The Vulnerabilities of Orphaned Children Participating in Research: A Critical Review and Factors for Consideration for Participation in Biomedical and Behavioral Research

Orphans are a subpopulation with a unique set of additional vulnerabilities. Increasing focus on children’s rights, pediatric global health, and pediatric research makes it imperative to recognize and address unique vulnerabilities of orphaned children. This paper describes the unique vulnerabilities of the orphaned pediatric population and offers a structured set of factors that require consideration when including orphans in biomedical research. Pediatric orphans are particularly vulnerable due to decreased economic resources, psychosocial instability, increased risk of abuse, and delayed/decreased access to healthcare. These vulnerabilities are significant. By carefully considering each issue in a population in a culturally specific and study-specific manner, researchers can make valuable contributions to the overall health and well-being of this uniquely vulnerable population

Computer-generated reminders and quality of pediatric HIV care in a resource-limited setting

OBJECTIVES: To evaluate the impact of clinician-targeted computer-generated reminders on compliance with HIV care guidelines in a resource-limited setting. METHODS: We conducted this randomized, controlled trial in an HIV referral clinic in Kenya caring for HIV-infected and HIV-exposed children (<14 years of age). For children randomly assigned to the intervention group, printed patient summaries containing computer-generated patient-specific reminders for overdue care recommendations were provided to the clinician at the time of the child's clinic visit. For children in the control group, clinicians received the summaries, but no computer-generated reminders. We compared differences between the intervention and control groups in completion of overdue tasks, including HIV testing, laboratory monitoring, initiating antiretroviral therapy, and making referrals. RESULTS: During the 5-month study period, 1611 patients (49% female, 70% HIV-infected) were eligible to receive at least 1 computer-generated reminder (ie, had an overdue clinical task). We observed a fourfold increase in the completion of overdue clinical tasks when reminders were availed to providers over the course of the study (68% intervention vs 18% control, P < .001). Orders also occurred earlier for the intervention group (77 days, SD 2.4 days) compared with the control group (104 days, SD 1.2 days) (P < .001). Response rates to reminders varied significantly by type of reminder and between clinicians. CONCLUSIONS: Clinician-targeted, computer-generated clinical reminders are associated with a significant increase in completion of overdue clinical tasks for HIV-infected and exposed children in a resource-limited setting

Charting the elements of pedagogic frailty

Background: The concept of pedagogic frailty has been proposed as a unifying concept that may help to integrate institutional efforts to enhance teaching improvement within universities by helping to maintain a simultaneous focus on four key areas that are thought to impede development. Purpose: The variation in internal structure of the four dimensions of pedagogic frailty and the links that have been proposed to connect them are explored here through the analysis of interviews with academics working in a variety of disciplinary areas. Methods: The application of concept map-mediated interviews allows us to view the variable connections within and between these dimensions and the personal ways they are conceptualised by academics working across the heterogeneous university context. Results: The data show that academics conceptualise the discourse of teaching in various ways that have implications for the links that may be developed to integrate the elements within the model. Conclusions: Whilst the form and content of the maps representing dimensions of the pedagogic frailty model exhibit considerable variation, it is suggested that factors such as academic resilience and the explicit use of integrative concepts within disciplines may help to overcome some of the vulnerabilities that accompany pedagogic frailty. The data also raises questions about the links between factors that tend to be under individual control and those that tend towards institutional control

Cryopreservation-related loss of antigen-specific IFN gamma producing CD4(+) T-cells can skew immunogenicity data in vaccine trials: Lessons from a malaria vaccine trial substudy

Ex vivo functional immunoassays such as ELISpot and intracellular cytokine staining (ICS) by flow cytometry are crucial tools in vaccine development both in the identification of novel immunogenic targets and in the immunological assessment of samples from clinical trials. Cryopreservation and subsequent thawing of PBMCs via validated processes has become a mainstay of clinical trials due to processing restrictions inherent in the disparate location and capacity of trial centres, and also in the need to standardize biological assays at central testing facilities. Logistical and financial requirement to batch process samples from multiple study timepoints are also key. We used ELISpot and ICS assays to assess antigen-specific immunogenicity in blood samples taken from subjects enrolled in a phase II malaria heterologous prime-boost vaccine trial and showed that the freeze thaw process can result in a 3–5-fold reduction of malaria antigen-specific IFNγ-producing CD3+CD4+ effector populations from PBMC samples taken post vaccination. We have also demonstrated that peptide responsive CD8+ T cells are relatively unaffected, as well as CD4+ T cell populations that do not produce IFNγ. These findings contribute to a growing body of data that could be consolidated and synthesised as guidelines for clinical trials with the aim of increasing the efficiency of vaccine development pipelines

