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Improving physical activity (PA) levels in autistic adults is an important population health goal. Limiting efforts to achieve this goal is an incomplete understanding of the barriers to PA in this high-risk group. This study utilized cross-sectional data collected via an electronic survey from 253 autistic adults aged 18–50 years to examine their perceived barriers to PA, how PA barriers differed by demographic factors, and the relationship between PA barriers and meeting PA guidelines. The Barriers to Physical Activity scale assessed the independent variable. Lack of motivation to exercise, perceiving exercise as boring, and lack of transportation were the most strongly endorsed barriers to PA. Participants who reported these barriers were significantly less likely (≤ 50%) to meet PA guidelines.

When deciding how long to keep waiting for delayed rewards that will arrive at an uncertain time, different distributions of reward times dictate different optimal strategies for maximizing reward. For example, when reward timing distributions are heavy-tailed (e.g., waiting on hold with customer service) there is a point in time at which waiting is no longer advantageous because the opportunity cost of waiting is too high. Alternatively, when reward timing distributions have a more predictable time scale (uniform or Gaussian), it can be advantageous to wait as long as necessary for the reward to arrive. Although people learn to approximate optimal strategies, little is known about how this learning occurs. One possibility is that people form a general cognitive representation of the probability distribution that governs reward timing and then infer a strategy from that model of the environment. Another possibility is that they learn an action policy more directly, without explicitly representing the reward timing distribution. Here, in a series of studies in which participants decided how long to persist for delayed rewards before quitting, we provided participants with general information about the reward timing distribution in several ways. Whether the information was provided through counterfactual feedback (Study 1), previous exposure (Study 2), or description (Study 3), it did not obviate the need for direct, feedback-driven learning in the decision context. These results suggest that learning when to quit waiting for delayed rewards might depend on task-specific experience, not solely on general probabilistic reasoning.

Although pharmacological interventions are efficacious for reducing tic severity, they yield suboptimal symptom relief for most patients and are often associated with side effects that limit long-term tolerability. Behavioral and cognitive–behavioral therapies have demonstrated efficacy for reducing tic severity and tic-related impairment in patients with Tourette disorder. This has led numerous professional organizations to recommend behavioral therapies such as habit reversal training and the Comprehensive Behavioral Intervention for Tics as first-line treatments for Tourette disorder. This chapter provides an overview of different behavioral and cognitive–behavioral therapies for Tourette disorder and reviews the extant evidence for each therapeutic approach. The chapter highlights challenges confronting behavioral and cognitive–behavioral therapies, discusses treatment mechanisms, and identifies steps to overcome these treatment challenges.

Horizontal axis wind turbines are now prevalent across the world for wind energy harvesting. Electric power is produced by the electric generator of a wind turbine that catches wind power through its wind rotor that is mainly driven by the lift force on its rotor blade. Airfoil characteristics such as airfoil shape, cord length, camber and airfoil twist are utilized to generate lift force that is perpendicular to the rotor axis. Although horizontal axis wind turbines have been widely used on wind farms, there is still room to further improve their efficiency and power generation. In this research, the power conversion efficiency or coefficient of a wind rotor is improved from airfoil twist. The airfoil twist angles of a rotor blade are selected based on maximizing the ratio between lift and drag forces. Three blade twist configurations are introduced for three different tip speed ratios. Four blades that have the three optimal and one reference twist configurations and their corresponding rotors are modeled and simulated. The simulation results show that the power conversion coefficients of the rotors with the optimal twist configurations have significant improvements on power conversion efficiency over that of the reference rotor.

Near misses recorded and reported by workers can provide awareness to the potential causes of injury and prompt safety management initiatives. Although most companies require near-miss reporting, it is unclear what the value of these reports are, if any, and how they influence subsequent actions or controls to reduce on-the-job risks. Researchers at the National Institute for Occupational Safety and Health (NIOSH) conducted a case study with an aggregates company in which near-miss reports were analyzed at each of their locations over an entire quarter during the summer of 2018. Within that quarter, workers recorded 249 near misses. Of those, 167 were valid near misses that occurred at work. Researchers coded the reports using a qualitative 5 × 5 risk matrix. Of the 167 near misses, 19% were deemed low risk, 25% moderate risk, 30% high risk, and 26% critical risk. Several patterns in the near-miss incidents were documented, including classification of incidents and common corrective actions referenced (i.e., elimination/substitution, engineering control or redesign, work process/procedures, and personal protective equipment). The analysis provides insight into ways that risk communication and management programs can be improved to reengage workers and their situational awareness on the job.

