Search

Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC).To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC.HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital.Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min.The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat.A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control).CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment.The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

Holbein Gardens is an office redevelopment project in London being delivered within the UKGBC’s net-zero carbon buildings framework. The project involves the refurbishment of a 1980s concrete-framed building and construction of a one-storey vertical extension. This article describes the design team's approach to minimising the embodied carbon of the project, with a particular focus on the use of reclaimed steel. The article discusses several considerations relating to the reuse of steelwork, including sourcing, design challenges, testing and insurance, and aesthetics. The use of 25t of reclaimed steel on the project is estimated to have saved 35t of carbon compared with new steelwork. An average figure of 0.3kgCO2e/kg (stages A1–A5) has been calculated for the reused steelwork, helping to deliver an overall figure of just 65kgCO2e/m2 for the structural embodied carbon of the building (excluding the facade).

Background Indigenous young people worldwide possess unique protective factors that support wellbeing. However, they experience mental illness at higher rates than their non-indigenous counterparts. Digital mental health (dMH) resources can increase access to structured, timely, and culturally tailored mental health interventions by reducing structural and attitudinal barriers to accessing treatment. The involvement of Indigenous young people in dMH resource development is recommended, however, no guidelines exist on how this can best be facilitated. Methods A scoping review examining processes to involve Indigenous young people in developing or evaluating dMH interventions was conducted. Studies reported between 1990–2022 involving Indigenous young people aged 12–24 years, originating from Canada, the United States of America, New Zealand, and Australia, in the development or evaluation of dMH interventions were eligible for inclusion. Following a three-step search process, four electronic databases were searched. Data were extracted, synthesised, and described under three categories: dMH intervention attributes, study design, and alignment with research best practice. Best practice recommendations for Indigenous research and participatory design were identified and synthesised. Included studies were assessed against these recommendations. Consultation with two Senior Indigenous Research Officers ensured Indigenous worldviews informed analysis. Results Nineteen studies describing ten dMH interventions met inclusion criteria. Studies included formative, design, pilot, and efficacy studies. Overall, most included studies demonstrated a high degree of Indigenous governance, capacity building, and community benefit. All studies adapted their research processes to ensure that local community protocols were followed and most aligned these within an Indigenous research paradigm. Formal agreements regarding existing and created intellectual property and implementation evaluations were rare. Outcomes were the primary focus of reporting, with limited detailed descriptions of governance and decision-making processes or strategies for managing predictable tensions between co-design stakeholders. Conclusions This study identified best practice recommendations in participatory design with Indigenous young people and evaluated the current literature against these criteria. Common gaps were evident in the reporting of study processes. Consistent, in-depth reporting is needed to allow assessment of best practice approaches for this hard-to-reach population. An emergent best practice model, informed by our findings, for guiding the involvement of Indigenous young people in the design and evaluation of dMH tools is presented. Systematic review registration: available via osf.io/2nkc6

What are the politics of picturing the end times? This online, open-access essay collection explores how art and visual culture has imagined Armageddon across the globe from the eighteenth century to the present. The book considers the ways in which apocalypticism has been contested by social conservatives and progressives, drawn on to perpetuate or challenge structures of power. Contributors discuss homophobia and queer utopias, climate change and nuclear anxieties, folk monsters and fears of revolt, imperial violence and anti-colonial imagination, the staging of conflict and disaster, popular culture and fascism, faith and denial in church congregations. Each reveal how a series of contradictions underpin the end times: beginnings and endings, annihilation and revelation.

