Symptoms at lung cancer diagnosis are associated with major differences in prognosis

We report a cohort study of survival of patients with lung cancer presenting to a single multidisciplinary team between 1997 and 2011, according to symptoms at presentation. The overall median survival of the 3800 lung cases was 183 days (95% CI 171 to 195). There was a statistically significant difference in survival between the 12 symptom groups identified both without and with adjustment for the prognostic variables of age, gender and histology (P<0.001). Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness (HR 1.86, 95% CI 1.54 to 2.24, n=359), systemic symptoms (HR 1.91, 95% CI 1.48 to 2.45, n=95), weight loss (HR 2.46, 95% CI 1.90 to 3.18, n=106), chest pain (HR 1.96, 95% CI 1.56 to 2.45, n=159), cough with breathlessness (HR 1.59 95% CI 1.28 to 1.98, n=177), neurological symptoms (HR 3.07, 95% CI 2.45 to 3.84, n=155) and other symptom combinations (HR 2.05, 95% CI 1.75 to 2.40, n=1963). Cough may deserve particular prominence in public health campaigns

Telephone follow-up to identify incident lung cancer symptoms in COPD patients

Background: COPD patients are at very high risk of lung cancer, yet new respiratory symptoms of lung cancer may be particularly hard to identify. Aim: We sought to assess the feasibility of actively seeking lung cancer symptoms to improve the timeliness of diagnosis in this group. Design and setting: Observational study to evaluate the feasibility and practicability of the intervention. Patients were recruited from a primary care COPD register and were contacted by telephone 4-monthly over 12 months. Chest X-ray rates were assessed over the 20 months before, during the intervention and for 20 months following it, in both the study group and in patients on the register who did not volunteer for the intervention. Results: Most symptoms were identified at the first call, with 13 (17%) subjects admitting to a new persistent cough and 7 (9%) to a change in their cough. As a result of symptoms identified on the first call, 21 (27%) of the participating patients were referred for a chest X-ray and 4 (5%) were referred urgently to secondary care. Incident symptoms continued frequently to be identified at all subsequent calls, with an overall total of 49% of patients qualifying for and receiving a chest X-ray. Interestingly, the chest X-ray rate remained significantly elevated for the 20 months following the intervention, whilst there appeared to be little change in the non-study COPD patients. Conclusion: The intervention was readily practicable and lung cancer symptoms were frequently identified. The intervention may have resulted in a behavior change leading to a persistently higher chest X-ray rate, although the comparator group was not a formal control group and further assessment in a randomized control trial appears justified

Semi-supervised prediction of protein interaction sentences exploiting semantically encoded metrics

Protein-protein interaction (PPI) identification is an integral component of many biomedical research and database curation tools. Automation of this task through classification is one of the key goals of text mining (TM). However, labelled PPI corpora required to train classifiers are generally small. In order to overcome this sparsity in the training data, we propose a novel method of integrating corpora that do not contain relevance judgements. Our approach uses a semantic language model to gather word similarity from a large unlabelled corpus. This additional information is integrated into the sentence classification process using kernel transformations and has a re-weighting effect on the training features that leads to an 8% improvement in F-score over the baseline results. Furthermore, we discover that some words which are generally considered indicative of interactions are actually neutralised by this process

RNA-seq and Tn-seq reveal fitness determinants of vancomycin-resistant Enterococcus faecium during growth in human serum

BACKGROUND: The Gram-positive bacterium Enterococcus faecium is a commensal of the human gastrointestinal tract and a frequent cause of bloodstream infections in hospitalized patients. The mechanisms by which E. faecium can survive and grow in blood during an infection have not yet been characterized. Here, we identify genes that contribute to growth of E. faecium in human serum through transcriptome profiling (RNA-seq) and a high-throughput transposon mutant library sequencing approach (Tn-seq). RESULTS: We first sequenced the genome of E. faecium E745, a vancomycin-resistant clinical isolate, using a combination of short- and long read sequencing, revealing a 2,765,010 nt chromosome and 6 plasmids, with sizes ranging between 9.3 kbp and 223.7 kbp. We then compared the transcriptome of E. faecium E745 during exponential growth in rich medium and in human serum by RNA-seq. This analysis revealed that 27.8% of genes on the E. faecium E745 genome were differentially expressed in these two conditions. A gene cluster with a role in purine biosynthesis was among the most upregulated genes in E. faecium E745 upon growth in serum. The E. faecium E745 transposon mutant library was then used to identify genes that were specifically required for growth of E. faecium in serum. Genes involved in de novo nucleotide biosynthesis (including pyrK_2, pyrF, purD, purH) and a gene encoding a phosphotransferase system subunit (manY_2) were thus identified to be contributing to E. faecium growth in human serum. Transposon mutants in pyrK_2, pyrF, purD, purH and manY_2 were isolated from the library and their impaired growth in human serum was confirmed. In addition, the pyrK_2 and manY_2 mutants were tested for their virulence in an intravenous zebrafish infection model and exhibited significantly attenuated virulence compared to E. faecium E745. CONCLUSIONS: Genes involved in carbohydrate metabolism and nucleotide biosynthesis of E. faecium are essential for growth in human serum and contribute to the pathogenesis of this organism. These genes may serve as targets for the development of novel anti-infectives for the treatment of E. faecium bloodstream infections

A class of exactly solvable Schroedinger equation with moving boundary conditions

Using first and second order supersymmetry formalism we obtain a class of exactly solvable potentials subject to moving boundary conditions

Space Shuttle Solid Rocket Booster Lightweight Recovery System

The cancellation of the Advanced Solid Rocket Booster Project and the earth-to-orbit payload requirements for the Space Station dictated that the National Aeronautics and Space Administration (NASA) look at performance enhancements from all Space Transportation System (STS) elements (Orbiter Project, Space Shuttle Main Engine Project, External Tank Project, Solid Rocket Motor Project, & Solid Rocket Booster Project). The manifest for launching of Space Station components indicated that an additional 12-13000 pound lift capability was required on 10 missions and 15-20,000 pound additional lift capability is required on two missions. Trade studies conducted by all STS elements indicate that by deleting the parachute Recovery System (and associated hardware) from the Solid Rocket Boosters (SRBS) and going to a lightweight External Tank (ET) the 20,000 pound additional lift capability can be realized for the two missions. The deletion of the parachute Recovery System means the loss of four SRBs and this option is two expensive (loss of reusable hardware) to be used on the other 10 Space Station missions. Accordingly, each STS element looked at potential methods of weight savings, increased performance, etc. As the SRB and ET projects are non-propulsive (i.e. does not have launch thrust elements) their only contribution to overall payload enhancement can be achieved by the saving of weight while maintaining adequate safety factors and margins. The enhancement factor for the SRB project is 1:10. That is for each 10 pounds saved on the two SRBS; approximately 1 additional pound of payload in the orbiter bay can be placed into orbit. The SRB project decided early that the SRB recovery system was a prime candidate for weight reduction as it was designed in the early 1970s and weight optimization had never been a primary criteria

Origin and evolution of the light nuclides

After a short historical (and highly subjective) introduction to the field, I discuss our current understanding of the origin and evolution of the light nuclides D, He-3, He-4, Li-6, Li-7, Be-9, B-10 and B-11. Despite considerable observational and theoretical progress, important uncertainties still persist for each and every one of those nuclides. The present-day abundance of D in the local interstellar medium is currently uncertain, making it difficult to infer the recent chemical evolution of the solar neighborhood. To account for the observed quasi-constancy of He-3 abundance from the Big Bang to our days, the stellar production of that nuclide must be negligible; however, the scarce observations of its abundance in planetary nebulae seem to contradict this idea. The observed Be and B evolution as primaries suggests that the source composition of cosmic rays has remained quasi-constant since the early days of the Galaxy, a suggestion with far reaching implications for the origin of cosmic rays; however, the main idea proposed to account for that constancy, namely that superbubbles are at the source of cosmic rays, encounters some serious difficulties. The best explanation for the mismatch between primordial Li and the observed "Spite-plateau" in halo stars appears to be depletion of Li in stellar envelopes, by some yet poorly understood mechanism. But this explanation impacts on the level of the recently discovered early ``Li-6 plateau'', which (if confirmed), seriously challenges current ideas of cosmic ray nucleosynthesis.Comment: 18 pages, 9 figs. Invited Review in "Symposium on the Composition of Matter", honoring Johannes Geiss on the occasion of his 80th birthday (Grindelwald, Switzerland, Sept. 2006), to be published in Space Science Series of ISS

Comparative empirical evaluations of internal migration models in subnational population projections

While population forecasters place considerable emphasis on the selection of appropriate migration assumptions, surprisingly little attention has been given to the effects on projection outcomes of the way internal migration is handled within population projection models. This paper compares population projections for Australia's states and territories prepared using ten different internal migration models but with identical assumptions for fertility, mortality and international migration and with the internal migration model parameters held constant. It is shown that the choice of migration model generates large differences in total population, geographical distribution and age--sex composition. It is argued that model choice should be guided by balancing model reality with practical utility and model performance is examined against these criteria. Of the ten models evaluated the authors argue that the migration pool, biregional, and biregional with net constraints models offer a good compromise between conceptual rigour and practicality. If the projected origin-destination flows are required then one of the versions of the standard multiregional model with reduced data inputs is preferred. The large variation in projection outputs points to the need for a better understanding of the spatio-temporal structure of migration in Australia

Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics

Published: April 13, 2023With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.Madeline G. Dans, Henni Piirainen, William Nguyen, Sachin Khurana, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Aurelie T. Dawson, Sujaan Das, Molly Parkyn Schneider, Thorey K. Jonsdottir, Mikha Gabriela, Maria R. Gancheva, Christopher J. Tonkin, Vanessa Mollard, Christopher Dean Goodman, Geoffrey I. McFadden, Danny W. Wilson, Kelly L. Rogers, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Brad E. Sleebs, Inari Kursula, Paul R. Gilso

Carotid artery plaque composition : Relationship to clinical presentation and ultrasound B-mode imaging

Objective: To correlate B-mode ultrasound findings to carotid plaque histology. Design: European multicentre study (nine centres). Material and Methods: Clinical presentation and risk factors were recorded and preoperative ultrasound Duplex scanning with special emphasis on B-mode imaging studies was performed in 270 patients undergoing carotid endarterectomy. Perioperatively macroscopic plaque features were evaluated and the removed specimens were analysed histologically for fibrous tissue, calcification and 'soft tissue' (primarily haemorrhage and lipid). Results: Males had more soft tissue than females (p = 0.0006), hypertensive patients less soft tissue than normotensive (p = 0.01) and patients with recent symptoms more soft tissue than patients with earlier symptoms (p = 0.004). There was no correlation between surface description on ultrasound images compared to the surface judged intraoperatively by the surgeon. Echogenicity on B-mode images was inversely related to soft tissue (p=0.005) and calcification ions directly related to echogenicity (p < 0.0001). Heterogeneous plaques contained more calcification than homogeneous (p = 0.003), however there was no difference in content of soft tissue. Conclusion: Ultrasound B-mode characteristics are related to the histological composition of carotid artery plaques and to patient's history. These results may imply that patients with distant symptoms may be regarded and treated as asymptomatic patients whereas asymptomatic patients with echolucent plaques should be considered for carotid endarterectomy