Introduction: Ductal carcinoma in situ (DCIS) is a pre-malignant lesion but 14-53% will not progress to an invasive cancer. Large, well characterized DCIS datasets with long term follow up are sparse, and there is uncertainty regarding the long term effects of various treatment modalities on subsequent breast events (SBE). Here, we analyze trends identified in the SBE rates from patients treated at two large academic breast care centers in California, UCSF and UCSD. Methods: Institutional Cancer Registries were used to collect demographic, clinical, imaging and pathologic data. Patients aged 18 years and older without any prior history of breast disease whose first diagnosed breast neoplasm was DCIS and who had at least 6 months of follow up were included. Only SBE beyond 6 months after initial diagnosis were included. All mastectomy types and associated adjuvant treatment were grouped. All patients not undergoing surgery were grouped. Differences between patients in the various treatment groups were assessed using χ2, Student’s t-test, and one-way ANOVA. Poisson regression was used to compare differences in SBE rates between treatment groups. For analysis, follow up times were divided into three 5 years periods (0-5, 6-10, 11-15 years) after initial DCIS diagnosis. Results: 2730 patients - 1575 (57.7%) at UCSF and 1155 (42.3%) at UCSD - were diagnosed between 1985 and 2017 and included in the study. 1910 (70.0%) underwent breast conserving surgery (BCS), 672 (24.6 %) had mastectomy, 144 (5.3%) did not have surgery, and 4 (0.1%) had missing surgery status. 623 (22.8%) received adjuvant endocrine therapy (ET), 2081 (76.2%) did not and 26 (1.0%) had missing adjuvant endocrine therapy status. 1092 (40.0%) received adjuvant radiation therapy (RT), 1619 (59.3%) did not and 19 (0.7%) had unknown radiation therapy status. Median follow up time for all patients was 7.9 years. 305 patients were diagnosed with SBE. Of these, 144 (47.2%) were in situ and 147 (48.2%) were invasive including 16 (5.2%) metastatic lesions, and 14 (4.6%) had missing invasiveness. Of the 289 patients who did not have a metastatic second lesion, 176 (60.9%) SBE were ipsilateral, 88 (30.4%) were contralateral, and 25 (8.7%) had missing SBE laterality. The overall incidence (i) for any SBE over the entire study period was 1.4%/yr. Compared to women who were treated with BCS alone (N=642, i=2.14%/yr, 95% CI 1.76-2.51), SBE rates were lower in women undergoing BCS with RT (N=719, i=1.13%/yr, 95% CI 0.87-1.40, p Conclusion: This large two-center registry study reveals that the rate of invasive and in situ SBE after an initial DCIS diagnosis are comparable. The effect of each treatment modality on SBE incidence rates are consistent with other published studies, with the notable exception of BCS and ET which requires deeper investigation. As expected, local treatment affects mostly ipsilateral events within the first 5 years after initial diagnosis, without impacting the rate of contralateral SBE. Complementary molecular and cellular profiling of selected specimens are underway to help build a more precise BSE risk model and prevent overtreatment. Citation Format: Thomas O'Keefe, Christina Yau, Eliza Jeong, Emma Iaconetti, Paul Kim, Ann Griffin, Joseph McGuire, Rita Mukhtar, Laura Esserman, Olivier Harismendy, Gillian L. Hirst. Risk of subsequent events after initial diagnosis of ductal carcinoma in situ - A large multi-center registry study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-05.

Improving physical activity (PA) levels in autistic adults is an important population health goal. Limiting efforts to achieve this goal is an incomplete understanding of the barriers to PA in this high-risk group. This study utilized cross-sectional data collected via an electronic survey from 253 autistic adults aged 18-50 years to examine their perceived barriers to PA, how PA barriers differed by demographic factors, and the relationship between PA barriers and meeting PA guidelines. The Barriers to Physical Activity scale assessed the independent variable. Lack of motivation to exercise, perceiving exercise as boring, and lack of transportation were the most strongly endorsed barriers to PA. Participants who reported these barriers were significantly less likely (≤ 50%) to meet PA guidelines.

Different contexts favor different patterns of adaptive learning. A surprising event that in one context would accelerate belief updating might, in another context, be downweighted as a meaningless outlier. Here, across two experiments, we examined whether participants performing a perceptual judgment task under spatial uncertainty (n=29, n=63) would spontaneously adapt their patterns of predictive gaze according to the informativeness or uninformativeness of surprising events in their current environment. Uninstructed predictive eye movements exhibited a form of metalearning in which surprise came to modulate event-by-event learning rates in opposite directions across contexts. Participants later appropriately readjusted their patterns of adaptive learning when the statistics of the environment underwent an unsignaled reversal. Although significant metalearning occurred in both directions, performance was consistently superior in contexts in which surprising events reflected meaningful change, potentially reflecting a bias toward interpreting surprise as informative. Overall, our results demonstrate remarkable flexibility in contextually adaptive metalearning.

