Targeted Lung Health Check: breast related incidental findings-imaging appearances and lessons learned.

OBJECTIVE: The introduction of Targeted Lung Health Checks (TLHC) to screen for lung cancer has highlighted that incidental findings are common and require management strategies. This study analyses retrospectively, incidentally detected breast lesions reported as part of the TLHC referred to the Breast Cancer clinicians. METHODS: All participants with incidental breast nodules referred to the Breast Cancer team in the first year of screening were reviewed. RESULTS: Fifty-two participants (48 female; 92.3%) were referred to the Breast Multidisciplinary Team Meeting for assessment of 43 breast nodules, 8 breast asymmetry/dense breasts, and 2 likely breast related metastatic disease. One participant declined breast team referral. For the 42 breast nodules investigated, the final diagnoses were 5 breast carcinomas, 10 normal breast tissue, and 27 benign nodules. One male patient was diagnosed with breast carcinoma. The 29 breast nodules classified as smooth and well defined were all benign. No malignancy was demonstrated in the group with asymmetric or dense breast tissue. Metastatic breast carcinoma was confirmed in two participants. Twenty-six out of thirty-seven (54%) females had prior breast screening mammograms precluding further investigation. CONCLUSION: Incidental breast nodules are common on THLC scans. Smooth, sharply defined breast nodules are likely to be benign but low-dose CT is poor at accurately assessing breast nodules. Agreed breast referral pathways prior to starting the Lung Cancer Screening programme are recommended. Access to screening mammograms can reduce referrals to the Breast clinic. ADVANCES IN KNOWLEDGE: Lessons learned from TLHC pilot studies can be useful to sites commencing national TLHC programme.

Evaluating the performance of artificial intelligence software for lung nodule detection on chest radiographs in a retrospective real-world UK population.

OBJECTIVES: Early identification of lung cancer on chest radiographs improves patient outcomes. Artificial intelligence (AI) tools may increase diagnostic accuracy and streamline this pathway. This study evaluated the performance of commercially available AI-based software trained to identify cancerous lung nodules on chest radiographs. DESIGN: This retrospective study included primary care chest radiographs acquired in a UK centre. The software evaluated each radiograph independently and outputs were compared with two reference standards: (1) the radiologist report and (2) the diagnosis of cancer by multidisciplinary team decision. Failure analysis was performed by interrogating the software marker locations on radiographs. PARTICIPANTS: 5722 consecutive chest radiographs were included from 5592 patients (median age 59 years, 53.8% women, 1.6% prevalence of cancer). RESULTS: Compared with radiologist reports for nodule detection, the software demonstrated sensitivity 54.5% (95% CI 44.2% to 64.4%), specificity 83.2% (82.2% to 84.1%), positive predictive value (PPV) 5.5% (4.6% to 6.6%) and negative predictive value (NPV) 99.0% (98.8% to 99.2%). Compared with cancer diagnosis, the software demonstrated sensitivity 60.9% (50.1% to 70.9%), specificity 83.3% (82.3% to 84.2%), PPV 5.6% (4.8% to 6.6%) and NPV 99.2% (99.0% to 99.4%). Normal or variant anatomy was misidentified as an abnormality in 69.9% of the 943 false positive cases. CONCLUSIONS: The software demonstrated considerable underperformance in this real-world patient cohort. Failure analysis suggested a lack of generalisability in the training and testing datasets as a potential factor. The low PPV carries the risk of over-investigation and limits the translation of the software to clinical practice. Our findings highlight the importance of training and testing software in representative datasets, with broader implications for the implementation of AI tools in imaging.

The reproducibility of manual RV/LV ratio measurement on CT pulmonary angiography.

Objectives: Right ventricular (RV) dysfunction carries elevated risk in acute pulmonary embolism (PE). An increased ratio between the size of the right and left ventricles (RV/LV ratio) is a biomarker of RV dysfunction. This study evaluated the reproducibility of RV/LV ratio measurement on CT pulmonary angiography (CTPA). Methods: 20 inpatient CTPA scans performed to assess for acute PE were retrospectively identified from a tertiary UK centre. Each scan was evaluated by 14 radiologists who provided a qualitative overall opinion on the presence of RV dysfunction and measured the RV/LV ratio. Using a threshold of 1.0, the RV/LV ratio measurements were classified as positive (≥1.0) or negative (<1.0) for RV dysfunction. Interobserver agreement was quantified using the Fleiss κ and intraclass correlation coefficient (ICC). Results: Qualitative opinion of RV dysfunction showed weak agreement (κ = 0.42, 95% CI 0.37-0.46). The mean RV/LV ratio measurement for all cases was 1.28 ± 0.68 with significant variation between reporters (p < 0.001). Although agreement for RV/LV measurement was good (ICC = 0.83, 95% CI 0.73-0.91), categorisation of RV dysfunction according to RV/LV ratio measurements showed weak agreement (κ = 0.46, 95% CI 0.41-0.50). Conclusion: Both qualitative opinion and quantitative manual RV/LV ratio measurement show poor agreement for identifying RV dysfunction on CTPA. Advances in knowledge: Caution should be exerted if using manual RV/LV ratio measurements to inform clinical risk stratification and management decisions.

Heterogeneous Compression of Large Collections of Evolutionary Trees.

Compressing heterogeneous collections of trees is an open problem in computational phylogenetics. In a heterogeneous tree collection, each tree can contain a unique set of taxa. An ideal compression method would allow for the efficient archival of large tree collections and enable scientists to identify common evolutionary relationships over disparate analyses. In this paper, we extend TreeZip to compress heterogeneous collections of trees. TreeZip is the most efficient algorithm for compressing homogeneous tree collections. To the best of our knowledge, no other domain-based compression algorithm exists for large heterogeneous tree collections or enable their rapid analysis. Our experimental results indicate that TreeZip averages 89.03 percent (72.69 percent) space savings on unweighted (weighted) collections of trees when the level of heterogeneity in a collection is moderate. The organization of the TRZ file allows for efficient computations over heterogeneous data. For example, consensus trees can be computed in mere seconds. Lastly, combining the TreeZip compressed (TRZ) file with general-purpose compression yields average space savings of 97.34 percent (81.43 percent) on unweighted (weighted) collections of trees. Our results lead us to believe that TreeZip will prove invaluable in the efficient archival of tree collections, and enables scientists to develop novel methods for relating heterogeneous collections of trees.

Geofold: topology-based protein unfolding pathways capture the effects of engineered disulfides on kinetic stability.

Protein unfolding is modeled as an ensemble of pathways, where each step in each pathway is the addition of one topologically possible conformational degree of freedom. Starting with a known protein structure, GeoFold hierarchically partitions (cuts) the native structure into substructures using revolute joints and translations. The energy of each cut and its activation barrier are calculated using buried solvent accessible surface area, side chain entropy, hydrogen bonding, buried cavities, and backbone degrees of freedom. A directed acyclic graph is constructed from the cuts, representing a network of simultaneous equilibria. Finite difference simulations on this graph simulate native unfolding pathways. Experimentally observed changes in the unfolding rates for disulfide mutants of barnase, T4 lysozyme, dihydrofolate reductase, and factor for inversion stimulation were qualitatively reproduced in these simulations. Detailed unfolding pathways for each case explain the effects of changes in the chain topology on the folding energy landscape. GeoFold is a useful tool for the inference of the effects of disulfide engineering on the energy landscape of protein unfolding.

An efficient and extensible approach for compressing phylogenetic trees.

BACKGROUND: Biologists require new algorithms to efficiently compress and store their large collections of phylogenetic trees. Our previous work showed that TreeZip is a promising approach for compressing phylogenetic trees. In this paper, we extend our TreeZip algorithm by handling trees with weighted branches. Furthermore, by using the compressed TreeZip file as input, we have designed an extensible decompressor that can extract subcollections of trees, compute majority and strict consensus trees, and merge tree collections using set operations such as union, intersection, and set difference. RESULTS: On unweighted phylogenetic trees, TreeZip is able to compress Newick files in excess of 98%. On weighted phylogenetic trees, TreeZip is able to compress a Newick file by at least 73%. TreeZip can be combined with 7zip with little overhead, allowing space savings in excess of 99% (unweighted) and 92%(weighted). Unlike TreeZip, 7zip is not immune to branch rotations, and performs worse as the level of variability in the Newick string representation increases. Finally, since the TreeZip compressed text (TRZ) file contains all the semantic information in a collection of trees, we can easily filter and decompress a subset of trees of interest (such as the set of unique trees), or build the resulting consensus tree in a matter of seconds. We also show the ease of which set operations can be performed on TRZ files, at speeds quicker than those performed on Newick or 7zip compressed Newick files, and without loss of space savings. CONCLUSIONS: TreeZip is an efficient approach for compressing large collections of phylogenetic trees. The semantic and compact nature of the TRZ file allow it to be operated upon directly and quickly, without a need to decompress the original Newick file. We believe that TreeZip will be vital for compressing and archiving trees in the biological community.

MrsRF: an efficient MapReduce algorithm for analyzing large collections of evolutionary trees.

BACKGROUND: MapReduce is a parallel framework that has been used effectively to design large-scale parallel applications for large computing clusters. In this paper, we evaluate the viability of the MapReduce framework for designing phylogenetic applications. The problem of interest is generating the all-to-all Robinson-Foulds distance matrix, which has many applications for visualizing and clustering large collections of evolutionary trees. We introduce MrsRF (MapReduce Speeds up RF), a multi-core algorithm to generate a t x t Robinson-Foulds distance matrix between t trees using the MapReduce paradigm. RESULTS: We studied the performance of our MrsRF algorithm on two large biological trees sets consisting of 20,000 trees of 150 taxa each and 33,306 trees of 567 taxa each. Our experiments show that MrsRF is a scalable approach reaching a speedup of over 18 on 32 total cores. Our results also show that achieving top speedup on a multi-core cluster requires different cluster configurations. Finally, we show how to use an RF matrix to summarize collections of phylogenetic trees visually. CONCLUSION: Our results show that MapReduce is a promising paradigm for developing multi-core phylogenetic applications. The results also demonstrate that different multi-core configurations must be tested in order to obtain optimum performance. We conclude that RF matrices play a critical role in developing techniques to summarize large collections of trees.

Using tree diversity to compare phylogenetic heuristics.

BACKGROUND: Evolutionary trees are family trees that represent the relationships between a group of organisms. Phylogenetic heuristics are used to search stochastically for the best-scoring trees in tree space. Given that better tree scores are believed to be better approximations of the true phylogeny, traditional evaluation techniques have used tree scores to determine the heuristics that find the best scores in the fastest time. We develop new techniques to evaluate phylogenetic heuristics based on both tree scores and topologies to compare Pauprat and Rec-I-DCM3, two popular Maximum Parsimony search algorithms. RESULTS: Our results show that although Pauprat and Rec-I-DCM3 find the trees with the same best scores, topologically these trees are quite different. Furthermore, the Rec-I-DCM3 trees cluster distinctly from the Pauprat trees. In addition to our heatmap visualizations of using parsimony scores and the Robinson-Foulds distance to compare best-scoring trees found by the two heuristics, we also develop entropy-based methods to show the diversity of the trees found. Overall, Pauprat identifies more diverse trees than Rec-I-DCM3. CONCLUSION: Overall, our work shows that there is value to comparing heuristics beyond the parsimony scores that they find. Pauprat is a slower heuristic than Rec-I-DCM3. However, our work shows that there is tremendous value in using Pauprat to reconstruct trees-especially since it finds identical scoring but topologically distinct trees. Hence, instead of discounting Pauprat, effort should go in improving its implementation. Ultimately, improved performance measures lead to better phylogenetic heuristics and will result in better approximations of the true evolutionary history of the organisms of interest.

IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection.

IFN-gamma-producing CD8(+) T lymphocytes are essential effector cells that mediate protective immunity during murine toxoplasmosis, and yet their effector development remains poorly characterized. Vaccination with the carbamoyl phosphate synthase (CPS) mutant strain of Toxoplasma gondii was used to examine the CD8(+) T cell response in the peritoneal effector site. Four CTL subpopulations with varying effector potentials were defined based on the expression of effector molecules and the cell surface activation markers CD62L and killer cell lectin-like receptor G1 (KLRG1). Further phenotypic analysis revealed that the acquisition of KLRG1 among effector subpopulations correlated with the down-regulation of both IL-7R and CD27, suggesting that KLRG1 marks dominant, end-stage effector cells. Using gene-targeted mice, we tested the in vivo requirements of key IL-12 signaling components for effector CTL differentiation. Contrary to established models of viral and bacterial infection, CD8(+) T cell-intrinsic IL-12 signaling was required for the generation of IFN-gamma-producing CTLs in response to T. gondii. Importantly, the development of the KLRG1(+) effector subpopulations, but not the memory precursor-containing KLRG1(-) effector subset, was critically reliant on IL-12. Furthermore, IL-12 signaling-dependent T-bet expression was also found to be important for differentiation of KLRG1(+) effectors. Our results underscore a vital role for IL-12 in not only the induction of IFN-gamma expression but also in the development of heterogeneous subpopulations of effector CD8(+) T cells generated in response to the intracellular parasite T. gondii.

Rapid elimination of Toxoplasma gondii by gamma interferon-primed mouse macrophages is independent of CD40 signaling.

Autophagy has been implicated in the intracellular destruction of Toxoplasma gondii by primed macrophages following gamma interferon (IFN-gamma) activation of p47 GTPases. CD40 ligation has also been shown to trigger autophagic elimination of T. gondii independent of IFN-gamma and p47 GTPases. Here we demonstrate that IFN-gamma/p47 GTPase-dependent elimination of T. gondii by strain CPS vaccine-primed macrophages is independent of CD40/tumor necrosis factor signaling. Similar to wild-type controls, both CD40-deficient and tumor necrosis factor receptor 1/2 (TNFR1/2)-deficient macrophages can efficiently eliminate invaded strain GFP-PTG and restrain its replication following priming. In contrast, macrophages from mice lacking the IFN-gamma receptor gene neither clear the parasites nor repress their proliferation. Thus, CD40 and IFN-gamma-induced pathogen elimination might represent two independent resistance pathways, the latter of which plays a primary role in anti-Toxoplasma immunity in mice.

Multislice computed tomography in staging lung cancer: the role of multiplanar image reconstruction.

OBJECTIVE: The role of multiplanar image reconstruction (MPR) in staging lung cancer was investigated using multislice helical computed tomography (CT), which allows high-quality volumetric imaging. METHODS: Forty-one consecutive patients with lung cancer (mean age = 71 years) underwent multislice CT of the thorax. The scans were acquired using contiguous 4-mm x 2.5-mm slices from the lung apex to the diaphragm in a single breath hold after injection of 100 mL intravenous contrast media. Contiguous axial, coronal, and sagittal images (5-mm slice thickness) were reconstructed in the lung and mediastinal windows. The axial images with and without multiplanar reformatted images were reviewed on a workstation on 2 separate occasions (a minimum of 6 weeks apart) by 2 experienced chest radiologists. The films were assessed for features relating to the primary lesion (size; location; and invasion of the chest wall, mediastinum, diaphragm, and/or fissures) and secondary features (mediastinal lymphadenopathy and lung metastases). The diagnostic confidence of each feature was expressed on a 4-point scale. RESULTS: A significant increase in confidence was seen on the part of both observers when diagnosing features relating to the primary lesion. The mean confidence score increased from 1.68 to 2.08 (P = 0.038) for observer A and from 1.50 to 1.80 (P = 0.020) for observer B. Confidence in assessing invasion of fissures was increased from 1.70 to 2.30 (P = 0.022) for observer A and from 1.67 to 2.27 (P = 0.006) for observer B. Improvement in interobserver agreement (kappa-value from 0.61 to 0.75) was observed with multiplanar reconstruction (MPR) in the assessment of tumor location. No statistical difference was demonstrated in the diagnosis of mediastinal lymphadenopathy or lung secondaries. CONCLUSION: Multiplanar imaging of the thorax is a useful supplementary tool in the staging of lung cancer, particularly in delineating the relation of the primary lesion to fissures and the diaphragm.