Confidence intervals for robust estimates of measurement uncertainty

Uncertainties arising at different stages of a measurement process can be estimated using Analysis of Variance (ANOVA) on duplicated measurements. In some cases it is also desirable to calculate confidence intervals for these uncertainties. This can be achieved using probability models that assume the measurement data are normally distributed. However, it is often the case in practice that a set of otherwise normally distributed measurement values is contaminated by a small number of outlying values, which may have a disproportionate effect on the variances calculated using the ‘classical’ form of ANOVA. In this case, robust ANOVA methods are able to provide variance estimates that are much closer to the parameters of the underlying normal distributions. A method using bootstrapping to calculate confidence intervals from robust estimates of variances is proposed and evaluated, and is shown to work well when the number of outlying values is small. The method has been implemented in a Visual Basic program

Optimising in situ gamma measurements to identify the presence of radioactive particles in land areas

High-coverage in situ surveys with gamma detectors are the best means of identifying small hotspots of activity, such as radioactive particles, in land areas. Scanning surveys can produce rapid results, but the probabilities of obtaining false positive or false negative errors are often unknown, and they may not satisfy other criteria such as estimation of mass activity concentrations. An alternative is to use portable gamma-detectors that are set up at a series of locations in a systematic sampling pattern, where any positive measurements are subsequently followed up in order to determine the exact location, extent and nature of the target source. The preliminary survey is typically designed using settings of detector height, measurement spacing and counting time that are based on convenience, rather than using settings that have been calculated to meet requirements. This paper introduces the basis of a repeatable method of setting these parameters at the outset of a survey, for pre-defined probabilities of false positive and false negative errors in locating spatially small radioactive particles in land areas. It is shown that an un-collimated detector is more effective than a collimated detector that might typically be used in the field

Adoption of technology enabled care to support the management of children and teenagers in rheumatology services: a protocol for a mixed-methods systematic review

Introduction COVID-19 catalysed a rapid move to provide care away from the hospital using online communication platforms. Technology enabled care (TEC) continues to be an important driver in progressing future healthcare services. Due to the complex and chronic nature of conditions seen within paediatric rheumatology, TEC may lead to better outcomes. Despite some growth in published literature into the adoption of TEC in paediatric rheumatology, there is limited synthesis. The aim of this review is to provide a comprehensive understanding and evaluation of the adoption of TEC by patients in paediatric rheumatology services, to establish best practices. Methods and analysis This proposed mixed-methods systematic review will be conducted by searching a wide variety of healthcare databases, grey literature resources and associated charities and societies, for articles reported in English language. Data extraction will include population demographics, technology intervention, factors affecting adoption of intervention and consequent study outcomes. A parallel-results convergent synthesis design is planned, with independent syntheses of quantitative and qualitative data, followed by comparison of the findings of each synthesis using a narrative approach. Normalisation process theory will be used to identify, characterise and explain implementation factors. The quality of included articles will be assessed using the Mixed Methods Appraisal Tool for research papers and the Authority, Accuracy, Coverage, Objectivity, Date, Significance checklist for grey literature. Overall confidence in quality and strength of evidence will be assessed using the Confidence in the Evidence from Reviews of Qualitative Research tool. Ethics and dissemination Ethical approval is not required due to the nature of this mixed-methods systematic review. The findings will be disseminated via a peer-reviewed journal, relevant conferences and any other methods (eg, via NHS Trust or NIHR YouTube channels) as advised by paediatric rheumatology patients

P20-19 LB. Extensive HLA-driven viral diversity following a single-source HIV-1 outbreak in rural China

Background: High rates of mutation in HIV infected individual allow the virus to adapt rapidly in vivo to selective forces such as anti-retroviral therapy (ART) and host immune pressure. This provides an opportunity to determine the relative contribution of different components of the immune response to HIV-1 infection in driving viral diversity, which may also facilitate assessment of their role in controlling viral replication. It is accepted that HIV-1-specific cytotoxic T-lymphocytes (CTL) may drive the selection of viral variants that can escape T-cell recognition but the extent of this selective pressure has been controversial. Methods: Two digit HLA typing; ELISPOT assay; HIV-1 sequence analysis; HIV sequence clustering and phylogenetic analysis of HLA associations using the neighbour-joining method, S-Plus 8.0, “Partitioning around medoids” (PAM) method and Stratification analysis by Mantel-Haenszel tests Results: Here we describe the consequences of HLA-associated selection on viral diversity in the main targets of T-cell recognition following an outbreak of HIV-1 in a cohort of 258 former plasma donors in rural China. The surprising finding that all the donors appear to have been infected with the same strain of clade B HIV-1 ensured that the analysis was not confounded by “founder effect”. At least 32.63% (232/711) of the mutations in the gag, pol and nef genes leading to amino acid substitutions were associated with class I HLA molecules: of these, 27.16% (63/232) were found within or close to known CD8+ T-cell epitopes. Conclusion: Taken together our data confirm that CD8+ T-cell pressure has a major impact on HIV-1 viral diversity and represent an important element of viral control in the infected host

Robust observational constraint of uncertain aerosol processes and emissions in a climate model and the effect on aerosol radiative forcing

The effect of observational constraint on the ranges of uncertain physical and chemical process parameters was explored in a global aerosol–climate model. The study uses 1 million variants of the Hadley Centre General Environment Model version 3 (HadGEM3) that sample 26 sources of uncertainty, together with over 9000 monthly aggregated grid-box measurements of aerosol optical depth, PM2.5, particle number concentrations, sulfate and organic mass concentrations. Despite many compensating effects in the model, the procedure constrains the probability distributions of parameters related to secondary organic aerosol, anthropogenic SO2 emissions, residential emissions, sea spray emissions, dry deposition rates of SO2 and aerosols, new particle formation, cloud droplet pH and the diameter of primary combustion particles. Observational constraint rules out nearly 98 % of the model variants. On constraint, the ±1σ (standard deviation) range of global annual mean direct radiative forcing (RFari) is reduced by 33 % to −0.14 to −0.26 W m−2, and the 95 % credible interval (CI) is reduced by 34 % to −0.1 to −0.32 W m−2. For the global annual mean aerosol–cloud radiative forcing, RFaci, the ±1σ range is reduced by 7 % to −1.66 to −2.48 W m−2, and the 95 % CI by 6 % to −1.28 to −2.88 W m−2. The tightness of the constraint is limited by parameter cancellation effects (model equifinality) as well as the large and poorly defined “representativeness error” associated with comparing point measurements with a global model. The constraint could also be narrowed if model structural errors that prevent simultaneous agreement with different measurement types in multiple locations and seasons could be improved. For example, constraints using either sulfate or PM2.5 measurements individually result in RFari±1σ ranges that only just overlap, which shows that emergent constraints based on one measurement type may be overconfident

Mitochondrial DNA depletion induces innate immune dysfunction rescued by interferon-γ

Monocytes from sepsis patients have mitochondrial DNA (mtDNA) depletion and immune deactivation. Here we find that THP-1 cell immune responses are impaired by experimentally depleting mtDNA, through dysregulated immune signalling, and rescued by interferon-γ treatment

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in ‘Creating Clinical Guidelines: Our Protocol’ by the British Society for Rheumatology

HLA Class I and Class II Associations in Dengue Viral Infections in a Sri Lankan Population

BACKGROUND: HLA class I and class II alleles have been shown to be associated with the development of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in different populations. However, the majority of studies have been based on limited numbers of patients. In this study we aimed to investigate the HLA-class I and class II alleles that are positively and negatively associated with the development of DSS in a cohort of patients with DHF and also the alleles associated with development of DHF during primary dengue infections in a Sri Lankan population. METHODOLOGY/PRINCIPAL FINDINGS: The allele frequencies of HLA class I and class II alleles were compared in 110 patients with DHF and 119 individuals from the population who had never reported a symptomatic dengue infection at the time of recruitment. We found that HLA-A*31 (corrected P = 0.01) and DRB1*08 (corrected P = 0.009) were associated with susceptibility to DSS when infected with the dengue virus, during secondary dengue infection. The frequency of DRB1*08 allele was 28.7 times higher than in the normal population in patients with DSS. HLA-A*31 allele was increased 16.6 fold in DHF who developed shock when compared to those who did not develop shock. A*24 (corrected P = 0.03) and DRB1*12 (corrected P = 0.041) were strongly associated with the development of DHF during primary dengue infection. CONCLUSIONS/SIGNIFICANCE: These data suggest that certain HLA alleles confer susceptibility/protection to severe dengue infections. As T cell epitope recognition depend on the HLA type of an individual, it would be now important to investigate how epitope specific T cells associate with primary and secondary dengue infections and in severe dengue infections

Nile red fluorescence screening facilitating neutral lipid phenotype determination in budding yeast, Saccharomyces cerevisiae, and the fission yeast Schizosaccharomyces pombe.

Investigation of yeast neutral lipid accumulation is important for biotechnology and also for modelling aberrant lipid metabolism in human disease. The Nile red (NR) method has been extensively utilised to determine lipid phenotypes of yeast cells via microscopic means. NR assays have been used to differentiate lipid accumulation and relative amounts of lipid in oleaginous species but have not been thoroughly validated for phenotype determination arising from genetic modification. A modified NR assay, first described by Sitepu et al. (J Microbiol Methods 91:321-328, 2012), was able to detect neutral lipid changes in Saccharomyces cerevisiae deletion mutants with sensitivity similar to more advanced methodology. We have also be able to, for the first time, successfully apply the NR assay to the well characterised fission yeast Schizosaccharomyces pombe, an increasingly important organism in biotechnology. The described NR fluorescence assay is suitable for increased throughput and rapid screening of genetically modified strains in both the biotechnology industry and for modelling ectopic lipid production for a variety of human diseases. This ultimately negates the need for labour intensive and time consuming lipid analyses of samples that may not yield a desirable lipid phenotype, whilst genetic modifications impacting significantly on the cellular lipid phenotype can be further promoted for more in depth analyses