BACKGROUND Virtual reality (VR) has shown promise in reducing children’s pain and anxiety during venipuncture, but studies on VR lack objective observations of pediatric coping. Notably, the process of capturing objective behavioral coping data can be labor- and personnel-intensive. OBJECTIVE The primary aims of this pilot trial were to assess the feasibility of conducting a trial of VR in a pediatric emergency department and the feasibility of documenting observed coping behaviors during pediatric procedures. Secondarily, this study examined whether VR affects child and caregiver coping and distress during venipuncture in the pediatric emergency department. METHODS This stratified, randomized, controlled pilot trial compared coping and distress between child life–supported VR engagement and child life specialist support without VR during painful procedures in children aged 7-22 years in the pediatric emergency department. An external control (reference group) received no standardized support. Primary feasibility outcomes included rates of recruitment, rates of withdrawal from VR, and rates of completed Child Adult Medical Procedure Interaction Scale-Short Form (CAMPIS-SF) observations. Secondary clinical outcomes were applied to venipuncture procedures and included CAMPIS-SF coping and distress (range 0-1.0), pain and anxiety on a visual analog scale (range 0-10), and cybersickness symptoms. RESULTS Overall recruitment was 93% (66/71), VR withdrawal rate was 27% (4/15), and of the completed procedures, 100% (63/63) CAMPIS-SF observations were completed. A total of 55 patients undergoing venipuncture in the pediatric emergency department were included in the analyses of clinical outcomes: 15 patients (15 caregivers) randomized to VR, 20 patients (15 caregivers) randomized to child life specialist support, and 20 patients (17 caregivers) in the reference group. Patient coping differed across groups with higher coping in the VR group and child life specialist group than in the reference group (P=.046). There were no significant differences in the distress and pain ratings for patients and caregivers between the groups. Caregivers rated the lowest perceived anxiety in the child life specialist group (P=.03). There was no apparent change in cybersickness symptoms before and after VR use (P=.37). CONCLUSIONS Real-time documentation of observed behaviors in patients and caregivers was feasible during medical procedures in which VR was utilized, particularly with the availability of research staff. VR and child life specialists improved coping in children during venipuncture procedures. Given the high participation rate, future studies to evaluate the efficacy of VR are recommended to determine whether an off-the-shelf VR headset can be a low-cost and low-risk tool to improve children’s coping during venipuncture or other related procedures. CLINICALTRIAL ClinicalTrials.gov NCT03686176; https://clinicaltrials.gov/ct2/show/NCT03686176

Background Autistic adults have low levels of physical activity [PA], high levels of sedentary behavior [SB], and insufficient sleep. Not known is the extent to which engagement in these movement behaviors vary by sex, age, and level of independence in activities of daily living (ADLs). Objective To characterize movement behaviors in a national sample of autistic adults by sex, age, and level of independence in ADLs. Methods A national sample of autistic adults and caregivers of autistic adults self-reported PA, SB and sleep behaviors as well as demographic variables using an electronic survey. Levels of engagement in movement behaviors were described, and compared by sex, age (young-adult versus middle-age), and level of independence in ADLs. Results Data were collected on 361 autistic adults (60.3% male, n = 217, mage = 30.82 years, SD = 10.24). Overall, 44% did not meet the PA guideline; PA guideline adherence was lowest among males and those who were dependent on others in ADLs. Overall, the SB guideline was not met by 43% of the sample at weekdays and 48% at weekends. SB guideline adherence was lowest among adults who were middle-aged, and those who were fully independent in ADLs. Overall, 35.2% did not meet the total sleep time (TST) guideline. Middle-aged autistic adults had the lowest adherence to the TST guideline. Conclusions These finding should prompt researchers to consider these demographic differences, and tailor research and programmatic efforts to account for the unique movement behavior profiles of different segments of this heterogenous population.

Background: A lack of diversity among clinical trial (CT) participants remains a critical problem. Few studies have examined recruitment variability in cancer treatment CTs by cancer type. Given the increasing organ-specific specialization of oncologic care, an understanding of this variability may affect institutional recruitment practices. Methods: This study examines three data sources from 2010 through 2014. The analyzed sample includes 3,580 CT participants identified in the institutional Clinical Trials Management System (CTMS) database and 20,305 incident cases of invasive cancer within a Comprehensive Cancer Center (CCC) institutional catchment area. A total of 341,114 incident cases of primary invasive cancer were identified through the California Cancer Registry (CCR). The primary study measurements were sociodemographic characteristics of the three populations (age, sex, race/ethnicity, and health insurance). Results: Racial/ethnic disparities were observed, with more incident cases of Whites seen in cancer center (68%) and enrolled in CTs (72%) compared to incident cases in catchment area (67%) (p

Successful decision making depends on the ability to form predictions about uncertain future events. Existing evidence suggests predictive representations are not limited to point estimates, but also include information about the associated level of predictive uncertainty. Dynamic, context-specific estimates of predictive uncertainty have an important role in governing the rate at which beliefs are updated in response to new observations. It is not yet known, however, whether the same form of uncertainty-modulated learning occurs naturally and spontaneously when there is no task requirement to express predictions explicitly. Here we used a gaze-based predictive inference paradigm to show that (1) predictive inference manifested in spontaneous gaze dynamics; (2) feedback-driven updating of spontaneous gaze-based predictions reflected adaptation to environmental statistics; and (3) anticipatory gaze variability tracked predictive uncertainty in an event-by-event manner. Our results demonstrate that oculomotor behavior can provide a multidimensional readout of internal predictive beliefs.

It is widely accepted that people can predict the relative imminence of future events. However, it is unknown whether the timing of future events is represented using only a "strength-like" estimate or if future events are represented conjunctively with their position on a mental timeline. We examined how people judge temporal relationships among anticipated future events using the novel Judgment of Anticipated Co-Occurence (JACO) task. Participants were initially trained on a stream of letters sampled from a probabilistically repeating sequence. During test trials, the stream was interrupted with pairs of probe letters and the participants' task was to choose the probe letter they expected to appear in the stream during a lagged target window 4-6 items (4.3-8.5 seconds) in the future. Participants performed above chance as they gained experience with the task. Because the correct item was sometimes the more imminent probe letter and other times the less imminent probe letter, these results rule out the possibility that participants relied solely on thresholding a strength-like estimate of temporal imminence. Rather, these results suggest that participants held 1) temporally organized predictions of the future letters in the stream, 2) a temporal estimate of the lagged target window, and 3) some means to compare the two and evaluate their temporal alignment. Response time increased with the lag to the more imminent probe letter, suggesting that participants accessed the future sequentially in a manner that mirrors scanning processes previously proposed to operate on memory representations in the short-term judgment of recency task.

