Clinically contextualised ECG interpretation: the impact of prior clinical exposure and case vignettes on ECG diagnostic accuracy

Background ECGs are often taught without clinical context. However, in the clinical setting, ECGs are rarely interpreted without knowing the clinical presentation. We aimed to determine whether ECG diagnostic accuracy was influenced by knowledge of the clinical context and/or prior clinical exposure to the ECG diagnosis. Methods Fourth- (junior) and sixth-year (senior) medical students, as well as medical residents were invited to complete two multiple-choice question (MCQ) tests and a survey. Test 1 comprised 25 ECGs without case vignettes. Test 2, completed immediately thereafter, comprised the same 25 ECGs and MCQs, but with case vignettes for each ECG. Subsequently, participants indicated in the survey when last, during prior clinical clerkships, they have seen each of the 25 conditions tested. Eligible participants completed both tests and survey. We estimated that a minimum sample size of 165 participants would provide 80% power to detect a mean difference of 7% in test scores, considering a type 1 error of 5%. Results This study comprised 176 participants (67 [38.1%] junior students, 55 [31.3%] senior students, 54 [30.7%] residents). Prior ECG exposure depended on their level of training, i.e., junior students were exposed to 52% of the conditions tested, senior students 63.4% and residents 96.9%. Overall, there was a marginal improvement in ECG diagnostic accuracy when the clinical context was known (Cohen’s d = 0.35, p < 0.001). Gains in diagnostic accuracy were more pronounced amongst residents (Cohen’s d = 0.59, p < 0.001), than senior (Cohen’s d = 0.38, p < 0.001) or junior students (Cohen’s d = 0.29, p < 0.001). All participants were more likely to make a correct ECG diagnosis if they reported having seen the condition during prior clinical training, whether they were provided with a case vignette (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.24–1.71) or not (OR 1.58, 95% CI 1.35–1.84). Conclusion ECG interpretation using clinical vignettes devoid of real patient experiences does not appear to have as great an impact on ECG diagnostic accuracy as prior clinical exposure. However, exposure to ECGs during clinical training is largely opportunistic and haphazard. ECG training should therefore not rely on experiential learning alone, but instead be supplemented by other formal methods of instruction

SUBA: the Arabidopsis Subcellular Database

Knowledge of protein localisation contributes towards our understanding of protein function and of biological inter-relationships. A variety of experimental methods are currently being used to produce localisation data that need to be made accessible in an integrated manner. Chimeric fluorescent fusion proteins have been used to define subcellular localisations with at least 1100 related experiments completed in Arabidopsis. More recently, many studies have employed mass spectrometry to undertake proteomic surveys of subcellular components in Arabidopsis yielding localisation information for ∼2600 proteins. Further protein localisation information may be obtained from other literature references to analysis of locations (AmiGO: ∼900 proteins), location information from Swiss-Prot annotations (∼2000 proteins); and location inferred from gene descriptions (∼2700 proteins). Additionally, an increasing volume of available software provides location prediction information for proteins based on amino acid sequence. We have undertaken to bring these various data sources together to build SUBA, a SUBcellular location database for Arabidopsis proteins. The localisation data in SUBA encompasses 10 distinct subcellular locations, >6743 non-redundant proteins and represents the proteins encoded in the transcripts responsible for 51% of Arabidopsis expressed sequence tags. The SUBA database provides a powerful means by which to assess protein subcellular localisation in Arabidopsis ()

Age determination of the Lower Watrous red-beds of the Williston Basin, Saskatchewan, Canada

The age of the Lower Watrous red-beds, which host hydrocarbon reserves in the Williston Basin, along with equivalent formations in Manitoba (Lower Amaranth Formation) and the U.S.A. (Saude Member of the Spearfish Formation) is a controversial subject, with this succession being assigned ages from Mississippian to Middle Jurassic; a timespan of over 150 million years. Using existing published data and new geochemical analyses on the Watrous Formation, we present a Triassic age for the Lower Watrous red-beds. An established well-log correlation dates the Saude Member red-beds as post-Middle Permian. Some previously published geochemical and palynological data from equivalent formations are in agreement with this age, but several palaeomagnetic studies have provided conflicting results, with age assignments of Mississippian through to Late Triassic. Our study demonstrates the equivalency of the Saude Member and Lower Watrous red-beds by extending the well-log correlation north, from the U.S.A. into Saskatchewan. The combined new strontium, sulfur and oxygen isotopic analyses of isolated Lower Watrous anhydrite nodules are most consistent with an Early or Late Triassic age, which is in agreement with the well-log correlation and potassium-argon dating of a pre-red-beds impact structure. A Pennsylvanian age for the Lower Watrous red-beds is considered most unlikely

