Multiple Functional Domains Research Articles

Correlating wearable activity monitor data with PROMIS detected distress and physical functioning in advanced cancer patients.

e21689 Background: Patients with advanced cancer experience significant distress. Timely identification and treatment of distress can improve outcomes and quality of life. Domains of distress (i.e. pain, fatigue, physical function) can be assessed using patient reported outcome (PRO) questionnaires. However, PROs can be burdensome to patients, particularly when performed serially. Given the relationship between physical activity and sleep with domains of distress, wearable activity monitors may assist in the real-time detection of distress in advanced cancer patients. Methods: We conducted a prospective, observational study at Cedars-Sinai Medical Center and enrolled patients with measurable stage 3+ cancer, ≥18yr, English speaking, ambulatory, with a smartphone, and prognosis of > 3 months. Patients wore a Fitbit Charge HR continuously through 3 consecutive clinic visits, and completed NIH PROMIS tools (Physical Function, Pain, Sleep, Fatigue, and Emotional Distress) during visits. Fitbits recorded average daily step counts, stairs climbed, and sleep time. We conducted regression analyses that adjusted for baseline confounding variables and accounted for correlated responses. Results: 35 patients (Mean age 62; 53% males; 82% GI cancers) were evaluated. Patients had ECOG PS of 0 (20%), 1 (40%), 2 (23%), and 3(17%). The table below displays regression coefficients for steps, floors, and sleep in each PROMIS distress domain. Conclusions: There is a significant association between steps and floors climbed with multiple domains of distress and physical functioning. The lack of association between total sleep time and these PROs, may suggest that other metrics of sleep quality (i.e. awakenings), may be more relevant. These findings support further exploration of wearable data as a continuously monitored PRO surrogate in advanced cancer patients; wearable data should be further validated for use in both clinical and therapeutic trial settings. Clinical trial information: NCT02659358. [Table: see text]

Nutritional determinants of frailty in older adults: A systematic review

BackgroundFrailty is a geriatric syndrome that affects multiple domains of human functioning. A variety of problems contributes to the development of this syndrome; poor nutritional status is an important determinant of this condition. The purpose of this systematic review was to examine recent evidence regarding the association between nutritional status and frailty syndrome in older adults.MethodsPubMed, Web of Science, and Scopus electronic databases were searched using specific key words, for observational papers that were published during the period from 2005 to February 2017 and that studied the association or relationship between nutritional status and frailty in older adults. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was followed to assess the quality of the included articles.ResultsOf the 2042 studies found, nineteen met the inclusion criteria. Of these studies, five provided data on micronutrients and frailty, and reported that frailty syndrome is associated with low intakes of specific micronutrients. Five studies provided data on macronutrients and frailty, and among those studies, four revealed that a higher protein intake was associated with a lower risk of frailty. Three studies examined the relationship between diet quality and frailty, and showed that the quality of the diet is inversely associated with the risk of being frail. Two studies provided data on the antioxidant capacity of the diet and frailty, and reported that a high dietary antioxidant capacity is associated with a lower risk of developing frailty. Finally, seven studies evaluated the relationship between scores on both the Mini Nutritional Assessment (MNA) and the MNA-SF (Short Form) and frailty, and revealed an association between malnutrition and/or the risk of malnutrition and frailty.ConclusionsThis systematic review confirms the importance of both quantitative (energy intake) and qualitative (nutrient quality) factors of nutrition in the development of frailty syndrome in older adults. However, more longitudinal studies on this topic are required to further understand the potential role of nutrition in the prevention, postponement, or even reversion of frailty syndrome.

Structure-function Studies in Mouse Embryonic Stem Cells Using Recombinase-mediated Cassette Exchange.

