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All aboard the discovery express
Welcome on board the Discovery Express! The year is 1937 and a conundrum is afoot: a professor on the verge of a brilliant discovery has disappeared. Can you help to solve the clues on this time-travelling adventure and track down the missing scientist? On your voyage, you'll travel the world, see some of the most important moments in the history of transport, meet the most brilliant engineers of all time, and ultimately unveil the design of the world's first jet engine! With clues to solve on every page, this interactive lift-flap adventure is sure to spark the imaginations of aspiring scientists and engineers everywhere, as you travel back in time to discover the history of transport.
Book
PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma
Background
After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC.
Methods
The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC.
Discussion
The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population.
Trial registration
EudraCT Number: 2018–000987-27 Clinical trial registry & ID:
ClinicalTrials.gov
:
NCT03682276
.
Journal Article
The red prince
\"When the young prince of Zapada is imprisoned by invaders, he needs all the help he can get to escape. As he flees dressed in his red pajamas, his captors are hot on his heels. But soon he realizes that he is not alone. The whole land of Zapada has joined forces to help him, each person dressing in red to confound and confuse his enemies. This exciting tale of adventure and escape is brought to life by the illustrator of Wall. A dramatic tale of escape and unity set against a frozen landscape.\"-- Provided by publisher
Book
Urban and Transport Planning Related Exposures and Mortality: A Health Impact Assessment for Cities
By 2050, nearly 70% of the global population is projected to live in urban areas. Because the environments we inhabit affect our health, urban and transport designs that promote healthy living are needed.
We estimated the number of premature deaths preventable under compliance with international exposure recommendations for physical activity (PA), air pollution, noise, heat, and access to green spaces.
We developed and applied the Urban and TranspOrt Planning Health Impact Assessment (UTOPHIA) tool to Barcelona, Spain. Exposure estimates and mortality data were available for 1,357,361 residents. We compared recommended with current exposure levels. We quantified the associations between exposures and mortality and calculated population attributable fractions to estimate the number of premature deaths preventable. We also modeled life-expectancy and economic impacts.
We estimated that annually, nearly 20% of mortality could be prevented if international recommendations for performance of PA; exposure to air pollution, noise, and heat; and access to green space were followed. Estimations showed that the greatest portion of preventable deaths was attributable to increases in PA, followed by reductions of exposure to air pollution, traffic noise, and heat. Access to green spaces had smaller effects on mortality. Compliance was estimated to increase the average life expectancy by 360 (95% CI: 219, 493) days and result in economic savings of 9.3 (95% CI: 4.9, 13.2) billion EUR/year.
PA factors and environmental exposures can be modified by changes in urban and transport planning. We emphasize the need for a) the reduction of motorized traffic through the promotion of active and public transport and b) the provision of green infrastructure, both of which are suggested to provide opportunities for PA and for mitigation of air pollution, noise, and heat. Citation: Mueller N, Rojas-Rueda D, Basagaña X, Cirach M, Cole-Hunter T, Dadvand P, Donaire-Gonzalez D, Foraster M, Gascon M, Martinez D, Tonne C, Triguero-Mas M, Valentín A, Nieuwenhuijsen M. 2017. Urban and transport planning related exposures and mortality: a health impact assessment for cities. Environ Health Perspect 125:89-96; http://dx.doi.org/10.1289/EHP220.
Journal Article
Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines
The optimal vaccination strategy to boost responses in the context of pre-existing immune memory to the SARS-CoV-2 spike (S) glycoprotein is an important question for global public health. To address this, we explored the SARS-CoV-2-specific humoral and cellular immune responses to a novel self-amplifying RNA (saRNA) vaccine followed by a UK authorised mRNA vaccine (BNT162b2) in individuals with and without previous COVID-19, and compared these responses with those who received an authorised vaccine alone. 35 subjects receiving saRNA (saRNA group) as part of the COVAC1 clinical trial and an additional 40 participants receiving an authorised SARS-CoV-2 vaccine only (non-saRNA group) were recruited. Antibody responses were measured by ELISA and a pseudoneutralisation assay for wildtype, Delta and Omicron variants. Cellular responses were measured by IFN-ƴ ELISpot and an activation induced marker (AIM) assay. Approximately 50% in each group had previous COVID-19 prior to vaccination, confirmed by PCR or antibody positivity on ELISA. All of those who received saRNA subsequently received a full course of an authorised vaccine. The majority (83%) of those receiving saRNA who were COVID-19 naïve at baseline seroconverted following the second dose, and those with previous COVID-19 had an increase in antibody titres two weeks following saRNA vaccination (median 27-fold), however titres were lower when compared to mRNA vaccination. Two weeks following the 2 nd authorised mRNA vaccine dose, binding and neutralising antibody titres were significantly higher in the saRNA participants with previous COVID-19, compared to non-saRNA, or COVID-19 naive saRNA participants. Cellular responses were again highest in this group, with a higher proportion of spike specific CD8+ than CD4+ T cells when compared to those receiving the mRNA vaccine only. These findings suggest an immunological benefit of increased antigen exposure, both from natural infection and vaccination, particularly evident in those receiving heterologous vaccination with saRNA and mRNA.
Journal Article
The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection—study protocol for a two-stage randomised phase II trial
Background
Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control.
Methods
RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (
n
= 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures.
Discussion
The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19.
Trial registration
The protocol is registered on
Clinical.trials.gov
and EudraCT and has approval from UK Ethics and MHRA.
Journal Article
The health impacts of waste-to-energy emissions: a systematic review of the literature
Waste-to-energy (WtE) processes, or the combustion of refuse-derived fuel (RDF) for energy generation, has the potential to reduce landfill volume while providing a renewable energy source. We aimed to systematically review and summarise current evidence on the potential health effects (benefits and risks) of exposure to WtE/RDF-related combustion emissions. We searched PubMed and Google Scholar using terms related to health and WtE/RDF combustion emissions, following PRISMA guidelines. Two authors independently screened titles, abstracts and then full-texts of original, peer-reviewed research articles published until 20th March 2020, plus their relevant references. Overall quality of included epidemiological studies were rated using an amended Navigation framework. We found 19 articles from 269 search results that met our inclusion criteria, including two epidemiological studies, five environmental monitoring studies, seven health impact or risk assessments (HIA/HRA), and five life-cycle assessments. We found a dearth of health studies related to the impacts of exposure to WtE emissions. The limited evidence suggests that well-designed and operated WtE facilities using sorted feedstock (RDF) are critical to reduce potential adverse health (cancer and non-cancer) impacts, due to lower hazardous combustion-related emissions, compared to landfill or unsorted incineration. Poorly fed WtE facilities may emit concentrated toxins with serious potential health risks, such as dioxins/furans and heavy metals; these toxins may remain problematic in bottom ash as a combustion by-product. Most modelling studies estimate that electricity (per unit) generated from WtE generally emits less health-relevant air pollutants (also less greenhouse gases) than from combustion of fossil fuels (e.g. coal). Some modelled estimates vary due to model sensitivity for type of waste processed, model inputs used, and facility operational conditions. We conclude that rigorous assessment (e.g. HRA including sensitivity analyses) of WtE facility/technological characteristics and refuse type used is necessary when planning/proposing facilities to protect human health as the technology is adopted worldwide.
Journal Article
Comparison of blood and lymph node cells after intramuscular injection with HIV envelope immunogens
Harnessing CD4+ T cell help in the lymph nodes through rational antigen design could enhance formation of broadly neutralizing antibodies (bNAbs) during experimental HIV immunization. This process has remained hidden due to difficulty with direct study, with clinical studies instead focusing on responses in the blood as a proxy for the secondary lymphoid tissue.
To address this, lymph node cells (LNC) were collected using ultrasound guided fine needle aspiration of axillary lymph nodes from 11 HIV negative participants in an experimental HIV immunogen study (European AIDS Vaccine Initiative EAVI2020_01 study, NCT04046978). Cells from lymph node and blood (PBMC), were collected after intramuscular injection with HIV Env Mosaic immunogens based on HIV Envelope glycoprotein and combined with a liposomal toll-like receptor-4 adjuvant; monophosphoryl lipid A. Simultaneously sampled cells from both blood and lymph node in the same donors were compared for phenotype, function, and antigen-specificity.
Unsupervised cluster analysis revealed tissue-specific differences in abundance, distribution, and functional response of LNC compared with PBMC. Monocytes were virtually absent from LNC, which were significantly enriched for CD4+ T cells compared with CD8+ T cells. T follicular helper cells with germinal center features were enriched in LNC, which contained specific CD4+ and CD8+ T cell subsets including CD4+ T cells that responded after a single injection with HIV Env Mosaic immunogens combined with adjuvant. Tissue-specific differences in response to an MHC-II dependent superantigen, staphylococcal enterotoxin B, indicated divergence in antigen presentation function between blood and lymph node.
LNC are phenotypically and functionally distinct from PBMC, suggesting that whole blood is only a limited proxy of the T cell lymphatic response to immunization. HIV-specific CD4+ T cells in the lymph node are rapidly inducible upon experimental injection with HIV immunogens. Monitoring evolution of CD4+ T cell memory in LNC with repeated experimental HIV immunization could indicate the strategies most likely to be successful in inducing HIV-specific bNAbs.
Journal Article