Tundra ecosystems hold large stocks of soil organic matter (SOM), likely due to low temperatures limiting rates of microbial SOM decomposition more than those of SOM accumulation from plant primary productivity and microbial necromass inputs. Here we test the hypotheses that distinct tundra vegetation types and their carbon supply to characteristic rhizosphere microbes determine SOM cycling independent of temperature. In the subarctic Scandes, we used a three-way factorial design with paired heath and meadow vegetation at each of two elevations, and with each combination of vegetation type and elevation subjected during one growing season to either ambient light (i.e., ambient plant productivity), or 95% shading (i.e., reduced plant productivity). We assessed potential above- and belowground ecosystem linkages by uni- and multivariate analyses of variance, and structural equation modelling. We observed direct coupling between tundra vegetation type and microbial community composition and function, which underpinned the ecosystem's potential for SOM storage. Greater primary productivity at low elevation and ambient light supported higher microbial biomass and nitrogen immobilisation, with lower microbial mass-specific enzymatic activity and SOM humification. Congruently, larger SOM at lower elevation and in heath sustained fungal-dominated microbial communities, which were less substrate-limited, and invested less into enzymatic SOM mineralisation, owing to a greater carbon-use efficiency (CUE). Our results highlight the importance of tundra plant community characteristics (i.e., productivity and vegetation type), via their effects on soil microbial community size, structure and physiology, as essential drivers of SOM turnover. The here documented concerted patterns in above- and belowground ecosystem functioning is strongly supportive of using plant community characteristics as surrogates for assessing tundra carbon storage potential and its evolution under climate and vegetation changes. Published version The study benefitted from internal CIRC funding for the use of the Abisko Scientific Research Station, kindly operated by the Swedish Polar Research Secretariat. K.G. was further supported by funding from the Swiss National Science Foundation (grant no. PZ00P2_174047).

We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.

The study of fission yields has a major impact on the characterization and understanding of the fission process and its applications. Fission yield evaluations represent the synthesis of experimental and theoretical knowledge in order to perform the best estimation of independent fission yields. Today, the lack of correlations between the different fission observables induces several inconsistencies in the evaluations. Different works proposed to estimate the correlations of the independent fission yields satisfying the consistency to the chain yield evaluations. Nevertheless, none of them introduces a prior correlations of the independent and chain evaluations in the evaluation process. Covariance matrix of fission yields depends on the evaluation method used according to the kinds of existing measurements. The consistency is deeply entangled to the statistical agreement between each dataset considering the covariance of measurements. Moreover, covariance of model parameters does not represent the only contribution to the evaluation covariance matrix. Thus, a new evaluation process is crucial to provide a complete and coherent evaluation file. The LEPh Laboratory of CEA Cadarache is developing this program for the future version of the JEFF-library.

A detailed description of the changes that occur during the formation of protein corona represents a fundamental question in nanoscience, given that it not only impacts the behaviour of nanoparticles but also affects the bound proteins. Relevant questions include whether proteins selectively bind particles, whether a specific orientation is preferred for binding, and whether particle binding leads to a modulation of their 3D fold. For allergens, it is important to answer these questions given that all these effects can modify the allergenic response of atopic individuals. These potential impacts on the bound allergen are closely related to the specific properties of the involved nanoparticles. One important property influencing the formation of protein corona is the nanotopography of the particles. Herein, we studied the effect of nanoparticle porosity on allergen binding using mesoporous and non-porous SiO2 NPs. We investigated (i) the selectivity of allergen binding from a mixture such as crude pollen extract, (ii) whether allergen binding results in a preferred orientation, (iii) the influence of binding on the conformation of the allergen, and (iv) how the binding affects the allergenic response. Nanotopography was found to play a major role in the formation of protein corona, impacting the physicochemical and biological properties of the NP-bound allergen. The porosity of the surface of the SiO2 nanoparticles resulted in a higher binding capacity with pronounced selectivity for (preferentially) binding the major birch pollen allergen Bet v 1. Furthermore, the binding of Bet v 1 to the mesoporous rather than the non-porous SiO2 nanoparticles influenced the 3D fold of the protein, resulting in at least partial unfolding. Consequently, this conformational change influenced the allergenic response, as observed by mediator release assays employing the sera of patients and immune effector cells. For an in-depth understanding of the bio-nano interactions, the properties of the particles need to be considered not only regarding the identity and morphology of the material, but also their nanotopography, given that porosity may greatly influence the structure, and hence the biological behaviour of the bound proteins. Thus, thorough structural investigations upon the formation of protein corona are important when considering immunological outcomes, as particle binding can influence the allergenic response elicited by the bound allergen., A detailed description of the changes that occur during the formation of protein corona represents a fundamental question in nanoscience, given that it not only impacts the behaviour of nanoparticles but also affects the bound proteins.

