Patients as researchers - innovative experiences in UK National Health Service research

Consumer involvement is an established priority in UK health and social care service development and research. To date, little has been published describing the process of consumer involvement and assessing ‘consumers’ contributions to research. This paper provides a practical account of the effective incorporation of consumers into a research team, and outlines the extent to which they can enhance the research cycle; from project development and conduct, through data analysis and interpretation, to dissemination. Salient points are illustrated using the example of their collaboration in a research project. Of particular note were consumers’ contributions to the development of an ethically enhanced, more robust project design, and enriched data interpretation, which may not have resulted had consumers not been an integral part of the research team

Case-mix fails to explain variation in mastectomy rates: management of screen-detected breast cancer in a UK region 1997–2003

Wide variation in the surgical management of breast cancer exists at hospital, regional, national and international level. To demonstrate whether variation in surgical practice observed at aggregate level between breast units persists following adjustment for case-mix, individual patient-level data from the Trent Breast Screening Programme Quality Assurance database (1997–2003) was analysed. Expected case-mix adjusted mastectomy rates were derived by logistic regression using the variables tumour size, site and grade, patient age and year of presentation, employing the region's overall case-mix adjusted practice as the reference population. The region's 11 breast screening units detected 5109 (3989 invasive) surgically managed primary breast cancers over the 6-year period. A total of 1828 mastectomies (Mx) were performed (Mx rate 35.8%, 95% confidence interval: 34.5–37.1%). Significant variation in mastectomy rates were observed between units (range 25–45%, P<0.0001), and persists following case-mix adjustment (P<0.0001). Two-fold variation in observed to expected unit mastectomy rate coefficient is demonstrated overall (range 0.66–1.36), increasing to almost four-fold variation in cancers less than 15 mm diameter (range 0.55–1.95). Significant variation in surgery for screen-detected primary breast cancer is not explained by case-mix. Further research is required to investigate potential patient and professional causative factors

Radiographers and COVID-19 pneumonia: diagnostic performance using CO-RADS

Introduction: A more structured role of radiographers is advisable to speed up the management of patients with suspected COVID-19. The purpose of our study was to evaluate the diagnostic performance of radiographers in the detection of COVID-19 pneumonia on chest CT using CO-RADS descriptors. Methods: CT images of patients who underwent RT-PCR and chest CT due to COVID-19 suspicion between March and July 2020 were analysed retrospectively. Six readers, including two radiologists, two highly experienced radiographers and two less experienced radiographers, independently scored each CT using the CO-RADS lexicon. ROC curves were used to investigate diagnostic accuracy, and Fleiss’κ statistics to evaluate inter-rater agreement. Results: 714 patients (419 men; 295 women; mean age: 64 years ±19SD) were evaluated. CO-RADS&gt; 3 was identified as optimal diagnostic threshold. Highly experienced radiographers achieved an average sensitivity of 58.7% (95%CI: 52.5–64.7), an average specificity of 81.8% (95%CI: 77.9–85.2), and a mean AUC of 0.72 (95%CI: 0.68–0.75). Among less experienced radiographers, an average sensitivity of 56.3% (95%CI: 50.1–62.2) and an average specificity of 81.5% (95%CI: 77.6–84.9) were observed, with a mean AUC of 0.71 (95%CI: 0.68–0.74). Consultant radiologists achieved an average sensitivity of 60.0% (95%CI: 53.7–65.8), an average specificity of 81.7% (95%CI: 77.8–85.1), and a mean AUC of 0.73 (95%CI: 0.70–0.77). Conclusion: Radiographers can adequately recognise the classic appearances of COVID-19 on CT, as described by the CO-RADS assessment scheme, in a way comparable to expert radiologists. Implications for practice: Radiographers, as the first healthcare professionals to evaluate CT images in patients with suspected SARS-CoV-2 infection, could diagnose COVID-19 pneumonia by means of a categorical reporting scheme at CT in a reliable way, hence playing a primary role in the early management of these patients

Diagnostic accuracy and interobserver variability of CO-RADS in patients with suspected coronavirus disease-2019: a multireader validation study

Objective: To conduct a multireader validation study to evaluate the interobserver variability and the diagnostic accuracy for the lung involvement by COVID-19 of COVID-19 Reporting and Data System (CO-RADS) score. Methods: This retrospective study included consecutive symptomatic patients who underwent chest CT and reverse transcriptase-polymerase chain reaction (RT-PCR) from March 2020 to May 2020 for suspected COVID-19. Twelve readers with different levels of expertise independently scored each CT using the CO-RADS scheme for detecting pulmonary involvement by COVID-19. Receiver operating characteristic (ROC) curves were computed to investigate diagnostic yield. Fleiss’ kappa statistics was used to evaluate interreader agreement. Results: A total of 572 patients (mean age, 63 ± 20 [standard deviation]; 329 men; 142 patients with COVID-19 and 430 patients without COVID-19) were evaluated. There was a moderate agreement for CO-RADS rating among all readers (Fleiss’ K = 0.43 [95% CI 0.42–0.44]) with a substantial agreement for CO-RADS 1 category (Fleiss’ K = 0.61 [95% CI 0.60–0.62]) and moderate agreement for CO-RADS 5 category (Fleiss’ K = 0.60 [95% CI 0.58–0.61]). ROC analysis showed the CO-RADS score ≥ 4 as the optimal threshold, with a cumulative area under the curve of 0.72 (95% CI 66–78%), sensitivity 61% (95% CI 52–69%), and specificity 81% (95% CI 77–84%). Conclusion: CO-RADS showed high diagnostic accuracy and moderate interrater agreement across readers with different levels of expertise. Specificity is higher than previously thought and that could lead to reconsider the role of CT in this clinical setting. Key Points: • COVID-19 Reporting and Data System (CO-RADS) demonstrated a good diagnostic accuracy for lung involvement by COVID-19 with an average AUC of 0.72 (95% CI 67–75%). • When a threshold of ≥ 4 was used, sensitivity and specificity were 61% (95% CI 52–69%) and 81% (95% CI 76–84%), respectively. • There was an overall moderate agreement for CO-RADS rating across readers with different levels of expertise (Fleiss’ K = 0.43 [95% CI 0.42–0.44])