The Peculiar Debris Disk of HD 111520 as Resolved by the Gemini Planet Imager

Using the Gemini Planet Imager (GPI), we have resolved the circumstellar debris disk around HD 111520 at a projected range of ~30-100 AU in both total and polarized $H$-band intensity. The disk is seen edge-on at a position angle of ~165$^{\circ}$ along the spine of emission. A slight inclination or asymmetric warping are covariant and alters the interpretation of the observed disk emission. We employ 3 point spread function (PSF) subtraction methods to reduce the stellar glare and instrumental artifacts to confirm that there is a roughly 2:1 brightness asymmetry between the NW and SE extension. This specific feature makes HD 111520 the most extreme examples of asymmetric debris disks observed in scattered light among similar highly inclined systems, such as HD 15115 and HD 106906. We further identify a tentative localized brightness enhancement and scale height enhancement associated with the disk at ~40 AU away from the star on the SE extension. We also find that the fractional polarization rises from 10 to 40% from 0.5" to 0.8" from the star. The combination of large brightness asymmetry and symmetric polarization fraction leads us to believe that an azimuthal dust density variation is causing the observed asymmetry.Comment: 9 pages, 8 Figures, 1 table, Accepted to Ap

Plasmodium knowlesi Genome Sequences from Clinical Isolates Reveal Extensive Genomic Dimorphism.

Plasmodium knowlesi is a newly described zoonosis that causes malaria in the human population that can be severe and fatal. The study of P. knowlesi parasites from human clinical isolates is relatively new and, in order to obtain maximum information from patient sample collections, we explored the possibility of generating P. knowlesi genome sequences from archived clinical isolates. Our patient sample collection consisted of frozen whole blood samples that contained excessive human DNA contamination and, in that form, were not suitable for parasite genome sequencing. We developed a method to reduce the amount of human DNA in the thawed blood samples in preparation for high throughput parasite genome sequencing using Illumina HiSeq and MiSeq sequencing platforms. Seven of fifteen samples processed had sufficiently pure P. knowlesi DNA for whole genome sequencing. The reads were mapped to the P. knowlesi H strain reference genome and an average mapping of 90% was obtained. Genes with low coverage were removed leaving 4623 genes for subsequent analyses. Previously we identified a DNA sequence dimorphism on a small fragment of the P. knowlesi normocyte binding protein xa gene on chromosome 14. We used the genome data to assemble full-length Pknbpxa sequences and discovered that the dimorphism extended along the gene. An in-house algorithm was developed to detect SNP sites co-associating with the dimorphism. More than half of the P. knowlesi genome was dimorphic, involving genes on all chromosomes and suggesting that two distinct types of P. knowlesi infect the human population in Sarawak, Malaysian Borneo. We use P. knowlesi clinical samples to demonstrate that Plasmodium DNA from archived patient samples can produce high quality genome data. We show that analyses, of even small numbers of difficult clinical malaria isolates, can generate comprehensive genomic information that will improve our understanding of malaria parasite diversity and pathobiology

History-Dependent Mechanical Properties of Permeabilized Rat Soleus Muscle Fibers

AbstractPermeabilized rat soleus muscle fibers were subjected to repeated triangular length changes (paired ramp stretches/releases, 0.03 l0,±0.1 l0 s−1 imposed under sarcomere length control) to investigate whether the rate of stiffness recovery after movement increased with the level of Ca2+ activation. Actively contracting fibers exhibited a characteristic tension response to stretch: tension rose sharply during the initial phase of the movement before dropping slightly to a plateau, which was maintained during the remainder of the stretch. When the fibers were stretched twice, the initial phase of the response was reduced by an amount that depended on both the level of Ca2+ activation and the elapsed time since the first movement. Detailed analysis revealed three new and important findings. 1) The rates of stiffness and tension recovery and 2) the relative height of the tension plateau each increased with the level of Ca2+ activation. 3) The tension plateau developed more quickly during the second stretch at high free Ca2+ concentrations than at low. These findings are consistent with a cross-bridge mechanism but suggest that the rate of the force-generating power-stroke increases with the intracellular Ca2+ concentration and cross-bridge strain