This chapter looks into Wilgefortis, a female bearded martyr. It starts with the gender confusion of a triptych by Hieronymus Bosch, which is currently exhibited in the Gallerie dell'Accademia in Venice. Arguments rose in favor of the identification of Bosch's crucified figure with Wilgefortis. The beard became a crucial attribute in the surviving images of Wilgefortis. The threat posed by female facial hair to aesthetic, social, and psychic norms may explain efforts on the part of at least some artists to render Wilgefortis' beard insubstantially. The chapter explains how the term “trans” encompasses the transition of both trans men and trans women without perceiving them to a gender binary.

Summary Background Accurately estimating HIV disease progression and retention on antiretroviral therapy (ART) can help inform interventions to control HIV microepidemics and mathematical models used to inform health-resource allocation decisions. Our objective was to estimate the monthly probabilities of on-ART CD4 T-cell count progression, mortality, ART dropout, and ART reinitiation using a continuous-time multistate Markov model. We also aimed to validate health-state transition probability estimates to ensure they accurately reproduced the regional HIV microepidemics across the USA. Methods In our modelling study, we considered a cohort of patients from the HIV Research Network, a consortium of 17 adult and paediatric HIV-care providers located in the northeastern (n=8), southern (n=5), and western (n=4) regions of the USA. Individuals aged 15 years or older who were in HIV care (defined as one CD4 test and one HIV-care visit in a calendar year period) with at least one ART prescription between Jan 1, 2010, and Dec 31, 2015, were included in the analysis. We used continuous-time multistate Markov models to estimate transitions between CD4 strata and between on-ART and off-ART states. We examined and adjusted for differences in probability of transition by region, race or ethnicity, sex, HIV risk group, and other baseline clinical indicators. Findings The median age of the 32 242 individuals included in the analysis was 44 years (interquartile range 35–51). Over a median follow-up of 4·9 years (2·6–6·0), 8614 (26·7%) of 32 242 people interrupted ART and 1325 (4·1%) of 32 242 people died. Women, men who have sex with men, and individuals with no previous ART experience had greater increases in CD4 cell counts, whereas black people and people who inject drugs had increased probabilities of ART dropout and faster disease progression. Regardless of CD4 strata, individuals had increased hazard for ART dropout if they were from the south (adjusted hazard ratio [aHR] range from 1·91, 95% CI 1·71–2·13, to 2·45, 2·29–2·62) or the west (aHR range from 1·29, 1·10–1·51, to 1·66, 1·51–1·82) of the USA, compared with individuals from the northeast USA. Interpretation Our results show heterogeneities in disease progression during ART and probability of ART retention across race and ethnicity, HIV risk groups, and regions. These differences should be viewed as targets for intervention and should be incorporated in mathematical models of regional HIV microepidemics in the USA. Funding US National Institutes of Health, Agency for Healthcare Research and Quality, and Health Resources and Services Administration.

The years immediately following 1996, when the standardized implementation of antiretroviral therapy as responsive AIDS treatment took place across the developed Global North, have thus far been ch...

Background Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D. Objectives We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration. Methods We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere. Results GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 x 10(-6)) and serum 25(OH)D concentration from 64.4 +/- 20.9 nmol/L to 68.5 +/- 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063). Conclusions We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries.

Background Current diagnostic blood tests for prostate cancer (PCa) are unreliable for the early stage disease, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance of negative biopsies in men with PCa. Predicting the risk of PCa is pivotal for making an informed decision on treatment options as the 5-year survival rate in the low-risk group is more than 95% and most men would benefit from surveillance rather than active treatment. Three-dimensional genome architecture and chromosome structures undergo early changes during tumourigenesis both in tumour and in circulating cells and can serve as a disease biomarker. Methods In this prospective study we screened whole blood of newly diagnosed, treatment naïve PCa patients (n = 140) and cancer-free controls (n = 96) for the presence of 14,241 chromosomal loops in the loci of 425 genes. Results We have detected specific chromosome conformation changes in the loci of ETS1, MAP3K14, SLC22A3 and CASP2 genes in peripheral blood from PCa patients yielding PCa detection with 80% sensitivity and 80% specificity. Further analysis between PCa risk groups yielded prognostic validation sets consisting of HSD3B2, VEGFC, APAF1, BMP6, ERG, MSR1, MUC1, ACAT1 and DAPK1 genes that achieved 80% sensitivity and 93% specificity stratifying high-risk category 3 vs low risk category 1 and 84% sensitivity and 89% specificity stratifying high risk category 3 vs intermediate risk category 2 disease. Conclusions Our results demonstrate specific chromosome conformations in the blood of PCa patients that allow PCa diagnosis and risk stratification with high sensitivity and specificity.

Additional file 2. Search terms.

Additional file 1. PRISMA-P 2015 Checklist.

ion haunts medieval art, both withdrawing figuration and suggesting elusive presence. How does it make or destroy meaning in the process? Does it suggest the failure of figuration, the faltering of iconography? Does medieval abstraction function because it is imperfect, incomplete, and uncorrected-and therefore cognitively, visually demanding? Is it, conversely, precisely about perfection? To what extent is the abstract predicated on theorization of the unrepresentable and imperceptible? Does medieval abstraction pit aesthetics against metaphysics, or does it enrich it, or frame it, or both? Essays in this collection explore these and other questions that coalesce around three broad themes: medieval abstraction as the untethering of the image from what it purports to represent; abstraction as a vehicle for signification; and abstraction as a form of figuration. Contributors approach the concept of medieval abstraction from a multitude of perspectives-formal, semiotic, iconographic, material, phenomenological, epistemological.

In order to explore opportunities for personalized and predictive health care, we collected serial clinical measurements, health surveys and multiomics profiles (genomics, proteomics, autoantibodies, metabolomics and gut microbiome) from 96 individuals. The participants underwent data-driven health coaching over a 16-month period with continuous digital monitoring of activity and sleep. Multiomics factor analysis resulted in an unsupervised, data-driven and integrated view of human health, revealing distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet and hormonal effects. The data revealed novel and previously uncovered associations between risk factors, molecular pathways, and quantitative lifestyle parameters. For example, ethinyl estradiol use had a distinct impact on metabolites, proteins and physiology. Multidimensional molecular and digital health signatures uncovered biological variability between people and quantitative effects of lifestyle changes, hence illustrating the value of the combined use of molecular and digital monitoring of human health.

Background Indigenous young people worldwide are at greater risk of developing mental health concerns due to ongoing inequity and disadvantage. Digital mental health (dMH) interventions are identified as a potential approach to improving access to mental health treatment for Indigenous youth. Although involvement in the development and evaluation of dMH resources is widely recommended, there is limited evidence to guide engagement of Indigenous young people in these processes. This scoping review aims to examine the methods used to involve Indigenous young people in the development or evaluation of dMH interventions. Methods Articles published in English, involving Indigenous young people (aged 10–24 years) in the development or evaluation of dMH interventions, originating from Australia, New Zealand, Canada and the USA will be eligible for inclusion. PubMed, Scopus and EBSCOhost databases (Academic Search Premiere, Computer and Applied Science complete, CINAHL, MEDLINE, APA PsychArticles, Psychology and Behavioural Sciences collection, APA PsychInfo) will be searched to identify eligible articles (from January 1990 onwards). Infomit and Google Scholar (limited to 200 results) will be searched for grey literature. Two reviewers will independently screen citations, abstracts and full-text articles. Study methods, methodologies, dMH intervention details, participant information and engagement, and dissemination methods will be extracted, analysed (utilising content analysis), and qualitatively assessed for alignment with best practice ethical guidelines for undertaking Indigenous health research. A narrative summary of findings will be presented. Reporting will follow the Consolidated Criteria for Strengthening Reporting of Health Research involving Indigenous peoples (CONSIDER) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines. Discussion To date, there are no reviews which analyse engagement of Indigenous young people in the development and evaluation of dMH interventions. This review will appraise alignment of current practice with best practice guidelines to inform future research. It will highlight appropriate methods for the engagement of young people in study processes, providing guidance for health practitioners, policy makers, and researchers working in the field of Indigenous youth and dMH. Systematic review registration Open Science Framework (osf.io/2nkc6).

Humans have always been in contact with natural airborne particles from many sources including biologic particulate matter (PM) which can exhibit allergenic properties. With industrialization, anthropogenic and combustion-derived particles have become a major fraction. Currently, an ever-growing number of diverse and innovative materials containing engineered nanoparticles (NPs) are being developed with great expectations in technology and medicine. Nanomaterials have entered everyday products including cosmetics, textiles, electronics, sports equipment, as well as food, and food packaging. As part of natural evolution humans have adapted to the exposure to particulate matter, aiming to protect the individual's integrity and health. At the respiratory barrier, complications can arise, when allergic sensitization and pulmonary diseases occur in response to particle exposure. Particulate matter in the form of plant pollen, dust mites feces, animal dander, but also aerosols arising from industrial processes in occupational settings including diverse mixtures thereof can exert such effects. This review article gives an overview of the allergic immune response and addresses specifically the mechanisms of particulates in the context of allergic sensitization, effector function and therapy. In regard of the first theme (i), an overview on exposure to particulates and the functionalities of the relevant immune cells involved in allergic sensitization as well as their interactions in innate and adaptive responses are described. As relevant for human disease, we aim to outline (ii) the potential effector mechanisms that lead to the aggravation of an ongoing immune deviation (such as asthma, chronic obstructive pulmonary disease, etc.) by inhaled particulates, including NPs. Even though adverse effects can be exerted by (nano)particles, leading to allergic sensitization, and the exacerbation of allergic symptoms, promising potential has been shown for their use in (iii) therapeutic approaches of allergic disease, for example as adjuvants. Hence, allergen-specific immunotherapy (AIT) is introduced and the role of adjuvants such as alum as well as the current understanding of their mechanisms of action is reviewed. Finally, future prospects of nanomedicines in allergy treatment are described, which involve modern platform technologies combining immunomodulatory effects at several (immuno-)functional levels.

Type I hypersensitivity reactions against environmental entities, i.e. allergens, are an ever growing problem, with increasing numbers of affected individuals in Western countries. In parallel, nanotechnology has been growing during the past decades, entering more and more areas of application in everyday life. Exposure to allergens may occur in a combined way with environmental particulate matter or (nano-)particles potentially abundant at the workplace. Such combinations may thus affect workers and consumers alike. The present study conceived a methodological and mechanistic approach based on recombinant allergen–SiO2 nanoparticle conjugates and the novel hAELVi cell line as two well-defined model systems to investigate the effects of co-exposure towards allergens and nanoparticles. We applied pristine nanoparticles, allergen–nanoparticle conjugates and unbound allergen under submerged and air–liquid interface conditions. The uptake kinetics and mechanisms, cellular localization and resulting immune responses were studied in hAELVi cells, a cell line derived from human alveolar epithelium showing the characteristics of type I epithelial cells. Modification in the uptake kinetics as well as an increase in pro-inflammatory cyto-/chemokine expression was observed under submerged conditions, but much less under air–liquid interface conditions. While for mechanistic investigations the submerged culture system still proved suitable, more robust and cost-effective, these culture conditions showed considerable deviations in cellular susceptibility observed under more realistic conditions.