An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet–platelet and platelet–vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10−5–10−4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress

Loading of a Phenanthroline-Based Platinum(II) Complex onto the Surface of a Carbon Nanotube via pi–pi Stacking

Stacking of the metal complex [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2þ (56MESS) onto the surface of two different fullerenes, a carbon nanotube (CNT), and a C60-buckyball was examined. The metal complex forms a supramolecular complex with multi-walled CNTs but not with buckyballs. Binding of 56MESS to the CNTs is highly efficient (90 %) but can be further stabilized by the addition of the surfactant, pluronic F-127, which resulted in a loading efficiency of 95 %. Molecular modelling shows that binding of 56MESS to the CNT is supported by the large surface area of the fullerene, whereas the more pronounced curvature and lack of a flat surface on the buckyball affects the ability of 56MESS to form bonds to its surface. The loading of 56MESS onto the CNT is via p–p stacking from the metal complex phenanthroline ligand and C–H p bonding fromthe diaminocyclohexane ligand. 56MESS has 13 critical bonding points with the CNT, eight of which are p–p stacking bonds, but the metal complex forms only seven bonds with the buckyball. In addition, the loading of 56MESS onto the CNT results in a charge transfer of 0.111 eV; however, charge transfer is almost negligible for binding to the buckyball

The anatomical origins of migratory dendritic cells in the intestine

The intestine is exposed to a vast array of harmless dietary antigen as well as an enormous community of commensal bacteria. Alongside this harmless antigen, pathogens can enter the body via the intestinal mucosal surface. The intestinal immune system must discriminate between pathogens and innocuous antigens. Dendritic cells (DCs), present in the small intestine (SI) and colon, are fundamental in controlling intestinal immune responses; they migrate to the mesenteric lymph node (MLN) and prime effector or regulatory T cells. Furthermore, DCs direct the immune response in the gut-associated lymphoid tissues (GALT), the Peyer’s patches (PP) and isolated lymphoid follicles (ILFs). The aim of this work was to determine the anatomical origins of DCs in the MLN. First, the anatomical organisation of lymphatic vessels draining to the MLN from the SI and colon was investigated. Second, DC migration in mice lacking specific GALT was explored. Finally, the migration of DCs from PPs to the MLN was investigated. To achieve these aims, DC migration was studied using a variety of labelling methods, mice that lacked specific GALT were employed, and surgical procedures were used to collect DCs from the thoracic duct. Here, I demonstrate the anatomical segregation of DCs that migrate to the MLN from the SI and colon. This was reflected in differences in DC subset composition and antigen presentation in the SI and colon-draining nodes of the MLN. Separate analysis of MLN nodes will allow a more refined understanding of intestinal immune responses. All but one DC subset, CD103-CD11b- DCs, were still present in pseudo-afferent lymph from mice lacking both PPs and ILFs. This subset is therefore likely to originate from either PPs or ILFs. Surprisingly, CD103+CD8α+ DCs were present in these mice, showing that many CD8α+ DCs were resident in the lamina propria and are not limited to lymphoid tissue. Four DC subsets are able to migrate from the intestine in PP-null mice, suggesting that CD103-CD11b- DCs migrate specifically from ILFs. I then demonstrated that DCs migrate from PPs to the MLN. These migrating PP DCs expanded in response to a DC specific growth factor and their migration depended on CCR7 and S1P. These cells may play an important role in driving immune responses in the MLN and their manipulation could lead to advances in controlling intestinal immune responses

“Disadvantaged patient populations”: A theory-informed education needs assessment in an urban teaching hospital

Recent calls in medical education and health care emphasize equitable care for disadvantaged patient populations (DPP), with education  highlighted as a key mechanism to move toward this goal. However, in order to develop effective education strategies we must first better understand the DPP concept. We conducted a theory-informed needs assessment to explore the concept of DPP as understood in our hospital.  Using an interpretive qualitative approach informed by principles of critical discourse analysis we conducted focus groups with trainees and staff across professions and groups, as identified in the hospital’s strategic plan, representing “patients experiencing disadvantage.” We identified three main perceptions about DPP:  1) disadvantaged patients require care above and beyond what is normal; 2) the system is to blame for failures in serving disadvantaged patients; and 3) labelling patients is problematic and stigmatizing. In response, patients wanted to be first seen as valuable human beings rather than as a burden or category. Patients appreciated that the DPP concept opened up better access to care, but also felt ‘othered’ by the concept. As a result, patients felt they were not accessing the same level of care in terms of compassion and respect.  Our findings suggest potential for three, theory-informed educational approaches to help improve care for patients experiencing disadvantage: 1) sharing authentic and varied stories; 2) fostering dialogue; and 3) aligning assessment approaches with educational approaches. Additionally, we suggest a need to define access beyond the ability to receive services; according to our participants, access must also engender a sense of common humanity and respect.&nbsp

Sustained Use of Patient Portal Features and Improvements in Diabetes Physiological Measures

BACKGROUND: Personal health records (PHRs) have the potential to improve patient self-management for chronic conditions such as diabetes. However, evidence is mixed as to whether there is an association between PHR use and improved health outcomes. OBJECTIVE: The aim of this study was to evaluate the association between sustained use of specific patient portal features (Web-based prescription refill and secure messaging-SM) and physiological measures important for the management of type 2 diabetes. METHODS: Using a retrospective cohort design, including Veterans with diabetes registered for the My Health e Vet patient portal who had not yet used the Web-based refill or SM features and who had at least one physiological measure (HbA1c, low-density lipoprotein (LDL) cholesterol, blood pressure) in 2009-2010 (baseline) that was above guideline recommendations (N=111,686), we assessed portal use between 2010 and 2014. We calculated the odds of achieving control of each measure by 2013 to 2014 (follow-up) by years of using each portal feature, adjusting for demographic and clinical characteristics associated with portal use. RESULTS: By 2013 to 2014, 34.13% (38,113/111,686) of the cohort was using Web-based refills, and 15.75% (17,592/111,686) of the cohort was using SM. Users were slightly younger (P \u3c .001), less likely to be eligible for free care based on economic means (P \u3c .001), and more likely to be women (P \u3c .001). In models adjusting for both features, patients with uncontrolled HbA1c at baseline who used SM were significantly more likely than nonusers to achieve glycemic control by follow-up if they used SM for 2 years (odds ratio-OR=1.24, CI: 1.14-1.34) or 3 or more years (OR=1.28, CI: 1.12-1.45). However, there was no significant association between Web-based refill use and glycemic control. Those with uncontrolled blood pressure at baseline who used Web-based refills were significantly more likely than nonusers to achieve control at follow-up with 2 (OR=1.07, CI: 1.01-1.13) or 3 (OR=1.08, CI: 1.02-1.14) more years of Web-based refill use. Both features were significantly associated with improvements in LDL cholesterol levels at follow-up. CONCLUSIONS: Although rates of use of the refill function were higher within the population, sustained SM use had a greater impact on HbA1c. Evaluations of patient portals should consider that individual components may have differential effects on health improvements

Perspectives on Transitioning Uninsured Persons from an Emergency Department to Federally Qualified Health Centers in East Baltimore

Many people in the United States rely on the emergency department (ED) for their usual source of primary care. Linking these ED users to a source of longitudinal primary care could provide significant health benefits. To assess an intervention attempting to connect ED users to federally qualified health cents (FQHCs), we conducted semi-structured, in-depth interviews with volunteers, health facility providers, and a patient and a focus group with program volunteers. All sessions were digitally recorded, transcribed and analyzed to develop emergent themes highlighting the barriers and facilitating factors that affect the process of connecting patients to primary care. Themes included that 1) the ED is the preferred source of primary care over FQHCs, 2) there are limited links between EDs and FQHCs and 3) the evaluated intervention acts through and depends on patients’ prioritization of health and access to resources. Our findings suggest that, in addition to addressing individual needs, social services programs are well positioned to help increase communication between providers at FQHCs and EDs about both the services available to patients and patients’ medical care histories

EGFR is required for Wnt9a-Fzd9b signalling specificity in haematopoietic stem cells.

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit β-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine

Dual Use of a Patient Portal and Clinical Video Telehealth by Veterans with Mental Health Diagnoses: Retrospective, Cross-Sectional Analysis

BACKGROUND: Access to mental health care is challenging. The Veterans Health Administration (VHA) has been addressing these challenges through technological innovations including the implementation of Clinical Video Telehealth, two-way interactive and synchronous videoconferencing between a provider and a patient, and an electronic patient portal and personal health record, My HealtheVet. OBJECTIVE: This study aimed to describe early adoption and use of My HealtheVet and Clinical Video Telehealth among VHA users with mental health diagnoses. METHODS: We conducted a retrospective, cross-sectional analysis of early My HealtheVet adoption and Clinical Video Telehealth engagement among veterans with one or more mental health diagnoses who were VHA users from 2007 to 2012. We categorized veterans into four electronic health (eHealth) technology use groups: My HealtheVet only, Clinical Video Telehealth only, dual users who used both, and nonusers of either. We examined demographic characteristics and mental health diagnoses by group. We explored My HealtheVet feature use among My HealtheVet adopters. We then explored predictors of My HealtheVet adoption, Clinical Video Telehealth engagement, and dual use using multivariate logistic regression. RESULTS: Among 2.17 million veterans with one or more mental health diagnoses, 1.51% (32,723/2,171,325) were dual users, and 71.72% (1,557,218/2,171,325) were nonusers of both My HealtheVet and Clinical Video Telehealth. African American and Latino patients were significantly less likely to engage in Clinical Video Telehealth or use My HealtheVet compared with white patients. Low-income patients who met the criteria for free care were significantly less likely to be My HealtheVet or dual users than those who did not. The odds of Clinical Video Telehealth engagement and dual use decreased with increasing age. Women were more likely than men to be My HealtheVet or dual users but less likely than men to be Clinical Video Telehealth users. Patients with schizophrenia or schizoaffective disorder were significantly less likely to be My HealtheVet or dual users than those with other mental health diagnoses (odds ratio, OR 0.50, CI 0.47-0.53 and OR 0.75, CI 0.69-0.80, respectively). Dual users were younger (53.08 years, SD 13.7, vs 60.11 years, SD 15.83), more likely to be white, and less likely to be low-income than the overall cohort. Although rural patients had 17% lower odds of My HealtheVet adoption compared with urban patients (OR 0.83, 95% CI 0.80-0.87), they were substantially more likely than their urban counterparts to engage in Clinical Video Telehealth and dual use (OR 2.45, 95% CI 1.95-3.09 for Clinical Video Telehealth and OR 2.11, 95% CI 1.81-2.47 for dual use). CONCLUSIONS: During this study (2007-2012), use of these technologies was low, leaving much potential for growth. There were sociodemographic disparities in access to My HealtheVet and Clinical Video Telehealth and in dual use of these technologies. There was also variation based on types of mental health diagnosis. More research is needed to ensure that these and other patient-facing eHealth technologies are accessible and effectively used by all vulnerable patients

Patient Use of Electronic Prescription Refill and Secure Messaging and Its Association With Undetectable HIV Viral Load: A Retrospective Cohort Study

BACKGROUND: Electronic personal health records (PHRs) can support patient self-management of chronic conditions. Managing human immunodeficiency virus (HIV) viral load, through taking antiretroviral therapy (ART) is crucial to long term survival of persons with HIV. Many persons with HIV have difficulty adhering to their ART over long periods of time. PHRs contribute to chronic disease self-care and may help persons with HIV remain adherent to ART. Proportionally veterans with HIV are among the most active users of the US Department of Veterans Affairs (VA) PHR, called My HealtheVet. Little is known about whether the use of the PHR is associated with improved HIV outcomes in this population. OBJECTIVE: The objective of this study was to investigate whether there are associations between the use of PHR tools (electronic prescription refill and secure messaging [SM] with providers) and HIV viral load in US veterans. METHODS: We conducted a retrospective cohort study using data from the VA\u27s electronic health record (EHR) and the PHR. We identified veterans in VA care from 2009-2012 who had HIV and who used the PHR. We examined which ones had achieved the positive outcome of suppressed HIV viral load, and whether achievement of this outcome was associated with electronic prescription refill or SM. From 18,913 veterans with HIV, there were 3374 who both had a detectable viral load in 2009 and who had had a follow-up viral load test in 2012. To assess relationships between electronic prescription refill and viral control, and SM and viral control, we fit a series of multivariable generalized estimating equation models, accounting for clustering in VA facilities. We adjusted for patient demographic and clinical characteristics associated with portal use. In the initial models, the predictor variables were included in dichotomous format. Subsequently, to evaluate a potential dose-effect, the predictor variables were included as ordinal variables. RESULTS: Among our sample of 3374 veterans with HIV who received VA care from 2009-2012, those who had transitioned from detectable HIV viral load in 2009 to undetectable viral load in 2012 tended to be older (P=.004), more likely to be white (P\u3c.001), and less likely to have a substance use disorder, problem alcohol use, or psychosis (P=.006, P=.03, P=.004, respectively). There was a statistically significant positive association between use of electronic prescription refill and change in HIV viral load status from 2009-2012, from detectable to undetectable (OR 1.36, CI 1.11-1.66). There was a similar association between SM use and viral load status, but without achieving statistical significance (OR 1.28, CI 0.89-1.85). Analyses did not demonstrate a dose-response of prescription refill or SM use for change in viral load. CONCLUSIONS: PHR use, specifically use of electronic prescription refill, was associated with greater control of HIV. Additional studies are needed to understand the mechanisms by which this may be occurring

Impact of Patient Access to Online VA Notes on Healthcare Utilization and Clinician Documentation: a Retrospective Cohort Study

BACKGROUND: In an effort to foster patient engagement, some healthcare systems provide their patients with open notes, enabling them to access their clinical notes online. In January 2013, the Veterans Health Administration (VA) implemented online access to clinical notes ( VA Notes ) through the Blue Button feature of its patient portal. OBJECTIVE: To measure the association of online patient access to clinical notes with changes in healthcare utilization and clinician documentation behaviors. DESIGN: A retrospective cohort study. PATIENTS: Patients accessing My HealtheVet (MHV), the VA\u27s online patient portal, between July 2011 and January 2015. MAIN MEASURES: Use of healthcare services (primary care clinic visits and online electronic secure messaging), and characteristics of physician clinical documentation (readability of notes). KEY RESULTS: Among 882,575 unique portal users, those who accessed clinical notes (16.2%; N = 122,972) were younger, more racially homogenous (white), and less likely to be financially vulnerable. Compared with non-users, Notes users more frequently used the secure messaging feature on the portal (mean of 2.6 messages (SD 7.0) v. 0.87 messages (SD 3.3) in January-July 2013), but their higher use of secure messaging began prior to VA Notes implementation, and thus was not temporally related to the implementation. When comparing clinic visit rates pre- and post-implementation, Notes users had a small but significant increase in rate of 0.36 primary care clinic visits (2012 v. 2013) compared to portal users who did not view their Notes (p = 0.01). At baseline, the mean reading ease of primary care clinical notes was 53.8 (SD 10.1) and did not improve after implementation of VA Notes. CONCLUSIONS: VA Notes users were different than patients with portal access who did not view their notes online, and they had higher rates of healthcare service use prior to and after VA Notes implementation. Opportunities exist to improve clinical note access and readability