Advancing contact angles formed by water and aqueous ethanol solutions were measured on both bare surfaces and film-covered surfaces of acrylic, glass, hydrophilic and hydrophobic silicon, polycarbonate, polyester, and #304 stainless steel. Each bare surface was initially characterized with respect to its hydrophilic/hydrophobic balance. Both homogeneous protein films and heterogenous milk films were prepared on each surface; the adsorbed mass comprising each film was measured with ellipsometry. Contact angle methods proved useful in detecting the presence of a protein film on sufficiently hydrophilic or hydrophobic surfaces, i.e., materials for which Wapwater (the polar component of the energy required to separate water from its surface) is greater than 55 mJ/m2 or less than 37 mJ/m2. Contact angle methods were found to be useful for detecting the presence of a milk film on solid surfaces as well. However, the detection limits were dependent not only on Wapwater but also on the ethanol concentration of the diagnostic liquid used.

Background Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. Methods Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. Results This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). Conclusions In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.

The effect of drop volume on the equilibrium contact angle, used in evaluation of food contact surface properties, was measured for liquids exhibiting both polar and nonpolar character on six different materials. Drop volumes used ranged from 2 to 40 μl. Contact angles were observed to increase with increasing drop volume in a range below some limiting value, identified as the critical drop volume (CDV). The CDV varied among materials and is explained with reference to surface energetic heterogeneities exhibited by each type of solid surface.

1092 Background: Response Evaluation Criteria in Solid Tumors (RECIST) criteria are often used to measure tumor response in cancer trials, especially in the stage IV setting. However, RECIST requires measurable disease, which is less common in invasive lobular breast carcinoma (ILC) of the breast, a diffusely growing tumor type, compared to invasive ductal carcinoma (IDC). We examined the prevalence of RECIST in breast cancer clinical trials, and whether there are differential trial enrollment rates by histology and stage. Methods: We analyzed the clinicaltrials.gov database to evaluate the proportion of interventional, stage IV clinical trials that require measurable disease as inclusion criteria or outcome measures. We then performed an institutional cohort study comparing the proportion of patients in the University of California, San Francisco (UCSF) OnCore clinical trials management system (CTMS) to the UCSF Cancer Registry between 2000-2018, stratified by histology and stage. We hypothesized that the proportion of patients with ILC in the CTMS would be significantly lower than in the cancer registry. Results: There were 146 actively-recruiting, interventional clinical trials for stage IV breast cancer that were identified in our search on clinicaltrials.gov. Overall, 108 (74%) required measurable disease for study participation. The UCSF Cancer Registry included 8,679 patients, while the UCSF OnCore CTMS included 1,511 patients (Table). In those with early stage disease, where RECIST is not typically used, there was no difference in the proportion of ILC patients enrolled in clinical trials versus in the cancer registry. However, among those with stage IV disease, there was a significantly lower proportion of patients with ILC in the CTMS than in the cancer registry (9.2% versus 17.9%, p = 0.005). In contrast, patients with stage IV IDC were overrepresented in the clinical trials database compared to the cancer registry. Conclusions: Patients with metastatic ILC were significantly less likely to be enrolled in clinical trials than those with metastatic IDC. This decreased enrollment may be due to the widespread use of RECIST, and further investigation is needed to ensure equity in access to clinical trials.[Table: see text]

Although exposure-based cognitive behavior therapy (CBT) and pharmacotherapy have demonstrated efficacy for obsessive-compulsive disorder (OCD), the lack of clinicians effectively trained in these treatments significantly limit effective intervention options for affected youth. This is very unfortunate since child onset is reported by 50% of adults with OCD. To ameliorate this serious global issue the 14 nation International Obsessive-Compulsive Disorders Accreditation Task Force (ATF) of The Canadian Institute for Obsessive Compulsive Disorders (CIOCD) has developed knowledge and competency standards recommended for specialized treatments for OCD through the lifespan. Currently available guidelines are considered by experts to be essential but insufficient because there are not enough clinicians with requisite knowledge and competencies to effectively treat OCD. This manuscript presents knowledge and competency standards recommended for specialized cognitive behavior therapy (CBT) for pediatric OCD, derived from comprehensive literature review and expert synthesis. In addition to standards covering the elements of individual CBT-based assessment and treatment, family and school interventions are addressed given the critical role these domains play in the psychosocial development of youths. The ATF standards presented in these phase two papers will be foundational to the upcoming development of certification (individuals) and accreditation (sites) for specialized treatments in OCD through the lifespan.

The incidence and patient survival rates of melanoma have increased over the last several decades, with a growing population of patients who develop multiple primary melanomas (MPMs). To determine risk factors for developing MPMs and compare the survival of patients with MPMs to those with single primary melanomas, a prospective, multidisciplinary database of patients with melanoma at a single tertiary care institution was retrospectively reviewed. From 1985 to 2013, 6,963 patients with single primary melanomas and 305 patients with MPMs were identified. Mean follow-up was 8.3 ± 6.3 years for patients with single primary melanomas and 8.8 ± 5.9 years for patients with MPMs. Risk of developing multiple melanomas increased with age at diagnosis of first melanoma (hazard ratio [HR] = 1.20 for a 10-year increase in age, 95% confidence interval [CI] = 1.11–1.29, P < 0.001), male sex (HR = 1.44, 95% CI = 1.12–1.84, P = 0.005), and white race (HR = 3.07, 95% CI = 1.45–6.51). Patients with invasive MPMs had increased risk of melanoma-specific death both before (HR = 1.47, 95% CI = 1.0–2.2) and after adjusting for age, sex, site, race, family history of melanoma, personal history of other cancer, and Surveillance, Epidemiology, and End Results Program (SEER) stage (HR = 1.44, 95% CI = 0.95–2.2); however, this result did not reach statistical significance.

