Promise and challenges of peptide-poly: ICLC vaccines for adult and pediatric gliomas

We currently run phase I studies of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes emulsified in Montanide-ISA-51 and intramuscular administration of poly-ICLC in HLA-A2+ adult and pediatric patients with gliomas. Primary endpoints were safety and CD8+ T-cell responses against vaccine-targeted GAAs: IL-13Rα2, EphA2, Survivin and WT1 (WT1 in adults only). Adults with WHO grade 2 low-grade glioma (LGG) have an extremely high risk for transformation to high-grade glioma (HGG), and most patients eventually die of the disease. Because patients with LGGs may not be as immuno-compromised as patients with HGG, they may exhibit greater immunological response to and benefit from the vaccines. We conducted a phase I vaccine study with: newly diagnosed high-risk LGG without prior radiation therapy (RT) (Cohort 1); newly diagnosed high-risk LGG with prior RT (Cohort 2); or recurrent LGG (Cohort 3). Cohorts 1, 2, and 3 have enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity has been encountered except for one case with Grade 3 fever (Cohort 1). Cohort 1 patients demonstrated significantly higher magnitude of IFN-γ ELISPOT responses than Cohort 3 patients for all 4 GAA epitopes, suggesting that newly diagnosed patients may have better vaccine-responsiveness than recurrent patients. The magnitude of the IFN-γ ELISPOT responses in this study is significantly higher than that observed in our previous phase I/II study in HGG patients. Median progression-free survival (PFS) periods are 21 months (Cohort 1; range 10-44) and 12 months (Cohort 3; range 3-28). In Cohort 1, 3 patients are still progression-free (32, 33 and 44 months to date). The only patient with large astrocytoma in Cohort 2 has been progression-free for over 54 months since diagnosis. There was a positive trend for IFN-γ ELISPOT responses and PFS. Diffuse brainstem gliomas (BSGs) and other HGGs of childhood carry a dismal prognosis. To date, 24 children were enrolled, 14 with newly diagnosed BSG treated with RT, and 10 with newly diagnosed BSG or HGG treated with RT and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to corticosteroids and was associated with prolonged survival. Nineteen had stable disease for > 2 cycles, 2 had partial responses, and 1 had prolonged disease-free status after surgery. Median survival among the BSG cohort exceeded 13 months. ELISPOT analysis in 15 children showed GAA responses in 12, to IL-13Rα2 in 9, EphA2 in 7, and survivin in 7. Careful monitoring and management of pseudoprogression is warranted

World Federation of Hemophilia Gene Therapy Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/2/hae14015_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/1/hae14015.pd

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

ARTP statement on pulmonary function testing 2020.

The Association for Respiratory Technology & Physiology (ARTP) last produced a statement on the performance of lung function testing in 1994. At that time the focus was on a practical statement for people working in lung function laboratories. Since that time there have been many technological advances and alterations to best practice in the measurement and interpretation of lung function assessments. In light of these advances an update was warranted. ARTP, therefore, have provided within this document, where available, the most up-to-date and evidence-based recommendations for the most common lung function assessments performed in laboratories across the UK. These recommendations set out the requirements and considerations that need to be made in terms of environmental and patient factors that may influence both the performance and interpretation of lung function tests. They also incorporate procedures to ensure quality assured diagnostic investigations that include those associated with equipment, the healthcare professional conducting the assessments and the results achieved by the subject. Each section aims to outline the common parameters provided for each investigation, a brief principle behind the measurements (where applicable), and suggested acceptability and reproducibility criteria

Submarine Magmatic-Hydrothermal Systems at the Monowai Volcanic Centre, Kermadec Arc