Uncertainties in the Anti-neutrino Production at Nuclear Reactors

Anti-neutrino emission rates from nuclear reactors are determined from thermal power measurements and fission rate calculations. The uncertainties in these quantities for commercial power plants and their impact on the calculated interaction rates in electron anti-neutrino detectors is examined. We discuss reactor-to-reactor correlations between the leading uncertainties and their relevance to reactor anti-neutrino experiments.Comment: Submitted to Phys Rev

On the alleged simplicity of impure proof

Roughly, a proof of a theorem, is “pure” if it draws only on what is “close” or “intrinsic” to that theorem. Mathematicians employ a variety of terms to identify pure proofs, saying that a pure proof is one that avoids what is “extrinsic,” “extraneous,” “distant,” “remote,” “alien,” or “foreign” to the problem or theorem under investigation. In the background of these attributions is the view that there is a distance measure (or a variety of such measures) between mathematical statements and proofs. Mathematicians have paid little attention to specifying such distance measures precisely because in practice certain methods of proof have seemed self- evidently impure by design: think for instance of analytic geometry and analytic number theory. By contrast, mathematicians have paid considerable attention to whether such impurities are a good thing or to be avoided, and some have claimed that they are valuable because generally impure proofs are simpler than pure proofs. This article is an investigation of this claim, formulated more precisely by proof- theoretic means. After assembling evidence from proof theory that may be thought to support this claim, we will argue that on the contrary this evidence does not support the claim

Genomic variation in baboons from central Mozambique unveils complex evolutionary relationships with other Papio species

Background: Gorongosa National Park in Mozambique hosts a large population of baboons, numbering over 200 troops. Gorongosa baboons have been tentatively identified as part of Papio ursinus on the basis of previous limited morphological analysis and a handful of mitochondrial DNA sequences. However, a recent morphological and morphometric analysis of Gorongosa baboons pinpointed the occurrence of several traits intermediate between&nbsp;P. ursinus&nbsp;and&nbsp;P. cynocephalus, leaving open the possibility of past and/or ongoing gene flow in the baboon population of Gorongosa National Park.&nbsp;In order to investigate the evolutionary history of baboons in Gorongosa, we generated high and low coverage whole genome sequence data of Gorongosa baboons and compared it to available&nbsp;Papio&nbsp;genomes. Results: We confirmed that&nbsp;P. ursinus&nbsp;is the species closest to Gorongosa baboons. However, the Gorongosa baboon genomes share more derived alleles with&nbsp;P. cynocephalus&nbsp;than&nbsp;P. ursinus&nbsp;does, but no recent gene flow between&nbsp;P. ursinus&nbsp;and&nbsp;P. cynocephalus&nbsp;was detected when available&nbsp;Papio&nbsp;genomes were analyzed. Our results, based on the analysis of autosomal, mitochondrial and Y chromosome data, suggest complex, possibly male-biased, gene flow between Gorongosa baboons and&nbsp;P. cynocephalus, hinting to direct or indirect contributions from baboons belonging to the “northern”&nbsp;Papio clade, and signal the presence of population structure within&nbsp;P. ursinus. Conclusions: The analysis of genome data generated from baboon samples collected in central Mozambique highlighted a complex set of evolutionary relationships with other baboons. Our results provided new insights in the population dynamics that have shaped baboon diversity

Functional Characterization of EngAMS, a P-Loop GTPase of Mycobacterium smegmatis

Bacterial P-loop GTPases belong to a family of proteins that selectively hydrolyze a small molecule guanosine tri-phosphate (GTP) to guanosine di-phosphate (GDP) and inorganic phosphate, and regulate several essential cellular activities such as cell division, chromosomal segregation and ribosomal assembly. A comparative genome sequence analysis of different mycobacterial species indicates the presence of multiple P-loop GTPases that exhibit highly conserved motifs. However, an exact function of most of these GTPases in mycobacteria remains elusive. In the present study we characterized the function of a P-loop GTPase in mycobacteria by employing an EngA homologue from Mycobacterium smegmatis, encoded by an open reading frame, designated as MSMEG_3738. Amino acid sequence alignment and phylogenetic analysis suggest that MSMEG_3738 (termed as EngAMS) is highly conserved in mycobacteria. Homology modeling of EngAMS reveals a cloverleaf structure comprising of α/β fold typical to EngA family of GTPases. Recombinant EngAMS purified from E. coli exhibits a GTP hydrolysis activity which is inhibited by the presence of GDP. Interestingly, the EngAMS protein is co-eluted with 16S and 23S ribosomal RNA during purification and exhibits association with 30S, 50S and 70S ribosomal subunits. Further studies demonstrate that GTP is essential for interaction of EngAMS with 50S subunit of ribosome and specifically C-terminal domains of EngAMS are required to facilitate this interaction. Moreover, EngAMS devoid of N-terminal region interacts well with 50S even in the absence of GTP, indicating a regulatory role of the N-terminal domain in EngAMS-50S interaction

DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity

DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation