Internet trials: participant experiences and perspectives

Background Use of the Internet to conduct randomised controlled trials is increasing, and provides potential to increase equity of access to medical research, increase the generalisability of trial results and decrease the costs involved in conducting large scale trials. Several studies have compared response rates, completeness of data, and reliability of surveys using the Internet and traditional methods, but very little is known about participants’ attitudes towards Internet-based randomised trials or their experience of participating in an Internet-based trial. Objective To obtain insights into the experiences and perspectives of participants in an Internet-based randomised controlled trial, their attitudes to the use of the Internet to conduct medical research, and their intentions regarding future participation in Internet research. Methods All English speaking participants in a recently completed Internet randomised controlled trial were invited to participate in an online survey. Results 1246 invitations were emailed. 416 participants completed the survey between May and October 2009 (33% response rate). Reasons given for participating in the Internet RCT fell into 4 main areas: personal interest in the research question and outcome, ease of participation, an appreciation of the importance of research and altruistic reasons. Participants’ comments and reflections on their experience of participating in a fully online trial were positive and less than half of participants would have participated in the trial had it been conducted using other means of data collection. However participants identified trade-offs between the benefits and downsides of participating in Internet-based trials. The main trade-off was between flexibility and convenience – a perceived benefit – and a lack connectedness and understanding – a perceived disadvantage. The other tradeoffs were in the areas of: ease or difficulty in use of the Internet; security, privacy and confidentiality issues; perceived benefits and disadvantages for researchers; technical aspects of using the Internet; and the impact of Internet data collection on information quality. Overall, more advantages were noted by participants, consistent with their preference for this mode of research over others. The majority of participants (69%) would prefer to participate in Internet-based research compared to other modes of data collection in the future. Conclusion Participants in our survey would prefer to participate in Internet-based trials in the future compared to other ways of conducting trials. From the participants’ perspective, participating in Internet-based trials involves trade-offs. The central trade-off is between flexibility and convenience – a perceived benefit – and lack of connectedness and understanding – a perceived disadvantage. Strategies to maintain the convenience of the Internet while increasing opportunities for participants to feel supported, well-informed and well-understood would seem likely to increase the acceptability of Internet-based trials. Keywords: Internet; Randomized controlled trials; Participant experience; Methods; Methodolog

Rapid influx and death of plasmacytoid dendritic cells in lymph nodes mediate depletion in acute simian immunodeficiency virus infection

Plasmacytoid dendritic cells (pDC) are essential innate immune system cells that are lost from the circulation in human immunodeficiency virus (HIV)-infected individuals associated with CD4+ T cell decline and disease progression. pDC depletion is thought to be caused by migration to tissues or cell death, although few studies have addressed this directly. We used precise methods of enumeration and in vivo labeling with 5-bromo-2′-deoxyuridine to track recently divided pDC in blood and tissue compartments of monkeys with acute pathogenic simian immunodeficiency virus (SIV) infection. We show that pDC are lost from blood and peripheral lymph nodes within 14 days of infection, despite a normal frequency of pDC in bone marrow. Paradoxically, pDC loss masked a highly dynamic response characterized by rapid pDC mobilization into blood and a 10- to 20-fold increase in recruitment to lymph nodes relative to uninfected animals. Within lymph nodes, pDC had increased levels of apoptosis and necrosis, were uniformly activated, and were infected at frequencies similar to CD4+ T cells. Nevertheless, remaining pDC had essentially normal functional responses to stimulation through Toll-like receptor 7, with half of lymph node pDC producing both TNF-α and IFN-α. These findings reveal that cell migration and death both contribute to pDC depletion in acute SIV infection. We propose that the rapid recruitment of pDC to inflamed lymph nodes in lentivirus infection has a pathologic consequence, bringing cells into close contact with virus, virus-infected cells, and pro-apoptotic factors leading to pDC death. © 2009 Brown et al

Fatigue in celiac disease: A review of the literature

Fatigue is increasingly recognized as a significant problem in patients with chronic inflammatory and autoimmune diseases. In celiac disease, a chronic immune‐mediated disease triggered by dietary gluten, conflicting opinions exist regarding both the size of the problem and the effect of a gluten‐free diet (GFD) on fatigue. We reviewed the existing literature regarding fatigue in celiac disease. We conducted a systematic search in the Embase, Ovid Medline, and Cochrane databases using subject terms from controlled vocabularies. Articles were reviewed based on language, type of article, title, and abstract or full text. Eighteen articles were finally selected for review. Fatigue was significantly greater in patients with celiac disease compared to healthy control subjects. Fatigue prevalence ranged from 8 to 100%. Fatigue severity was assessed in six studies. The fatigue visual analogue scale was the most frequently used fatigue instrument with scores from 57 to 79 prior to starting a GFD and from 39 to 59 in patients on a GFD. Seven studies investigated the effect of a GFD on fatigue, including five studies that reported less fatigue while on the diet and two studies that showed no significant difference. This review concludes that fatigue is a substantial complaint in patients with celiac disease. A GFD seems to reduce fatigue, but existing data are limited.publishedVersio

