevent thrombosis and consumptive coagulation without using excessive amount of heparin. This can be achieved with heparin dose response (HDR) test in vitro to calculate an individualized heparin bolus to reach a target activated clotting time (ACT) and heparin concentration. However, we often observe that the measured ACT (mACT) with the calculated heparin bolus gives significant errors, both positive (mACT is higher than expected) and negative (mACT is lower), from expected ACT (eACT). METHODS: We performed a retrospective study of 250 patients who underwent cardiac surgery to attain an error distribution of the mACT from eACT with calculated heparin bolus. In addition, it is aimed to identify possible patterns of baseline ACT (bACT), calculated heparin concentration (CHC) and HDR slope that are associated with the significant positive and negative errors. RESULTS: We found that individualized heparin bolus by HDR test is consistently underestimated while it gave a significant number of positive and negative errors. Further analysis indicates that significant negative errors correlate with high bACT and slope and low CHC while significant positive errors with low bACT and slope and high CHC. CONCLUSION: The mACT can be substantially different from eACT. The accuracy of the HDR test appears to be dependent upon bACT, slope, and CHC. Based on our analysis, we provide several recommendations and a flow chart to improve the quality of individualized heparin management on CPB.

Development of a Control-Oriented Model of Social Cognitive Theory for Optimized mHealth Behavioral Interventions.

Mobile health (mHealth) technologies are contributing to the increasing relevance of control engineering principles in understanding and improving health behaviors, such as physical activity. Social Cognitive Theory (SCT), one of the most influential theories of health behavior, has been used as the conceptual basis for behavioral interventions for smoking cessation, weight management, and other health-related outcomes. This paper presents a control-oriented dynamical systems model of SCT based on fluid analogies that can be used in system identification and control design problems relevant to the design and analysis of intensively adaptive interventions. Following model development, a series of simulation scenarios illustrating the basic workings of the model are presented. The model's usefulness is demonstrated in the solution of two important practical problems: 1) semiphysical model estimation from data gathered in a physical activity intervention (the MILES study) and 2) as a means for discerning the range of "ambitious but doable" daily step goals in a closed-loop behavioral intervention aimed at sedentary adults. The model is the basis for ongoing experimental validation efforts, and should encourage additional research in applying control engineering technologies to the social and behavioral sciences.

Efficacy and cost-effectiveness of behavioral interventions in nonclinical settings for improving health outcomes.

This paper examines three distinct examples of interventions in nonclinical settings selected to highlight the challenges and opportunities for evaluating cost-effectiveness in the field of health psychology and behavioral medicine. Nonclinical settings are defined as those involving systems outside of traditional medical/clinical settings, and include interventions tested in clinical settings that can also be implemented in nonclinical settings. The examples in this paper reflect the use of a varying degree of existing cost-effectiveness data and previous health economic analyses. First, the Chronic Disease Self-Management Program model reflects an intervention protocol designed to increase patients' confidence and mastery in their ability to manage their conditions that has been shown to be cost effective for a variety of chronic disease conditions. Second, the cost and cost-effectiveness of tobacco quitlines (e.g., National Tobacco Quit Line) has been the subject of several preliminary cost-effectiveness examinations and has proven to have significant reach and impact on tobacco-related behaviors. Finally, environmental interventions for promoting walking and physical activity in community-based contexts (e.g., PATH trial) are presented and have been shown to be highly relevant for demonstrating cost-effectiveness. Overall, the disciplines of health psychology and behavioral medicine are in a unique position to develop, implement, and evaluate a broader range of interventions in more diverse environments than cost-effectiveness applications in more traditional, clinical settings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas.

INTRODUCTION: Postoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction. METHODS: This is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2 or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05. ETHICS AND DISSEMINATION: The Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital. TRIAL REGISTRATION NUMBER: NCT02836899.

Implications of the 21st Century Cures Act for the Behavioral and Social Sciences at the National Institutes of Health.

The 21st Century Cures Act provides funding for key initiatives relevant to the behavioral and social sciences and includes administrative provisions that facilitate health research and increase the privacy protections of research participants. At about the same time as the passage of the Act, the National Institutes of Health Office of Behavioral and Social Sciences Research released its Strategic Plan 2017-2021, which addresses three scientific priorities: (a) improve the synergy of basic and applied behavioral and social sciences research; (b) enhance and promote the research infrastructure, methods, and measures needed to support a more cumulative and integrated approach to behavioral and social sciences; and (c) facilitate the adoption of behavioral and social sciences research findings in health research and in practice. This commentary describes the implications of the Cures Act on these scientific priorities and on the behavioral and social sciences more broadly.