Gene engineering in mouse embryos or embryonic stem cells (mESCs) allows for the study of the function of a given protein. Proteins are the workhorses of the cell and often consist of multiple functional domains, which can be influenced by posttranslational modifications. The depletion of the entire protein in conditional or constitutive knock-out (KO) mice does not take into account this functional diversity and regulation. An mESC line and a derived mouse model, in which a docking site for FLPe recombination-mediated cassette exchange (RMCE) was inserted within the ROSA26 (R26) locus, was previously reported. Here, we report on a structure-function approach that allows for molecular dissection of the different functionalities of a multidomain protein. To this end, RMCE-compatible mice must be crossed with KO mice and then RMCE-compatible KO mESCs must be isolated. Next, a panel of putative rescue constructs can be introduced into the R26 locus via RMCE targeting. The candidate rescue cDNAs can be easily inserted between RMCE sites of the targeting vector using recombination cloning. Next, KO mESCs are transfected with the targeting vector in combination with an FLPe recombinase expression plasmid. RMCE reactivates the promoter-less neomycin-resistance gene in the ROSA26 docking sites and allows for the selection of the correct targeting event. In this way, high targeting efficiencies close to 100% are obtained, allowing for insertion of multiple putative rescue constructs in a semi-high throughput manner. Finally, a multitude of R26-driven rescue constructs can be tested for their ability to rescue the phenotype that was observed in parental KO mESCs. We present a proof-of-principle structure-function study in p120 catenin (p120ctn) KO mESCs using endoderm differentiation in embryoid bodies (EBs) as the phenotypic readout. This approach enables the identification of important domains, putative downstream pathways, and disease-relevant point mutations that underlie KO phenotypes for a given protein.

Validation of the NIH Toolbox in Individuals with Neurologic Disorders.

Individuals with spinal cord injury (SCI), traumatic brain injury (TBI), and stroke experience a variety of neurologically related deficits across multiple domains of function. The NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) examines motor, sensation, cognition, and emotional functioning. The purpose of this paper is to establish the validity of the NIHTB in individuals with neurologic conditions. Community-dwelling individuals with SCI (n = 209), TBI (n = 184), or stroke (n = 211) completed the NIHTB. Relative risks for impaired performance were examined relative to a matched control groups. The largest group differences were observed on the Motor domain and for the Fluid Cognition measures. All groups were at increased risk for motor impairment relative to normative standards and matched controls. Fluid cognitive abilities varied across groups such that individuals with stroke and TBI performed more poorly than individuals with SCI; increased relative risks for impaired fluid cognition were seen for individuals in the stroke and TBI groups, but not for those in the SCI group. All three neurologic groups performed normally on most measures in the Sensation Battery, although TBI participants evidenced increased risk for impaired odor identification and the stroke group showed more vision difficulties. On the Emotion Battery, participants in all three groups showed comparably poor psychological well-being, social satisfaction, and self-efficacy, whereas the TBI group also evidenced slightly increased negative affect. Data provide support for the validity of the NIHTB in individuals with neurologic conditions.

The soy-derived peptide Lunasin inhibits invasive potential of melanoma initiating cells.

Lunasin is a 44 amino acid peptide with multiple functional domains including an aspartic acid tail, an RGD domain, and a chromatin-binding helical domain. We recently showed that Lunasin induced a phenotype switch of cancer initiating cells (CIC) out of the stem compartment by inducing melanocyte-associated differentiation markers while simultaneously reducing stem-cell-associated transcription factors. In the present study, we advance the hypothesis that Lunasin can reduce pools of melanoma cells with stem cell-like properties, and demonstrate that Lunasin treatment effectively inhibits the invasive potential of CICs in vitro as well as in vivo in a mouse experimental metastasis model. Mice receiving Lunasin treatment had significantly reduced pulmonary colonization after injection of highly metastatic B16-F10 melanoma cells compared to mice in the control group. Mechanistic studies demonstrate that Lunasin reduced activating phosphorylations of the intracellular kinases FAK and AKT as well as reduced histone acetylation of lysine residues in H3 and H4 histones. Using peptides with mutated activity domains, we functionally demonstrated that the RGD domain is necessary for Lunasin uptake and its ability to inhibit oncosphere formation by CICs, thus confirming that Lunasin's ability to affect CICs is at least in part due to the suppression of integrin signaling. Our studies suggest that Lunasin represents a unique anticancer agent that could be developed to help prevent metastasis and patient relapse by reducing the activity of CICs which are known to be resistant to current chemotherapies.

An Empirical vs Risk-Based Approach Algorithm to Intracavernosal Injection Therapy: A Prospective Study.

IntroductionIntracavernosal injection (ICI) therapy is widely used for the treatment of erectile dysfunction (ED). Its use in practice is largely empirical and has not been validated with evidence-based approaches.AimTo compare two strategies for ICI, specifically a risk-based approach and an empiric-based approach, and assess the efficacy, patient satisfaction, and complication rates of the two treatment approaches.MethodsAfter obtaining approval from the institutional review board, a prospective database of patients enrolled in the ICI program at the Johns Hopkins Hospital (Baltimore, MD, USA) from May 2012 through May 2014 was amassed. Demographic information, treatment outcomes, and subjective patient evaluations of sexual function (International Index of Erectile Function erectile function domain [IIEF-EF], Quality of Erection Questionnaire [QEQ], Sexual Quality of Life [SQoL], and Erectile Dysfunction Inventory of Treatment Satisfaction [EDITS]) were obtained at baseline and at 3 and 6 months. Two approaches were compared. Group 1 received empiric ICI treatment initially with prostaglandin E1 (PGE1) 10 μg irrespective of ED etiology or severity. After initial dosing with PGE1 in the clinic, adjustments were made to titrate or change formulations pending on patient results. Group 2 received a risk-based approach, in which an algorithm that factored in ED etiology and number of ED risk factors was used for a bimix (papaverine 30 mg/mL, phentolamine 1 mg/mL), a low-dose trimix (papaverine 30 mg/mL, phentolamine 1 mg/mL, PGE1 10 μg/mL), or a high-dose trimix (papaverine 30 mg/mL, phentolamine 2 mg/mL, PGE1 40 μg/mL). Dose titration was permitted in the two groups. Statistical analysis was carried out using t-test and χ2 analysis.Main Outcome MeasuresThe study design was powered for a non-inferiority comparison of the two approaches, in which the primary end point was a 15-point difference on the EDITS score or a 20% difference in the IIEF-EF score.ResultsOne hundred seventy-five patients were enrolled (57 in group 1, 118 in group 2) with 3- and 6-month follow-up at 57% and 35%, respectively, and similar between groups. Baseline patient characteristics and sexual function questionnaire responses were similar between groups 1 and 2, although group 1 reported higher-quality erections at baseline (QEQ score = 14.3 vs 7.3, P = .05) and had a smaller proportion of patients with prostatectomy (54.4% vs 74.6%, P = .02). In the two groups, QEQ score (mean = 10.78 vs 56.76, P < .05), SQoL score (mean = 38.41 vs 50.25, P < .05), and IIEF-EF score (mean = 7.51 vs 18.48, P < .05) improved with treatment. However, at 3 and 6 months, there were no statistically significant differences in responses for IIEF, QEQ, SQoL, or EDITS scores and no difference in failure or medication switch rates between groups. There were no significant differences in complication rates, although at 3 months group 2 reported a higher incidence of priapism and pain (23% vs 7.4%, P = .08).ConclusionEmpiric and risk-based strategies for ICI therapy resulted in significant improvements across multiple domains of sexual function. Complication rates, satisfaction, and efficacy overall were similar between the two approaches. Clinicians can be reassured that no one approach to ICI therapy for ED management appears inferior to another.

Developing a Problem-Solving Treatment for Gulf War Illness: Cognitive Rehabilitation of Veterans with Complex Post-Deployment Health Concerns

Social workers play an essential role in facilitating veterans’ reintegration into their communities and daily lives. Many veterans, particularly those who have been deployed, experience comorbid physical, psychological, and neurocognitive problems that significantly impact their health function in multiple domains. Veterans deployed to Operation Desert Shield/Operation Desert Storm have reported a wide range of persistent, diverse, medically unexplained symptoms that have come to be known as Gulf War Illness (GWI). These symptoms make it difficult for veterans to participate in daily activities, thereby impacting health function. There are few effective treatments to improve the health function for those with GWI. The goals of this article are to provide social workers with information about GWI, and describe how we modified an evidence-based treatment, problem-solving therapy, for veterans with GWI. This tailoring of an existing treatment may serve as a model for adapting evidence-based treatments for veterans and civilians with multiple chronic symptoms and other complex health concerns. Furthermore, the detailed description provided may facilitate dissemination of problem-solving therapy among social workers and trainees.

A complex dynamic systems approach to lasting positive change: The Synergistic Change Model

This paper argues that psychological and social functioning is fundamentally complex, and that this complexity is critical to understanding how lasting positive changes can be achieved. Principles from complex systems theory are integrated into an empirical positive psychological framework to propose a domain-based systems model of positive change called the Synergistic Change Model. This model proposes that enduring positive change depends on the formation of mutually supportive interactions across multiple domains of psychological and social functioning. The paper uses the model to explore three types of response to intervention – relapse, spill-over, and synergy – which have been supported in the existing positive psychology literature. Three practical intervention strategies arising from the model are outlined to inform the design of future positive interventions. The model challenges reductionistic approaches to positive change and offers several approaches to embrace the complexities of lasting positive change in future theory and research.

Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer

To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer. From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function. Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy. ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction.

Abstract TMP45: Predicting Long-term Body Function, Activity &amp; Participation After Stroke: The Prevailing Role of Cognition in Determining Functional Outcome

Background: Stroke can impact multiple levels of function and result in complex disability. Few studies have examined limitations across the range of functions from body function to social participation, or explored the impact of post-stroke comorbidities, such as depression, obstructive sleep apnea (OSA) and cognition, on function, especially in the long-term. We aimed to determine post-stroke predictors of multiple levels of functioning approximately 2 years after a stroke, and to specifically evaluate the impact of depressive symptoms, OSA and cognitive impairment on outcome. Hypothesis: We hypothesized that in addition to traditional predictors of outcome–age and stroke severity–depression, OSA and cognitive impairment will predict functional outcome in multiple domains. Methods: Baseline assessment of depression, apnea and cognitive impairment with 2-year follow-up assessment of functional outcome to evaluate each of the three levels of functioning as stated in the WHO International Classification of Functioning: Body Function (Montreal Cognitive Assessment), Activity (modified Rankin) and Participation (Reintegration to Normal Living Index). Results: A total of 162 patients were enrolled at approximately 2 years and 5 months post-stroke. Forty one percent had activity limitations, 58% were cognitively impaired and 68% had restrictions in participation. Long-term activity limitation was predicted by greater age (OR = 0.95), stroke severity (OR = 1.69) and cognitive impairment (OR = 1.28) at baseline. Body function impairment was predicted by greater age (OR = 0.96), and cognitive impairment (OR = 1.49). Participation restriction was predicted by cognitive impairment (OR = 1.26). Conclusion: Baseline cognition predicts long-term function in multiple domains and is a better predictor of long-term participation than age or baseline stroke severity. In view of the widespread impact of post-stroke cognitive impairment on every level of functioning, routine post-stroke cognitive screening and target interventions are warranted. Greater attention to functional domains beyond activity could further optimize recovery and enhance outcome after stroke.

"Still feeling healthy after all these years": The paradox of subjective stability versus objective decline in very old adults' health and functioning across five years.

Indicators of objective functioning, such as everyday competence or sensory and sensorimotor functions, typically show pronounced declines in very old age. However, less is known about how very old adults perceive their abilities across multiple domains of health and functioning and to what extent changes in perceived functioning mirror changes in objective functioning. We compared changes in perceived versus objective health and functioning indicators among very old adults (n = 124; baseline age between 87 and 97 years, M = 90.56 years, SD = 2.92 years) across 11 measurement occasions, spanning approximately 5 years. Functioning was assessed by self-reports (subjective health, subjective movement ability, subjective vision, and number of perceived symptoms) and by objective and mostly performance-based tests (everyday competence, visual acuity, chair stand test, and grip strength). All objective measures exhibited a significant mean-level decline across 5 years, whereas most subjective indicators did not reveal significant mean-level changes. Interindividual variation in intraindividual change patterns was considerable in most domains. Correlations between trajectories of the different indicators were mostly weak, and predicting late-life changes in subjective functioning by time-varying objective functioning indicators accounted for only modest amounts of variance. Our findings suggest that there is a somewhat paradoxical pattern of discrepant late-life change trends in subjective versus objective indicators of health and functioning. We argue that a differentiated understanding of the fourth age is required and that common health definitions frequently applied to old and very old age need to be challenged. (PsycINFO Database Record

The Spectrum of Hand Dysfunction After Hemodialysis Fistula Placement

IntroductionContemporary dogma has classically attributed hand dysfunction following hemodialysis arteriovenous fistula (AVF) placement to regional ischemia. We hypothesize that hemodynamic perturbations alone do not entirely explain the postoperative changes in hand function and, furthermore, that various elements of hand function are differentially affected following surgery.MethodsBilateral wrist and digital pressures and upper extremity nerve conduction tests were recorded preoperatively and at 6 weeks and 6 months following upper extremity AVF construction in 46 patients. Concurrently, biomechanical tests were administered to evaluate multiple limb functional domains, including grip strength, dexterity, sensation, and perception of hand function.ResultsMean participant age was 59 ± 14 years (75% male), and 48% were on hemodialysis at the time of access placement. Of the participants, 69% had a brachial-based AVF, and the remainder had radial-based accesses. Six weeks following AVF placement, a significant decrease in access-side digital pressures was observed, with only partial recovery at 6 months (P < 0.0001). Grip strength was significantly worse in the access-side limb (P = 0.0003), and the Disability of Arm, Shoulder and Hand (DASH) questionnaire score substantially worsened postoperatively (P = 0.06). Digital sensation and limb dexterity did not differ between limb sides (P > 0.1) or change significantly over time (P > 0.1). Principal component analyses demonstrated that nerve conduction parameters tended to track the biomechanical parameters, yet both were relatively independent of the hemodynamic parameters.DiscussionOur findings suggest that ischemia alone does not completely explain access-related hand dysfunction and that future study is needed to elucidate alternative mechanisms.

The C-terminal dimerization motif of cyclase-associated protein is essential for actin monomer regulation.

Cyclase-associated protein (CAP) is a conserved actin-regulatory protein that functions together with actin depolymerizing factor (ADF)/cofilin to enhance actin filament dynamics. CAP has multiple functional domains, and the function to regulate actin monomers is carried out by its C-terminal half containing a Wiskott-Aldrich Syndrome protein homology 2 (WH2) domain, a CAP and X-linked retinitis pigmentosa 2 (CARP) domain, and a dimerization motif. WH2 and CARP are implicated in binding to actin monomers and important for enhancing filament turnover. However, the role of the dimerization motif is unknown. Here, we investigated the function of the dimerization motif of CAS-2, a CAP isoform in the nematode Caenorhabditis elegans, in actin monomer regulation. CAS-2 promotes ATP-dependent recycling of ADF/cofilin-bound actin monomers for polymerization by enhancing exchange of actin-bound nucleotides. The C-terminal half of CAS-2 (CAS-2C) has nearly as strong activity as full-length CAS-2. Maltose-binding protein (MBP)-tagged CAS-2C is a dimer. However, MBP-CAS-2C with a truncation of either one or two C-terminal β-strands is monomeric. Truncations of the dimerization motif in MBP-CAS-2C nearly completely abolish its activity to sequester actin monomers from polymerization and enhance nucleotide exchange on actin monomers. As a result, these CAS-2C variants, also in the context of full-length CAS-2, fail to compete with ADF/cofilin to release actin monomers for polymerization. CAS-2C variants lacking the dimerization motif exhibit enhanced binding to actin filaments, which is mediated by WH2. Taken together, these results suggest that the evolutionarily conserved dimerization motif of CAP is essential for its C-terminal region to exert the actin monomer-specific regulatory function.