Authors listed on this Accepted Manuscript vary slightly from those listed on the Version of Record. Harold L. Gibson is an additional author on the published version.The Monowai volcanic centre (MVC) is located at the mid-point along the ~2530 km long Tonga-Kermadec arc system, is probably the most hydrothermally active submarine volcanic system globally. The MVC is comprised of a large elongate caldera (Monowai caldera, 7.9 x 5.7 km; 35 km²; depth to caldera floor is 1590 m), which has formed within an older caldera some 84 km² in area. To the south of the nested caldera system is a large composite volcano, Monowai cone, which rises to within ~ 100 m of the sea surface and has been volcanically active for at least several decades. Despite the large size, mafic volcanic rocks dominate the MVC; basalts are the most common rock type recovered; less common are basaltic andesites and andesites. Hydrothermal plume mapping during the 2004 NZAPLUME III cruise showed at least three major hydrothermal systems associated with the caldera and cone. Monowai cone has hydrothermal venting from the summit. This summit plume is gas-rich and acidic; plume samples show a pH shift of -2.00 pH units, δ³He up to 358 ‰, H₂S concentrations up to 32 μM and CH₄ concentrations up to 900 nM. The summit plume is also metal-rich with elevated total dissolvable Fe (TDFe up to 4200 nM), TDMn (up to 412 nM), and TDFe/TDMn (up to 20.4). Monowai caldera has a major hydrothermal vent system with plumes extending from ~ 1000 to 1400 m depth. The caldera plume has lower values for TDFe, although ranges to higher TDMn concentrations than the summit plume, and is relatively gas-poor (no H₂S detected, pH shift of -0.06 pH units, CH₄ concentrations up to 26 nM). Hydrothermal vents have been observed associated with prominent basaltic andesite ridges (Mussel Ridge) proximal to the southwest wall of the caldera (1025 – 1171 m depth). However, the composition of the hydrothermal plumes in the caldera are different to the vents, indicating that the source of the caldera plumes is at greater depth and is more metal-rich and therefore likely higher temperature. Minor plumes detected as light scattering anomalies down the northern flank of Monowai caldera most likely represent resuspension of volcanic debris. Particulate samples from both the cone sites and the caldera site are enriched in Al, Ti, Ca, Mg, Si, and S, with the cone summit plume especially enriched in K, As, W and Cu, Pb, Zn. The elevated Ti and Al suggest acidic water-rock reactions and intense high-sulfidation alteration of the host volcanic rocks. Observations from submersible dives with Pisces V in 2005 and the remotely operated vehicle ROPOS in 2007 of Mussel Ridge indicate numerous low temperature vents (< 60°C), with a large biomass of vent-associated fauna, in particular large accumulations of the mussel Bathymodiolus sp. and the tubeworm Lamellibrachia sp. We interpret the Monowai volcanic centre as possessing a robust high-sulfidation magmatic-hydrothermal system, with significant differences in the style and composition of venting at the cone and caldera sites. At Monowai cone, the large shifts in pH, elevated TDFe and TDFe/TDMn, and H₂S-, CH₄- and ³He-rich nature of the plume fluids coupled with elevated Ti, P, V, S and Al in the particulates indicates significant magmatic volatile ± metal contributions to the hydrothermal system and aggressive acidic water-rock interaction. By contrast, Monowai caldera has low TDFe/TDMn in hydrothermal plumes; however, end-member vent fluid compositions, combined with presence of alunite, sulfide minerals and native sulfur in samples from Mussel Ridge suggest recent acid volatile-rich venting and active Fe-sulfide formation in the subsurface, and the potential for the presence of significant SMS mineralization

Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas

Background: The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. Methods: In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. Results and Discussion: In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-γ Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883-891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled vaccinations with no incidence of major adverse events. Monocyte-derived DCs produced high levels of IL-12 p70. Treatment was well tolerated; however, we were unable to observe detectable IFN-γ post-vaccine responses or prolonged progression-free survival in these participants. Conclusion: Feasibility challenges inherent in the generation of a patient-specific gene transfection-based vaccine strongly suggests the need for more practical formulations that would allow for the timely administration of vaccines. Nevertheless, successful generation of type-1 DCs and preliminary safety in the current study provide a strong rationale for further efforts to develop novel glioma vaccines. © 2007 Okada et al; licensee BioMed Central Ltd

Scale-dependent perspectives on the geomorphology and evolution of beachdune systems

Despite widespread recognition that landforms are complex Earth systems with process-response linkages that span temporal scales from seconds to millennia and spatial scales from sand grains to landscapes, research that integrates knowledge across these scales is fairly uncommon. As a result, understanding of geomorphic systems is often scale-constrained due to a host of methodological, logistical, and theoretical factors that limit the scope of how Earth scientists study landforms and broader landscapes. This paper reviews recent advances in understanding of the geomorphology of beach-dune systems derived from over a decade of collaborative research from Prince Edward Island (PEI), Canada. A comprehensive summary of key findings is provided from short-term experiments embedded within a decade-long monitoring program and a multi-decadal reconstruction of coastal landscape change. Specific attention is paid to the challenges of scale integration and the contextual limitations research at specific spatial and/or temporal scales imposes. A conceptual framework is presented that integrates across key scales of investigation in geomorphology and is grounded in classic ideas in Earth surface sciences on the effectiveness of formative events at different scales. The paper uses this framework to organize the review of this body of research in a 'scale aware' way and, thereby, identifies many new advances in knowledge on the form and function of subaerial beach-dune systems. Finally, the paper offers a synopsis of how greater understanding of the complexities at different scales can be used to inform the development of predictive models, especially those at a temporal scale of decades to centuries, which are most relevant to coastal management issues. Models at this (landform) scale require an understanding of controls that exist at both ‘landscape’ and ‘plot’ scales. Landscape scale controls such as sea level change, regional climate, and the underlying geologic framework essentially provide bounding conditions for independent variables such as winds, waves, water levels, and littoral sediment supply. Similarly, an holistic understanding of the range of processes, feedbacks, and linkages at the finer plot scale is required to inform and verify the assumptions that underly the physical modelling of beach-dune interaction at the landform scale

Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

Background: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p&lt;0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15–1·22] in men and 1·10 [1·06–1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval −0·84 g/L [95% CI −0·99 to −0·70] in men and −0·45 g/L [–0·59 to −0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval −6·5% [95% CI −7·6 to −5·5] in men and −5·3% [–6·5 to −4·2] in women; all p&lt;0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p&gt;0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p&lt;0·0001). Interpretation: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. Funding: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article