Palliative care is recommended along with oncologic care for patients with advanced cancer. However, there are limited data about how the timing of palliative care affects quality and costs.Comparison of health care utilization and care quality for patients with cancer who died having received early versus late palliative care.Analysis of cancer registry, administrative, and billing databases.Patients with cancer who died having received specialty palliative care consultation.Comparing early (more than 90 days prior to death) versus late (less than 90 days prior to death) palliative care, outcome measures included rates of health care utilization and health care costs.Among 922 decedents, 297 (32.2%) had palliative care referrals, with 93 (10.1%) receiving early referrals and 204 (22.1%) late referrals. Compared to patients receiving late palliative care, early palliative care patients had lower rates of inpatient (33% versus 66%, p 0.01), ICU (5% versus 20%, p 0.01), and ED utilization (34% versus 54%, p = 0.04) in the last month of life. Direct costs of inpatient care in the last 6 months of life for patients with early palliative care were lower compared to late palliative care ($19,067 versus $25,754, p 0.01), while direct outpatient costs were similar ($13,040 versus $11,549, p = 0.85). Early palliative care was predominantly delivered in the outpatient setting (84%) while late palliative care was mostly delivered in the hospital (82%).Early palliative care is associated with less intensive medical care, improved quality outcomes, and cost savings at the end of life for patients with cancer. Despite recommendations that early palliative care be offered to all patients with metastatic cancer, palliative care services remain underutilized.

Earlier work provided direction for development of responsive drug delivery systems based on modulation of the structure, amphiphilicity, and surface density of bioactive peptides entrapped within pendant polyethylene oxide (PEO) brush layers. In this work, we describe the sequential and competitive adsorption behavior of such peptides at pendant PEO layers. Three cationic peptides were used for this purpose: the arginine-rich, amphiphilic peptide WLBU2, a peptide chemically identical to WLBU2 but of scrambled sequence (S-WLBU2), and the non-amphiphilic peptide poly- l -arginine (PLR). Optical waveguide lightmode spectroscopy (OWLS) was used to quantify the rate and extent of peptide adsorption and elution at surfaces coated with PEO. UV spectroscopy and time-of-flight secondary ion mass spectrometry (TOF-SIMS) were used to quantify the extent of peptide exchange during the course of sequential and competitive adsorption. Circular dichroism (CD) was used to evaluate conformational changes after adsorption of peptide mixtures at PEO-coated silica nanoparticles. Results indicated that amphiphilic peptides are able to displace adsorbed, non-amphiphilic peptides in PEO layers, while non-amphiphilic peptides were not able to displace more amphiphilic peptides. In addition, peptides of greater amphiphilicity dominated the adsorption at the PEO layer from mixtures with less amphiphilic or non-amphiphilic peptides.

Obstruction of fluid flow by stationary bubbles in a microchannel hemodialyzer decreases filtration performance and increases damage to blood cells through flow maldistribution. A polyethylene oxide (PEO)-polybutadiene (PB)-polyethylene oxide surface modification, previously shown to reduce protein fouling and water/air contact angle in polycarbonate microchannel hemodialyzers, can improve microchannel wettability and may reduce bubble stagnation by lessening the resistive forces that compete with fluid flow. In this study, the effect of the PEO-PB-PEO coating on bubble retention in a microchannel array was investigated. Polycarbonate microchannel surfaces were coated with PEO-PB-PEO triblock polymer via radiolytic grafting. Channel obstruction was measured for coated and uncoated microchannels after injecting a short stream of air bubbles into the device under average nominal water velocities of 0.9 to 7.2 cm/s in the channels. The presence of the PEO coating reduced obstruction of microchannels by stationary bubbles within the range of 1.8 to 3.6 cm/s, average nominal velocity. Numerical simulations based on the lattice Boltzmann method indicate that beneficial effects may be due to the maintenance of a lubricating, thin liquid film around the bubble. The determined effective range of the PEO coating for bubble management serves as an important design constraint. These findings serve to validate the multiutility of the PEO-PB-PEO coating (bubble lubrication, biocompatibility, and therapeutic loading). © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 941-948, 2016.

Detection of enhanced surface tension depression by surfactant in the presence of protein was recently suggested as a basis for determining whether protein stabilization by that surfactant is owing to surfactant forming a steric barrier at interfaces or surfactant association with the protein. In particular, protein interaction with surfactant aggregates may lead to an increased concentration of monomers thus enhancing surfactant adsorption, or to formation of surfactant-protein complexes having little or no effect on adsorption. We compared the initial rates of surface tension depression by poloxamer 188 and polysorbate 80 (PS 80) in the presence and absence of a human recombinant factor VIII (rFVIII). Indirect evidence had suggested poloxamer 188 enters into stable associations with rFVIII in solution but does not form a steric barrier at the interface, while PS 80 behaves in contrary fashion. In this study, we show the presence of rFVIII caused an increase in the rate (reduction in the activation energy) of PS 80 adsorption, while no such change was recorded in the case of poloxamer 188. Thus, we provide substantiation for detection of protein-mediated acceleration of surfactant adsorption as a means to compare different surfactants in relation to their favored mechanism for protein stabilization.