Development of the interRAI home care frailty scale.

BackgroundThe concept of frailty, a relative state of weakness reflecting multiple functional and health domains, continues to receive attention within the geriatrics field. It offers a summary of key personal characteristics, providing perspective on an individual’s life course.There have been multiple attempts to measure frailty, some focusing on physiologic losses, others on specific diseases, disabilities or health deficits. Recently, multidimensional approaches to measuring frailty have included cognition, mood and social components. The purpose of this project was to develop and evaluate a Home Care Frailty Scale and provide a grounded basis for assessing a person’s risk for decline that included functional and cognitive health, social deficits and troubling diagnostic and clinical conditions.MethodsA secondary analysis design was used to develop the Home Care Frailty Scale. The data set consisted of client level home care data from service agencies around the world. The baseline sample included 967,865 assessments while the 6-month follow-up sample of persons still being served by the home care agencies consisted of 464,788 assessments. A pool of 70 candidate independent variables were screened for possible inclusion and 16 problem outcomes referencing accumulating declines and clinical complications served as the dependent variables. Multiple regression techniques were used to analyze the data.ResultsThe resulting Home Care Frailty Scale consisted of a final set of 29 items. The items fall across 6 categories of function, movement, cognition and communication, social life, nutrition, and clinical symptoms. The prevalence of the items ranged from a high of 87% for persons requiring help with meal preparation to 3.7% for persons who have experienced a recent decline in the amount of food eaten.ConclusionsThe interRAI Home Care Frailty Scale is based on a strong conceptual foundation and in our analysis, performed as expected. Given the use of the interRAI Home Care Assessment System in multiple, diverse countries, the Home Care Frailty Scale will have wide applicability to support program planning and policy decision-making impacting home care clients and their formal and informal caregivers throughout the world.

Viral challenge reveals further evidence of skin-deep resilience in African Americans from disadvantaged backgrounds.

Studies have revealed a phenomenon called skin-deep resilience, which develops in upwardly mobile African American youth. They perform well in school, maintain good mental health, and avoid legal problems. Despite outward indications of success, they also show evidence of worse health in biomarker studies. Here we extend this research, asking whether it manifests in differential susceptibility to upper respiratory infection, and if it emerges in European Americans as well. The sample included 514 adults in good health, as judged by physician examination and laboratory testing. Participants completed questionnaires about lifecourse socioeconomic conditions, conscientiousness, psychosocial adjustment, and lifestyle factors. They were subsequently inoculated with a rhinovirus that causes upper respiratory infection, and monitored in quarantine for 5 days the development of illness. Consistent with past work, African Americans from disadvantaged backgrounds displayed indications of skin-deep resilience. To the extent these participants were high in conscientiousness, they fared better across multiple domains of psychosocial functioning, as reflected in educational attainment, symptoms of depression, and close relationship quality (p values = .01-.04). But analyses of these participants' susceptibility to infection revealed the opposite pattern; higher conscientiousness was associated with a greater likelihood of becoming ill following inoculation (p value = .03). In European Americans, there was no evidence of skin-deep resilience; conscientiousness was associated with better psychosocial outcomes, but not infection risk. These observations suggest that resilience may be a double-edged sword for African Americans from disadvantaged backgrounds. The same characteristics associated with academic success and psychological adjustment forecast increased vulnerability to health problems. (PsycINFO Database Record

Towards a multidimensional healthy ageing phenotype.

There is great interest in developing tools to measure healthy ageing and to identify early stages of health impairment, which may guide the implementation of interventions to prevent or delay the development of disease, disability, and mortality. Here, we review the most recent developments directed to operationalize, and test, definitions of healthy ageing. There is lack of consensus about how to define healthy ageing and, unsurprisingly, diversity in the instruments for its measurement. However, progress is being made in describing and in devising tools to capture the healthy ageing phenotype. Attempts to measure healthy ageing have relied primarily on cross-sectional data collected in older people. More recent studies have assessed the healthy ageing phenotype using markers of multiple functional domains and have used longitudinal data to model the dynamics and trajectories of healthy ageing. Given the complexity of the ageing process, no single measure is able to predict the ageing trajectory. Current attempts to operationalize the healthy ageing phenotype have relied on markers and data from earlier cohort studies and are limited by the tools used to collect data in those studies. Such data are often unsuitable to detect early subtle declines in function and/or are inappropriate for use in younger old adults. Future studies employing more objective and novel markers of healthy ageing are likely to offer opportunities to define and operationalize the healthy ageing phenotype.

363 - Mechanism of Damage to Arterial Extracellular Derived Fibronectin by Myeloperoxidase-Derived Oxidants during Chronic Inflammation

Background The extracellular matrix (ECM), which consists of a complex mixture of glycosaminoglycans, proteoglycans and glycoproteins, is of critical importance for the structure and function of the artery wall, and regulates cell activity via cell-ECM interactions and binding of cytokines and enzymes. Fibronectin, a key ECM component, possesses multiple functional domains, including cell-binding (CBF), and heparin-binding fragments (HBF). At sites of inflammation, including the artery wall during the development of atherosclerosis, activated leukocytes release myeloperoxidase (MPO), which utilises H2O2 and Cl– to generate the powerful oxidant hypochlorous acid (HOCl). Hypothesis: That HOCl and MPO/H2O2/Cl– modify fibronectin resulting in endothelial cell dysfunction. Results Exposure of human fibronectin to increasing molar ratios of HOCl, or a MPO/Cl– with increasing concentration of H2O2, resulted in a loss of antibody reactivity against the CBF and HBF domains of fibronectin (detected by silver staining, Western blotting and ELISA). Significant oxidation and cross-linking was detected on gels, with some cross-linking being reversible by DTT, consistent with disulfide bond formation. HOCl treatment resulted in a decrease in Trp and Met levels and an increase in Met sulfoxide. Oxidant treatment was accompanied by a loss of adhesion of human coronary artery endothelial cells consistent with modifications to the cell-binding domain. Analogous modifications were detected in advanced human atherosclerotic lesions by immunofluorescence. Conclusions These data support the hypothesis that fibronectin, and particularly its CBF and HBF domains are susceptible to modification by HOCl or MPO/H2O2/Cl-, with this resulting in modification to its structure and functional properties. These changes may contribute to endothelial dysfunction and rupture of atherosclerotic lesions.

A Review of Factors that Promote Resilience in Youth with ADHD and ADHD Symptoms.

The vast majority of research on youth with ADHD has focused on risk factors and describing the types of impairment individuals with ADHD experience. However, functional outcomes associated with ADHD are heterogeneous, and although many youth with ADHD experience significant negative outcomes (e.g., school dropout), some are successful in multiple domains of functioning (e.g., pursue and graduate college). There is a growing body of literature supporting the existence of factors that protect youth with ADHD from experiencing negative outcomes, but there is no published synthesis of this literature. Accordingly, the goals of this review are to conceptualize risk-resilience in the context of ADHD using a developmental psychopathology framework and to systematically review and critique evidence for promotive and protective factors in the context of ADHD. The literature search focused specifically on resilience in the context of ADHD symptoms or an ADHD diagnosis and identified 21 studies, including clinic, school, and community samples. Findings of promotive and/or protective factors are summarized across individual, family, and social-community systems. Overall, we know very little of the buffering processes for these youth, given that the study of promotive and protective factors in ADHD is in its infancy. The strongest evidence to date was found for social- and family-level systems. Specifically, multiple longitudinal studies support social acceptance as a protective factor, buffering against negative outcomes such as poor academic performance and comorbid depressive symptoms for youth with ADHD. There was also compelling evidence supporting positive parenting as a promotive factor. In terms of individual-level factors, positive or modest self-perceptions of competence were identified as a promotive factor in multiple studies. Future directions for research that will catalyze the study of resilience with ADHD are provided, and the potential for targeting protective mechanisms with intervention and prevention is discussed.

Sexual functioning of men and women with severe obesity before bariatric surgery

BackgroundObesity may impair sexual function through multiple mechanisms, but little is known about sexual dysfunction among adults with severe obesity seeking bariatric procedures. ObjectivesTo describe sexual function and associated factors before bariatric surgery. SettingTen U.S. clinical facilities. MethodsBefore bariatric surgery, 2225 of 2458 Longitudinal Assessment of Bariatric Surgery-2 study participants (79% female, median age 45 years and median body mass index 46 kg/m2) completed a survey about sexual function over the past month. Mixed effects ordinal logistic regression models were used to identify factors independently related to 4 domains of sexual function. ResultsOne third of women (34%) and one quarter of men (25%) were not sexually active, alone or with a partner, in the past month. Twenty-six percent of women and 12% of men reported no sexual desire. Physical health limited sexual activity at least moderately in 38% of women and 44% of men. About one half of the women (49%) and the men (54%) were moderately or very dissatisfied with their sexual life. Among women, older age, being Caucasian, urinary incontinence, depressive symptoms, and antidepressant medication use were associated with poorer sexual function in multiple domains. In men, older age, not being married, depressive symptoms, and antidepressant medication use were associated with poorer sexual function in multiple domains. ConclusionBefore bariatric surgery, approximately one half of women and men with severe obesity are dissatisfied with their sexual life. Older age, severity of depressive symptoms, and antidepressant medication use are associated with poorer sexual function in both sexes.

Neurocognitive and executive functioning in adult survivors of congenital heart disease.

Congenital heart disease (CHD) can affect the developing central nervous system, resulting in neurocognitive and behavioral deficits. Preoperative neurological abnormalities as well as sequelae of the open heart operations required to correct structural abnormalities of the heart contribute to these deficits. There are few studies examining the neurocognitive functioning of adults with CHD. This study sought to investigate multiple domains of neurocognitive functioning in adult survivors of CHD who had childhood cardiac surgery with either moderate or severe disease complexity. A total of 48 adults (18-49 years of age) who had undergone cardiac surgery for CHD prior to five years of age participated in the study. CHD severity was classified as moderate or severe according to the 32nd Bethesda Guidelines. A computerized battery of standardized neurocognitive tests (CNS-Vital Signs), a validated rating scale of executive functioning, and demographic questionnaires were administered. There were no significant differences between the moderate CHD group and normative data on any cognitive measure. In contrast, the severe CHD group differed from norms in multiple domains: psychomotor speed, processing speed, complex attention, reaction time, and on the overall neurocognitive index. Number of surgeries was strongly related to worse executive functioning. There was no association between age at first surgery or time since last surgery and neuropsychological functioning. Number of surgeries was also unrelated to neurocognitive test performance. Patients with severe CHD performed significantly worse on measures of processing speed, attention, and executive functioning. These findings may be useful in the long-term care of adults with congenital heart disease.