What makes for effective feedback: staff and student perspectives

Since the early 2010s the literature has shifted to view feedback as a process that students do where they make sense of information about work they have done, and use it to improve the quality of their subsequent work. In this view, effective feedback needs to demonstrate effects. However, it is unclear if educators and students share this understanding of feedback. This paper reports a qualitative investigation of what educators and students think the purpose of feedback is, and what they think makes feedback effective. We administered a survey on feedback that was completed by 406 staff and 4514 students from two Australian universities. Inductive thematic analysis was conducted on data from a sample of 323 staff with assessment responsibilities and 400 students. Staff and students largely thought the purpose of feedback was improvement. With respect to what makes feedback effective, staff mostly discussed feedback design matters like timing, modalities and connected tasks. In contrast, students mostly wrote that high-quality feedback comments make feedback effective – especially comments that are usable, detailed, considerate of affect and personalised to the student’s own work. This study may assist researchers, educators and academic developers in refocusing their efforts in improving feedbac

Polyfunctional T-Cell Responses Are Disrupted by the Ovarian Cancer Ascites Environment and Only Partially Restored by Clinically Relevant Cytokines

Host T-cell responses are associated with favorable outcomes in epithelial ovarian cancer (EOC), but it remains unclear how best to promote these responses in patients. Toward this goal, we evaluated a panel of clinically relevant cytokines for the ability to enhance multiple T-cell effector functions (polyfunctionality) in the native tumor environment.Experiments were performed with resident CD8+ and CD4+ T cells in bulk ascites cell preparations from high-grade serous EOC patients. T cells were stimulated with α-CD3 in the presence of 100% autologous ascites fluid with or without exogenous IL-2, IL-12, IL-18 or IL-21, alone or in combination. T-cell proliferation (Ki-67) and function (IFN-γ, TNF-α, IL-2, CCL4, and CD107a expression) were assessed by multi-parameter flow cytometry. In parallel, 27 cytokines were measured in culture supernatants. While ascites fluid had variable effects on CD8+ and CD4+ T-cell proliferation, it inhibited T-cell function in most patient samples, with CD107a, IFN-γ, and CCL4 showing the greatest inhibition. This was accompanied by reduced levels of IL-1β, IL-1ra, IL-9, IL-17, G-CSF, GM-CSF, Mip-1α, PDGF-bb, and bFGF in culture supernatants. T-cell proliferation was enhanced by exogenous IL-2, but other T-cell functions were largely unaffected by single cytokines. The combination of IL-2 with cytokines engaging complementary signaling pathways, in particular IL-12 and IL-18, enhanced expression of IFN-γ, TNF-α, and CCL4 in all patient samples by promoting polyfunctional T-cell responses. Despite this, other functional parameters generally remained inhibited.The EOC ascites environment disrupts multiple T-cell functions, and exogenous cytokines engaging diverse signaling pathways only partially reverse these effects. Our results may explain the limited efficacy of cytokine therapies for EOC to date. Full restoration of T-cell function will require activation of signaling pathways beyond those engaged by IL-2, IL-12, IL-18, and IL-21

'Duck to water' or 'fish out of water'? Diversity in the experience of negotiating the transition to university

Winstone and Hulme present a critical discussion of the notion of transition to university. They argue that the common emphasis on the challenging nature of the transition fails to acknowledge the diversity in students’ experiences; for some students, the liminality and discomfort experienced during this critical period in their educational journey can be a transformational and empowering rite of passage. Rather than homogenising students’ experiences, Winstone and Hulme argue that it is beneficial to explore the transition experience through the lens of students’ expectations and subsequent experiences and to view the transition to university as part of a trajectory of transition experience within a student’s educational journey. The chapter also presents practical suggestions for engaging multiple student voices in understanding and facilitating positive transition experiences

A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans.

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime-boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime-MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development