Integrated Approach to Reduce Perinatal Adverse Events: Standardized Processes, Interdisciplinary Teamwork Training, and Performance Feedback.

OBJECTIVE: To improve safety practices and reduce adverse events in perinatal units of acute care hospitals. DATA SOURCES: Primary data collected from perinatal units of 14 hospitals participating in the intervention between 2008 and 2012. Baseline secondary data collected from the same hospitals between 2006 and 2007. STUDY DESIGN: A prospective study involving 342,754 deliveries was conducted using a quality improvement collaborative that supported three primary interventions. Primary measures include adoption of three standardized care processes and four measures of outcomes. DATA COLLECTION METHODS: Chart audits were conducted to measure the implementation of standardized care processes. Outcome measures were collected and validated by the National Perinatal Information Center. PRINCIPAL FINDINGS: The hospital perinatal units increased use of all three care processes, raising consolidated overall use from 38 to 81 percent between 2008 and 2012. The harms measured by the Adverse Outcome Index decreased 14 percent, and a run chart analysis revealed two special causes associated with the interventions. CONCLUSIONS: This study demonstrates the ability of hospital perinatal staff to implement efforts to reduce perinatal harm using a quality improvement collaborative. Findings help inform the relationship between the use of standardized care processes, teamwork training, and improved perinatal outcomes, and suggest that a multiplicity of integrated strategies, rather than a single intervention, may be essential to achieve high reliability.

Development of a dynamic computational model of social cognitive theory.

Social cognitive theory (SCT) is among the most influential theories of behavior change and has been used as the conceptual basis of health behavior interventions for smoking cessation, weight management, and other health behaviors. SCT and other behavior theories were developed primarily to explain differences between individuals, but explanatory theories of within-person behavioral variability are increasingly needed as new technologies allow for intensive longitudinal measures and interventions adapted from these inputs. These within-person explanatory theoretical applications can be modeled as dynamical systems. SCT constructs, such as reciprocal determinism, are inherently dynamical in nature, but SCT has not been modeled as a dynamical system. This paper describes the development of a dynamical system model of SCT using fluid analogies and control systems principles drawn from engineering. Simulations of this model were performed to assess if the model performed as predicted based on theory and empirical studies of SCT. This initial model generates precise and testable quantitative predictions for future intensive longitudinal research. Dynamic modeling approaches provide a rigorous method for advancing health behavior theory development and refinement and for guiding the development of more potent and efficient interventions.

Advancing Cancer Prevention and Behavior Theory in the Era of Big Data.

The era of "Big Data" presents opportunities to substantively address cancer prevention and control issues by improving health behaviors and refining theoretical models designed to understand and intervene in those behaviors. Yet, the terms "model" and "Big Data" have been used rather loosely, and clarification of these terms is required to advance the science in this area. The objectives of this paper are to discuss conceptual definitions of the terms "model" and "Big Data", as well as examine the promises and challenges of Big Data to advance cancer prevention and control research using behavioral theories. Specific recommendations for harnessing Big Data for cancer prevention and control are offered.

Decreasing Malpractice Claims by Reducing Preventable Perinatal Harm.

OBJECTIVE: To evaluate the association of improved patient safety practices with medical malpractice claims and costs in the perinatal units of acute care hospitals. DATA SOURCES: Malpractice and harm data from participating hospitals; litigation records and medical malpractice claims data from American Excess Insurance Exchange, RRG, whose data are managed by Premier Insurance Management Services, Inc. (owned by Premier Inc., a health care improvement company). STUDY DESIGN: A quasi-experimental prospective design to compare baseline and postintervention data. Statistical significance tests for differences were performed using chi-square, Wilcoxon signed-rank test, and t-test. DATA COLLECTION: Claims data were collected and evaluated by experienced senior claims managers through on-site claim audits to evaluate claim frequency, severity, and financial information. Data were provided to the analyzing institution through confidentiality contracts. PRINCIPAL FINDINGS: There is a significant reduction in the number of perinatal malpractice claims paid, losses paid, and indemnity payments (43.9 percent, 77.6 percent, and 84.6 percent, respectively) following interventions to improve perinatal patient safety and reduce perinatal harm. This compares with no significant reductions in the nonperinatal claims in the same hospitals during the same time period. CONCLUSIONS: The number of perinatal malpractice claims and dollar amount of claims payments decreased significantly in the participating hospitals, while there was no significant decrease in nonperinatal malpractice claims activity in the same hospitals.

Clinical validity of PROMIS Depression, Anxiety, and Anger across diverse clinical samples.

OBJECTIVES: The purpose of this study was to evaluate the responsiveness to change of the PROMIS negative affect measures (depression, anxiety, and anger) using longitudinal data collected in six chronic health conditions. STUDY DESIGN AND SETTING: Individuals with major depressive disorder (MDD), back pain, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and cancer completed PROMIS negative affect instruments as computerized adaptive test or as fixed-length short form at baseline and a clinically relevant follow-up interval. Participants also completed global ratings of health. Linear mixed effects models and standardized response means (SRM) were estimated at baseline and follow-up. RESULTS: A total of 903 individuals participated (back pain, n = 218; cancer, n = 304; CHF, n = 60; COPD, n = 125; MDD, n = 196). All three negative affect instruments improved significantly for treatments of depression and pain. Depression improved for CHF patients (anxiety and anger not administered), whereas anxiety improved significantly in COPD groups (stable and exacerbation). Response to treatment was not assessed in cancer. Subgroups of patients reporting better or worse health showed a corresponding positive or negative average SRM for negative affect across samples. CONCLUSION: This study provides evidence that the PROMIS negative affect scores are sensitive to change in intervention studies in which negative affect is expected to change. These results inform the estimation of meaningful change and enable comparative effectiveness research.

Cancer prevention and control interventions using social media: user-generated approaches.

Social media are now used by a majority of American internet users. Social media platforms encourage participants to share information with their online social connections and exchange user-generated content. Significant numbers of people are already using social media to share health-related information. As such, social media provide an opportunity for "user-generated" cancer control and prevention interventions that employ users' behavior, knowledge, and existing social networks for the creation and dissemination of interventions. These interventions also enable novel data collection techniques and research designs that will allow investigators to examine real-time behavioral responses to interventions. Emerging social media-based interventions for modifying cancer-related behaviors have been applied to such domains as tobacco use, diet, physical activity, and sexual practices, and several examples are discussed for illustration purposes. Despite some promising early findings, challenges including inadequate user engagement, privacy concerns, and lack of internet access among some groups need to be addressed in future research. Recommendations for advancing the field include stronger partnerships with commercial technology companies, utilization of rapid and adaptive designs to identify successful strategies for user engagement, rigorous and iterative efficacy testing of these strategies, and inclusive methods for intervention dissemination.

The promise of intensive longitudinal data capture for behavioral health research.

Advances in technology and the associated cultural norms, especially the advent of the smartphone, offer an unprecedented opportunity to collect data on relevant health behaviors and experiences unobtrusively at a greater frequency and in greater volumes than ever before. This special issue will acquaint the readership of Nicotine and Tobacco Research with the potential for intensive longitudinal data and will illustrate some innovative analytic techniques for addressing research questions associated with this type of complex data. This introductory article will provide a brief history of the analytic techniques for intensive longitudinal data and will point to some resources that support and enable the use of these techniques.

Behavioral research in cancer prevention and control: a look to the future.

Human behavior is central to the etiology and management of cancer outcomes and presents several avenues for targeted and sustained intervention. Psychosocial experiences such as stress and health behaviors including tobacco use, sun exposure, poor diet, and a sedentary lifestyle increase the risk of some cancers yet are often quite resistant to change. Cancer screening and other health services are misunderstood and over-utilized, and vaccination underutilized, in part because of the avalanche of information about cancer prevention. Coordination of cancer care is suboptimal, and only a small fraction of cancer patients enroll in clinical trials essential to the development of new cancer treatments. A growing population of cancer survivors has necessitated a fresh view of cancer as a chronic rather than acute disease. Fortunately, behavioral research can address a wide variety of key processes and outcomes across the cancer control continuum from prevention to end-of-life care. Here we consider effects at the biobehavioral and psychological, social and organizational, and environmental levels. We challenge the research community to address key behavioral targets across all levels of influence, while taking into account the many new methodological tools that can facilitate this important work.

Leveraging intensive longitudinal data to better understand health behaviors.

Behavioral scientists have historically relied on static modeling methodologies. The rise in mobile and wearable sensors has made intensive longitudinal data (ILD) -- behavioral data measured frequently over time -- increasingly available. Consequently, analytical frameworks are emerging that seek to reliably quantify dynamics reflected in these data. Employing an input-output perspective, dynamical systems models from engineering can characterize time-varying behaviors as processes of change. Specifically, ILD and parameter estimation routines from system identification can be leveraged together to offer parsimonious and quantitative descriptions of dynamic behavioral constructs. The utility of this approach for facilitating a better understanding of health behaviors is illustrated with two examples. In the first example, dynamical systems models are developed for Social Cognitive Theory (SCT), a prominent concept in behavioral science that considers interrelationships between personal factors, the environment, and behaviors. Estimated models are then obtained that explore the role of SCT in a physical activity intervention. The second example uses ILD to model day-to-day changes in smoking levels as a craving-mediated process of behavior change.