Screening for cervical, prostate and breast cancer: interpreting the evidence

Cancer screening is well-established in high income countries, but its evidence base is constantly evolving and often contentious. This leaves physicians and policymakers in a difficult position, forced to act in the context of methodological complexity and substantive disagreement.1,2 Three cases of screening for cancer or cancer risk are considered: cervical, prostate and breast screening. The unique characteristics of the disease, test and program in each case are outlined in Table 1. Tables 2-4, catalogue sources of controversy in each case; these are discussed in more depth below. The concluding section presents five common themes that may help explain the ongoing controversies. The aim is not to synthesize the evidence, but to provide the ‘backroom’ story of the evidence on cancer screening, and so illuminate why experts so often disagree.This work is supported by the Australian National Health and Medical Research Council (NHMRC), under Project Grant 1023197. SC is supported by NHMRC Career Development Fellowship 1032963. LP is supported by NHMRC Postgraduate Scholarship 1038517. JG is supported by NHMRC Postgraduate Scholarship 1074626. JW is supported by an Australian Postgraduate Award

Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans

Background: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms ( SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort ( 1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF- II levels. Results: Both offspring's and mother's H19 2992C> T SNP genotypes showed associations with offspring birthweight ( P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels ( P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype ( P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight ( P = 0.04) and higher cord blood IGF-II levels ( P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies ( P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight ( P = 0.04) and with mother's glucose levels ( P = 0.01) in first pregnancies. Conclusion: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants

Abnormal IgD and IgA1 O-glycosylation in hyperimmunoglobulinaemia D and periodic fever syndrome

In order to determine the glycosylation pattern for IgD, and to examine whether there are changes in the pattern of IgD and IgA1 O-glycosylation in patients with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) during acute febrile attacks and during periods of quiescence, serum was obtained from 20 patients with HIDS and 20 control subjects. In the HIDS group, serum was obtained either during an acute febrile episode (n = 9) or during a period of quiescence (n = 11). The O-glycosylation profiles of native and desialylated IgA1 and IgD were measured in an ELISA-type system using the lectins Helix aspersa and peanut agglutinin, which bind to alternative forms of O-glycan moieties. IgD is more heavily O-galactosylated and less O-sialylated than IgA1 in healthy subjects. HIDS is associated with more extensive O-galactosylation of IgD and a reduction in O-sialylation of both IgD and IgA1. These changes are present both during acute febrile attacks and periods of quiescence. The T cell IgD receptor is a lectin with binding affinity for the O-glycans of both IgD and IgA1. The observed changes in IgD and IgA1 O-glycosylation are likely to have a significant effect on IgD/IgA1–T cell IgD receptor interactions including basal immunoglobulin synthesis, and possibly myeloid IgD receptor-mediated cytokine release

Psychological morbidity of celiac disease: a review of the literature

BACKGROUND: Celiac disease has been linked to decreased quality of life and certain mood disorders. The effect of the gluten free diet on these psychological aspects of the disease is still unclear. OBJECTIVES: The objective of this article is to review the literature on psychological morbidity of celiac disease. METHODS: We performed a PubMed search for the time period from 1900 until June 1, 2014, to identify papers on psychological aspects of celiac disease looking specifically at quality of life, anxiety, depression and fatigue. RESULTS: Anxiety, depression and fatigue are common complaints in patients with untreated celiac disease and contribute to lower quality of life. While aspects of these conditions may improve within a few months after starting a gluten-free diet, some patients continue to suffer from significant psychological morbidity. Psychological symptoms may affect the quality of life and the dietary adherence. CONCLUSION: Health care professionals need to be aware of the ongoing psychological burden of celiac disease in order to support patients with this disease

Dendritic Cell Subtypes from Lymph Nodes and Blood Show Contrasted Gene Expression Programs upon Bluetongue Virus Infection

Chantier qualité GAHuman and animal hemorrhagic viruses initially target dendritic cells (DCs). It has been proposed, but not documented, that both plasmacytoid DCs (pDCs) and conventional DCs (cDCs) may participate in the cytokine storm encountered in these infections. In order to evaluate the contribution of DCs in hemorrhagic virus pathogenesis, we performed a genome-wide expression analysis during infection by Bluetongue virus (BTV), a double-stranded RNA virus that induces hemorrhagic fever in sheep and initially infects cDCs. Both pDCs and cDCs accumulated in regional lymph nodes and spleen during BTV infection. The gene response profiles were performed at the onset of the disease and markedly differed with the DC subtypes and their lymphoid organ location. An integrative knowledge-based analysis revealed that blood pDCs displayed a gene signature related to activation of systemic inflammation and permeability of vasculature. In contrast, the gene profile of pDCs and cDCs in lymph nodes was oriented to inhibition of inflammation, whereas spleen cDCs did not show a clear functional orientation. These analyses indicate that tissue location and DC subtype affect the functional gene expression program induced by BTV and suggest the involvement of blood pDCs in the inflammation and plasma leakage/hemorrhage during BTV infection in the real natural host of the virus. These findings open the avenue to target DCs for therapeutic interventions in viral hemorrhagic diseases

Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis