Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke ( POINT ) Trial: Rationale and design

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99014/1/ijs12129.pd

Attitude change and increased confidence with management of chronic breathlessness following a health professional training workshop: a survey evaluation

Abstract: Background: Clinicians and people living with chronic breathlessness have expressed a need to better understand and manage this symptom. The aim of this study was to evaluate a 3-day health professional training workshop on the practical management of chronic breathlessness. Methods: Workshop design and delivery were based on current understandings and clinical models of chronic breathlessness management, principles of transformative learning, and included sessions co-designed with people living with breathlessness. Registrants were invited to complete pre and post-workshop surveys. Pre and 1-week post-workshop online questionnaires assessed familiarity and confidence about workshop objectives (0[lowest]-10[highest] visual analogue scale), attitudes and practices regarding chronic breathlessness (agreement with statements on 5-point Likert scales). Post-workshop, participants were asked to describe implementation plans and anticipated barriers. Baseline familiarity and confidence were reported as mean (SD) and change examined with paired t-tests. Pre-post attitudes and practices were summarised by frequency/percentages and change examined non-parametrically (5-point Likert scale responses) or using a McNemar test of change (binary responses). Results: Forty-seven of 55 registrants joined the study; 39 completed both pre and post-workshop questionnaires (35 female; 87% clinicians; median 8 years working with people with chronic breathlessness). Post-workshop, greatest gains in confidence were demonstrated for describing biopsychosocial concepts unpinning chronic breathlessness (mean change confidence = 3.2 points; 95% CI 2.7 to 4.0, p < 0.001). Respondents significantly changed their belief toward agreement that people are able to rate their breathlessness intensity on a scale (60 to 81% agreement) although only a minority strongly agreed with this statement at both time points (pre 11%, post 22%). The largest shift in attitude was toward agreement (z statistic 3.74, p < 0.001, effect size r = 0.6) that a person’s experience of breathlessness should be used to guide treatment decisions (from 43 to 73% strong agreement). Participants’ belief that cognitive behavioural strategies are effective for relief of breathlessness changed further toward agreement after the workshop (81 to 100%, McNemar test chi- square = 5.14, p = 0.02). Conclusion: The focus of this training on biopsychosocial understandings of chronic breathlessness and involvement of people living with this symptom were valued. These features were identified as facilitators of change in fundamental attitudes and preparedness for practice

Attitude change and increased confidence with management of chronic breathlessness following a health professional training workshop: a survey evaluation

Abstract: Background: Clinicians and people living with chronic breathlessness have expressed a need to better understand and manage this symptom. The aim of this study was to evaluate a 3-day health professional training workshop on the practical management of chronic breathlessness. Methods: Workshop design and delivery were based on current understandings and clinical models of chronic breathlessness management, principles of transformative learning, and included sessions co-designed with people living with breathlessness. Registrants were invited to complete pre and post-workshop surveys. Pre and 1-week post-workshop online questionnaires assessed familiarity and confidence about workshop objectives (0[lowest]-10[highest] visual analogue scale), attitudes and practices regarding chronic breathlessness (agreement with statements on 5-point Likert scales). Post-workshop, participants were asked to describe implementation plans and anticipated barriers. Baseline familiarity and confidence were reported as mean (SD) and change examined with paired t-tests. Pre-post attitudes and practices were summarised by frequency/percentages and change examined non-parametrically (5-point Likert scale responses) or using a McNemar test of change (binary responses). Results: Forty-seven of 55 registrants joined the study; 39 completed both pre and post-workshop questionnaires (35 female; 87% clinicians; median 8 years working with people with chronic breathlessness). Post-workshop, greatest gains in confidence were demonstrated for describing biopsychosocial concepts unpinning chronic breathlessness (mean change confidence = 3.2 points; 95% CI 2.7 to 4.0, p < 0.001). Respondents significantly changed their belief toward agreement that people are able to rate their breathlessness intensity on a scale (60 to 81% agreement) although only a minority strongly agreed with this statement at both time points (pre 11%, post 22%). The largest shift in attitude was toward agreement (z statistic 3.74, p < 0.001, effect size r = 0.6) that a person’s experience of breathlessness should be used to guide treatment decisions (from 43 to 73% strong agreement). Participants’ belief that cognitive behavioural strategies are effective for relief of breathlessness changed further toward agreement after the workshop (81 to 100%, McNemar test chi- square = 5.14, p = 0.02). Conclusion: The focus of this training on biopsychosocial understandings of chronic breathlessness and involvement of people living with this symptom were valued. These features were identified as facilitators of change in fundamental attitudes and preparedness for practice

Evaluation of Messages to Promote Intake of Calcium-Rich Foods in Early Adolescents

Parental practices influence intake of calcium-rich foods and beverages (CRFB) in adolescents. This study aimed to test two posters promoting such parental practices for comprehension, cultural and personal relevance, and ability to motivate parents to encourage CRFB intake. Interviews were conducted with 14 Hispanic and 6 Asian parents to evaluate two posters entitled “Good play starts with calcium” and “Strong families start with good nutrition.” Responses were reviewed for themes. For “Good play,” both racial/ethnic groups of parents understood the message to provide CRFB. Only Hispanics, however, recognized the connection between calcium and strong bones. For “Strong families,” both groups had difficulty understanding that foods pictured were calcium rich. Both posters were considered culturally and personally relevant; however, not all respondents indicated motivation to provide CRFB. Modifications are needed to emphasize the connection between images and taglines and calcium intake for use in a future intervention to improve CRFB-promoting practices

The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog

Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p &#60; 0.05). Analysis of spinal cord tissue from DM and control material found that clusterin expression was evident in neurons and that the clusterin mRNA levels from tissue extracts were elevated in DM compared to the control. The plasma clusterin levels was comparable between these groups. However, a comparison of clusterin CSF levels in a number of neurological conditions found that clusterin was elevated in both DM and chronic intervertebral disc disease (cIVDD) but not in meningoencephalitis and IE. These findings indicate that clusterin may potentially serve as a marker for chronic spinal cord disease in the dog; however, additional markers are required to differentiate DM from a concurrent condition such as cIVDD

Limited Durability of Viral Control following Treated Acute HIV Infection

BACKGROUND: Early treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection. METHODS AND FINDINGS: Fourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria. CONCLUSIONS: These data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve

HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1

Background: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression. Methods and Findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection. Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression

Fully Differentiated HIV-1 Specific CD8+ T Effector Cells are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection

Background: CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-γ+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. Methodology/Principal Findings: We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were “Controllers” (median 1140 RNA copies/ml plasma, range less than 50 to 2520), and 20 “progressors” of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to greater than 750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. Conclusions/Significance: These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function

Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon γ assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions

Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates Against Drug-Resistant Cancer Cells

Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multi-drug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. We describe a series of 2-aryl-2-(3-indolyl)acetohydroxamic acids, which are active against apoptosis- and multidrug-resistant cancer cells as well as glioblastoma neurosphere stem-like cell cultures derived from patients. Thus, the described compounds serve as a novel chemical scaffold for the development of potentially highly effective clinical cancer drugs