Virchow: A Million-Slide Digital Pathology Foundation Model

Computational pathology uses artificial intelligence to enable precision medicine and decision support systems through the analysis of whole slide images. It has the potential to revolutionize the diagnosis and treatment of cancer. However, a major challenge to this objective is that for many specific computational pathology tasks the amount of data is inadequate for development. To address this challenge, we created Virchow, a 632 million parameter deep neural network foundation model for computational pathology. Using self-supervised learning, Virchow is trained on 1.5 million hematoxylin and eosin stained whole slide images from diverse tissue groups, which is orders of magnitude more data than previous works. When evaluated on downstream tasks including tile-level pan-cancer detection and subtyping and slide-level biomarker prediction, Virchow outperforms state-of-the-art systems both on internal datasets drawn from the same population as the pretraining data as well as external public datasets. Virchow achieves 93% balanced accuracy for pancancer tile classification, and AUCs of 0.983 for colon microsatellite instability status prediction and 0.967 for breast CDH1 status prediction. The gains in performance highlight the importance of pretraining on massive pathology image datasets, suggesting pretraining on even larger datasets could continue improving performance for many high-impact applications where limited amounts of training data are available, such as drug outcome prediction

Tissue-specific immunopathology in fatal COVID-19

Funding: Inflammation in COVID-19: Exploration of Critical Aspects of Pathogenesis (ICECAP) receives funding and support from the Chief Scientist Office (RapidResearch in COVID-19 programme [RARC-19] funding call, “Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis; COV/EDI/20/10” to D.A.D., C.D.L., C.D.R., J.K.B., and D.J.H.), LifeArc (through the University of Edinburgh STOPCOVID funding award to K.D., D.A.D., and C.D.L.), UK Research and Innovation (UKRI) (Coronavirus Disease [COVID-19] Rapid Response Initiative; MR/V028790/1 to C.D.L., D.A.D., and J.A.H.), and Medical Research Scotland (CVG-1722-2020 to D.A.D., C.D.L., C.D.R., J.K.B., and D.J.H.). C.D.L. is funded by a Wellcome Trust Clinical Career Development Fellowship(206566/Z/17/Z). J.K.B. and C.D.R. are supported by the Medical Research Council (grant MC_PC_19059) as part of the International Severe AcuteRespiratory Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC-4C). D.J.H., I.H.U., and M.E. are supported by the Industrial Centre for Artificial Intelligence Research in Digital Diagnostics. S.P. is supported by Kidney Research UK, and G.T. is supported by the Melville Trust for the Cure and Care of Cancer. Identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and sequencing work was supported by theU.S. Food and Drug Administration grant HHSF223201510104C (“Ebola Virus Disease: correlates of protection, determinants of outcome and clinicalmanagement”; amended to incorporate urgent COVID-19 studies) and contract 75F40120C00085 (“Characterization of severe coronavirus infection inhumans and model systems for medical countermeasure development and evaluation”; awarded to J.A.H.). J.A.H. is also funded by the Centre of Excellence in Infectious Diseases Research and the Alder Hey Charity. R.P.-R. is directly supported by the Medical Research Council Discovery Medicine North Doctoral Training Partnership. The group of J.A.H. is supported by the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England and in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.Rationale: In life-threatening Covid-19, corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of SARS-CoV-2 or an independent immunopathologic process is unknown. Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses, and the relationships between viral presence, inflammation, and organ injury. Methods: Tissue was acquired from eleven detailed post-mortem examinations. SARS-CoV-2 organotropism was mapped by multiplex PCR and sequencing, with cellular resolution achieved by in situ viral spike protein detection. Histological evidence of inflammation was quantified from 37 anatomical sites, and the pulmonary immune response characterized by multiplex immunofluorescence. Measurements and main results: Multiple aberrant immune responses in fatal Covid-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues. An arteritis was identified in the lung, which was further characterised as a monocyte/myeloid-rich vasculitis, and occurred along with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticulo-endothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Conclusions: Tissue-specific immunopathology occurs in Covid-19, implicating a significant component of immune-mediated, virus-independent immunopathology as a primary mechanism in severe disease. Our data highlight novel immunopathological mechanisms, and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma cell responses as well as promoting pathogen tolerance in Covid-19.Publisher PDFPeer reviewe