In earlier work, we have provided direction for development of responsive drug delivery systems based on modulation of structure and amphiphilicity of bioactive peptides entrapped within pendant polyethylene oxide (PEO) brush layers. Amphiphilicity promotes retention of the peptides within the hydrophobic inner region of the PEO brush layer. In this work, we describe the effects of peptide surface density on the conformational changes caused by peptide-peptide interactions, and show that this phenomenon substantially affects the rate and extent of peptide elution from PEO brush layers. Three cationic peptides were used in this study: the arginine-rich amphiphilic peptide WLBU2, the chemically identical but scrambled peptide S-WLBU2, and the non-amphiphilic homopolymer poly-l-arginine (PLR). Circular dichroism (CD) was used to evaluate surface density effects on the structure of these peptides at uncoated (hydrophobic) and PEO-coated silica nanoparticles. UV spectroscopy and a quartz crystal microbalance with dissipation monitoring (QCM-D) were used to quantify changes in the extent of peptide elution caused by those conformational changes. For amphiphilic peptides at sufficiently high surface density, peptide-peptide interactions result in conformational changes which compromise their resistance to elution. In contrast, elution of a non-amphiphilic peptide is substantially independent of its surface density, presumably due to the absence of peptide-peptide interactions. The results presented here provide a strategy to control the rate and extent of release of bioactive peptides from PEO layers, based on modulation of their amphiphilicity and surface density.

Surfactants stabilize proteins through two major mechanisms: (1) their preferential location at nearby interfaces, in this way precluding protein adsorption; and/or (2) their association with protein into "complexes" that prevent proteins from interacting with surfaces as well as each other. However, selection of surfactants for protein stabilization currently is not typically made with benefit of any quantitative, predictive information to ensure that either mechanism will be enforced. We compared surface tension depression by poloxamer 188, polysorbate (PS) 80, and PS 20 in the presence and absence of lysozyme or a recombinant protein. The kinetic results were interpreted with reference to a mechanism for surfactant adsorption governed by the formation of a rate-limiting structural intermediate (i.e., an "activated complex") composed of surfactant and protein. The presence of protein was seen to increase the rate of surfactant adsorption in relation to surfactant acting alone for the PSs, with very little change in kinetics owing to protein in the case of poloxamer 188. A simple thermodynamic analysis indicated the presence of protein caused a reduction in ΔG for the surfactant adsorption process, deriving entirely from a reduction in ΔH. Thus, protein likely accelerates the adsorption of these surfactants by disrupting their self-associations, increasing the concentration of surfactant monomers near the interface.

A number of sufficiently small peptides have been shown to integrate into polyethylene oxide (PEO) brush layers in accordance with their amphiphilicity and ordered structure. Those results have suggested that responsive drug delivery systems based on peptide-loaded PEO layers can be controlled by modulation of solution conditions and peptide amphiphilicity. However, the presence of entrapped peptide may compromise the protein repulsive character of the PEO layer, and in this way reduce the viability of a medical device coating based on such an approach. Nisin is a cationic, amphiphilic, and antimicrobial peptide that has been shown to integrate into PEO brush layers. In this work, the preferential location of fibrinogen at PEO-coated, nisin-loaded layers was investigated in nisin-fibrinogen sequential adsorption experiments using detection of fluorescein isothiocyanate labeled fibrinogen, detection of changes in zeta potential, and measurement of adsorption and elution kinetics by optical waveguide lightmode spectroscopy. Results from each technique indicate that the presence of entrapped nisin does not affect fibrinogen interaction with the PEO layer. In addition, entrapment of blood solutes within PEO layers contacted with 25% equine plasma in phosphate-buffered saline was reduced by the prior entrapment of nisin within the layer.

The marked increase in surface-to-volume ratio associated with microscale devices for hemodialysis leads to problems with hemocompatibility and blood flow distribution that are more challenging to manage than those encountered at the conventional scale. In this work stable surface modifications with pendant polyethylene oxide (PEO) chains were produced on polydimethylsiloxane (PDMS), polycarbonate microchannel, and polyacrylonitrile membrane materials used in construction of microchannel hemodialyzer test articles. PEO layers were prepared by radiolytic grafting of PEO-polybutadiene-PEO (PEO-PB-PEO) triblock polymers to the material surfaces. Protein repulsion was evaluated by measurement of surface-bound enzyme activity following contact of uncoated and PEO-coated surfaces with β-galactosidase. Protein adsorption was decreased on PEO-coated polycarbonate and PDMS materials to about 20% of the level recorded on the uncoated materials. Neither the triblocks nor the irradiation process was observed to have any effect on protein interaction with the polyacrylonitrile membrane, or its permeability to urea. This approach holds promise as a means for in situ application of safe, efficacious coatings to microfluidic devices for blood processing that will ensure good hemocompatibility and blood flow distribution, with no adverse effects on mass transfer. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 1014–1020, 2014.

Optical waveguide lightmode spectroscopy (OWLS), based on the incoupling of laser light into a waveguide sensor by an optical grating, allows for the in situ measurement of protein adsorption. Few reports have described cleaning methods for the surfaces of such sensors, and in this investigation, we compare common methods for cleaning of silica surfaces in relation to their effectiveness for cleaning silica-coated waveguide sensors used in OWLS. For this purpose, atomic force microscopy (AFM) analysis of surface morphology and OWLS detection of protein adsorption kinetics were used to evaluate waveguide sensors before and after cleaning. While AFM line scans showed a substantial increase in average waveguide peak-to-valley height after RCA cleaning relative to all other methods tested, chemical etching owing to the alkaline component of the rolling circle amplification method rendered the waveguide unusable for detection of protein adsorption with OWLS. A revised method, based on replacement of the alkaline step with immersion in sodium dodecyl sulfate, was not only effective at cleaning OWLS waveguides off-the-shelf but also showed excellent protein adsorption reproducibility after ex situ cleaning. Moreover, the revised method showed excellent reproducibility when applied in situ, between repeated adsorption-elution cycles. Copyright © 2013 John Wiley & Sons, Ltd.

A more quantitative understanding of peptide loading and release from polyethylene oxide (PEO) brush layers will provide direction for development of new strategies for drug storage and delivery. In this work we recorded selected effects of peptide structure and amphiphilicity on adsorption into PEO brush layers based on covalently stabilized Pluronic(®)F 108. Optical waveguide lightmode spectroscopy and circular dichroism measurements were used to characterize the adsorption of poly-l-glutamic acid, poly-l-lysine, and the cationic amphiphilic peptide WLBU2, to the brush layers. The structure of WLBU2 as well as that of the similarly-sized homopolymers was controlled between disordered and more ordered (helical) forms by varying solution conditions. Adsorption kinetic patterns were interpreted with reference to a simple model for protein adsorption, in order to evaluate rate constants for peptide adsorption and desorption from loosely and tightly bound states. While more ordered peptide structure apparently promoted faster adsorption and elution rates, resistance to elution while in the PEO layer was dependent on peptide amphiphilicity. The results presented here are compelling evidence of the potential to create anti-fouling surface coatings capable of storing and delivering therapeutics.

Stable, pendant polyethylene oxide (PEO) layers were formed on medical-grade Pellethane® and Tygon® polyurethane surfaces, by adsorption and gamma-irradiation of PEO-polybutadiene-PEO triblock surfactants. Coated and uncoated polyurethanes were challenged individually or sequentially with nisin (a small polypeptide with antimicrobial activity) and/or fibrinogen, and then analyzed with time-of-flight secondary ion mass spectrometry (TOF-SIMS). Data reduction by robust principal components analysis (PCA) allowed detection of outliers, and distinguished adsorbed nisin and fibrinogen. Fibrinogen-contacted surfaces, with or without nisin, were very similar on uncoated polymer surfaces, consistent with nearly complete displacement or coverage of previously-adsorbed nisin by fibrinogen. In contrast, nisin-loaded PEO layers remained essentially unchanged upon challenge with fibrinogen, suggesting that the adsorbed nisin is stabilized within the pendant PEO layer, while the peptide-loaded PEO layer retains its ability to repel large proteins. Coatings of PEO loaded with therapeutic polypeptides on medical polymers have the potential to be used to produce anti-fouling and biofunctional surfaces for implantable or blood-contacting devices.

The adsorption and elution of the antimicrobial peptide nisin at silanized silica surfaces coated to present pendant polyethylene oxide chains was detected in situ by zeta potential measurements. Silica microspheres were treated with trichlorovinylsilane to introduce hydrophobic vinyl groups, followed by self assembly of the polyethylene oxide–polypropylene oxide–polyethylene oxide (PEO–PPO–PEO) triblock surfactant Pluronic® F108, or an F108 derivative with nitrilotriacetic acid end groups. Triblock-coated microspheres were γ-irradiated to covalently stabilize the PPO-surface association. PEO layer stability was evaluated by triblock resistance to elution by SDS, and layer uniformity was evaluated by fibrinogen repulsion. Introduction of nisin to uncoated or triblock-coated microspheres produced a significant positive change in surface charge (zeta potential) as a result of adsorption of the cationic peptide. In sequential adsorption experiments, the introduction of fibrinogen to nisin-loaded triblock layers caused a decrease in zeta potential that was consistent with partial elution of nisin and/or preferential location of fibrinogen at the interface. This change was substantially more pronounced for uncoated than triblock-coated silica, indicating that the PEO layer offers enhanced resistance to nisin elution.

Thiol (–SH) groups were introduced into unfractionated heparin by reaction of carboxyl groups in its uronic acid residues with 3,3′dithiobis(propanoic)hydrazide. Thiolated heparin derivatives were then linked to pyridyl disulfide-activated polyethylene oxide–polypropylene oxide–polyethylene oxide triblocks, which had previously been coated onto the surfaces of 1.15 μm polystyrene microspheres. The heparin immobilization reaction was monitored spectrophotometrically as colored pyridine-2-thione was released. In addition, the zeta potentials of uncoated, triblock-coated, and heparin-containing microsphere suspensions were recorded to demonstrate the successful attachment of heparin on the surface. However this “side-on” attachment of heparin to pendant, polyethylene oxide chains did not significantly increase the anticoagulant or anti-Factor Xa activity of microsphere suspensions.

The air–water surface tension kinetic and steady state behavior exhibited by a recombinant Factor VIII were recorded in the presence of the surfactant Tween 80. The rate of surface tension decrease was determined to be greater for rFVIII–Tween mixtures than for Tween acting alone, at all Tween concentrations studied (8–108 ppm). In addition, steady state interfacial behavior was determined to be governed entirely by surfactant adsorption in mixtures with Tween concentrations greater than or equal to about 18 ppm. The formation of aggregates, tertiary structure change, and biological activity of rFVIII in agitated as well as unagitated samples were monitored using turbidity measurements, intrinsic fluorescence spectroscopy, and the activated partial thromboplastin time, respectively. The results are consistent with two mechanisms characterizing the surfactant-mediated stabilization of rFVIII: the rapid, preferential adsorption of Tween molecules relative to rFVIII molecules at the air–water interface, and Tween association with rFVIII in solution to provide a steric barrier to aggregation. While both mechanisms are relevant in the presence of an interface, evidence recorded here suggests that the preferential adsorption of Tween at the interface is the major stabilization mechanism while the effectiveness of Tween association with rFVIII is compromised in agitated samples. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3099–3107, 2009

The adsorption, structural alteration and biological activity of a recombinant Factor VIII was investigated in the presence of the surfactant Tween-80, at hydrophilic and hydrophobic solid-water interfaces. Hydrophilic and silanized, hydrophobic silica surfaces were used as substrates for protein and surfactant adsorption, which was monitored in situ, with ellipsometry. At the hydrophobic surface, the presence of Tween in the protein solution resulted in a reduction in amount of protein adsorbed, while rFVIII adsorption at the hydrophilic surface was entirely unaffected by the presence of Tween. These observations were attributed to high binding strength between Tween and the hydrophobic surface, and low binding strength between Tween and the hydrophilic surface. Colloidal particles bearing hydrophilic and hydrophobic surfaces, and net positive or negative surface charge, were used as substrates for rFVIII adsorption in evaluation of tertiary structure change and biological activity retention at interfaces. Fluorescence emission spectroscopy showed that rFVIII tertiary structure was changed upon exposure to hydrophobic nanoparticle surfaces. Similarly, the biological activity of rFVIII (based on the activated partial thromboplastin time) was reduced at hydrophobic surfaces. At high surfactant concentration, these properties were better preserved. This was attributed to Tween adsorption sterically inhibiting rFVIII adsorption. While hydrophilic surfaces were associated with relatively high rFVIII adsorption, they did not induce large changes in structure or activity. This was attributed to the formation of a tightly packed, ordered adsorbed layer on these surfaces, governed by electrostatic attraction and not mediated by the rFVIII active site.

The adsorption and elution of the antimicrobial peptide nisin at hydrophobic, silanized silica surfaces coated with the poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) surfactant Pluronic® F108 were measured in situ, with ellipsometry. While such layers are known to inhibit protein adsorption, nisin was observed to adsorb in multilayer quantities, to an extent similar to its adsorption at uncoated, hydrophobic surfaces. The rates of nisin adsorption and elution were generally slower at F108-coated surfaces. And, the sequential adsorption of nisin, including two adsorption–elution cycles at each surface, showed greater differences in adsorption rates between the first and second adsorption cycles, when evaluated at identical mass density, for uncoated relative to F108-coated surfaces. These results indicate that nisin adsorption occurs via “entrapment” within the PEO brush layer at F108-coated surfaces, in this way slowing adsorption and spontaneous elution, and inhibiting post-adsorptive molecular rearrangements by reducing the lateral mobility of nisin. While F108-coated layers rejected adsorption of serum albumin, sequential adsorption experiments carried out with nisin and albumin showed a low level of albumin adsorption when nisin was present at the interface.

Heparin was modified with adipic dihydrazide and covalently linked to surface-activated silica wafers. X-ray photoelectron spectroscopy was used at each stage of derivatization and showed that successful immobilization had taken place. Surfaces were imaged with atomic force microscopy to determine the uniformity of the heparin layer as well as its thickness. In situ ellipsometry was used to estimate layer thickness as well, and to study protein concentration and adsorption time effects on the adsorption and elution kinetics exhibited by human plasma fibrinogen. The adsorbed amount of fibrinogen increased with time and concentration on each type of surface. Under all experimental conditions, fibrinogen adsorbed at a lower rate and to a lower extent on heparinized as compared to unheparinized silica. In addition, buffer elution experiments showed that fibrinogen was less tightly bound to heparinized silica. In order to examine behavior relative to fibrinogen mobility at these interfaces, the sequential adsorption of fibrinogen was recorded. The difference in adsorption rates between the first and second adsorption cycles, evaluated at identical mass density, indicated that post-adsorptive molecular rearrangements had taken place. In general, higher solution concentration and longer adsorption time in the first adsorption step led to more rearrangement, and these history dependent effects were more pronounced on the heparinized silica. These rearrangements are suggested to involve clustering of adsorbed fibrinogen, in this way increasing the amount of unoccupied area at the interface. These rearrangements were presumably facilitated on the heparinized silica by enhanced lateral mobility of fibrinogen at this negatively charged, highly hydrophilic interface.