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A novel technique for detecting Lagrangian vortices is applied to a helical magnetohydrodynamic dynamo simulation. The vortices are given by tubular level surfaces of the Lagrangian averaged vorticity deviation, the trajectory integral of the normed difference of the vorticity from its spatial mean. This simple method is objective, i.e. invariant under time-dependent rotations and translations of the coordinate frame. We also adapt the technique to use it on magnetic fields and propose the method of integrated averaged current deviation to determine precisely the boundary of magnetic vortices. The relevance of the results for the study of vortices in solar plasmas is discussed. [ABSTRACT FROM AUTHOR]

We study the development of coherent structures in local simulations of the magnetorotational instability in accretion discs in regimes of on–off intermittency. In a previous paper, we have shown that the laminar and bursty states due to the on–off spatiotemporal intermittency in a one-dimensional model of non-linear waves correspond, respectively, to non-attracting coherent structures with higher and lower degrees of amplitude-phase synchronization. In this paper, we extend these results to a three-dimensional model of magnetized Keplerian shear flows. Keeping the kinetic Reynolds number and the magnetic Prandtl number fixed, we investigate two different intermittent regimes by varying the plasma beta parameter. The first regime is characterized by turbulent patterns interrupted by the recurrent emergence of a large-scale coherent structure known as two-channel flow, where the state of the system can be described by a single Fourier mode. The second regime is dominated by the turbulence with sporadic emergence of coherent structures with shapes that are reminiscent of a perturbed channel flow. By computing the Fourier power and phase spectral entropies in three dimensions, we show that the large-scale coherent structures are characterized by a high degree of amplitude-phase synchronization. [ABSTRACT FROM PUBLISHER]

In a recent paper (Koga et al., 2007) it was shown that the intermittent nature of solar wind turbulence can be characterized by kurtosis and phase coherence index. In this paper, we apply these two nonlinear time series techniques to characterize the intermittent nature of atmospheric turbulence above and within the Amazon forest canopy using the day-time data of temperature and vertical wind velocity measured by a micrometeorological tower at two different heights. By applying kurtosis and phase coherence index to quantify the degree of phase coherence, we identify an enhanced scalar-velocity similarity for in-canopy turbulence compared to the above-canopy turbulence, during the interval of data analysis. [ABSTRACT FROM AUTHOR]

The complex dynamics of Alfvén waves described by the derivative nonlinear Schrödinger equation is investigated. In a region of the parameters space where multistability is observed, this complex system is driven towards an intermittent regime by the addition of noise. The effects of Gaussian and non-Gaussian noise are compared. In the intermittent regime, the Alfvén wave exhibits random qualitative changes in its dynamics as the result of a competition between three attractors and a chaotic saddle embedded in the fractal basin boundary. [ABSTRACT FROM AUTHOR]

A new type of economic intermittency is found in non-linear business cycles. Following a merging crisis, a complex economic system has the ability to retain memory of its weakly chaotic dynamics prior to crisis. The resulting time series exhibits episodic regime switching between periods of weakly and strongly chaotic fluctuations of economic variables. The characteristic intermittency time, useful for forecasting the average duration of contractionary phases and the turning point to the expansionary phase of business cycles, is computed from the simulated time series. [ABSTRACT FROM AUTHOR]

The chaotic dynamics of Alfvén waves in space plasmas governed by the derivative nonlinear Schrödinger equation, in the low-dimensional limit described by stationary spatial solutions, is studied. A bifurcation diagram is constructed, by varying the driver amplitude, to identify a number of nonlinear dynamical processes including saddle-node bifurcation, boundary crisis, and interior crisis. The roles played by unstable periodic orbits and chaotic saddles in these transitions are analyzed, and the conversion from a chaotic saddle to a chaotic attractor in these dynamical processes is demonstrated. In particular, the phenomenon of gap-filling in the chaotic transition from weak chaos to strong chaos via an interior crisis is investigated. A coupling unstable periodic orbit created by an explosion, within the gaps of the chaotic saddles embedded in a chaotic attractor following an interior crisis, is found numerically. The gap-filling unstable periodic orbits are responsible for coupling the banded chaotic saddle (BCS) to the surrounding chaotic saddle (SCS), leading to crisis-induced intermittency. The physical relevance of chaos for Alfvén intermittent turbulence observed in the solar wind is discussed. [ABSTRACT FROM AUTHOR]

Background: There is a lack of information from Canadian hospitals on the role of hospital characteristics such as procedure volume and teaching status on the survival of patients who undergo major cancer resection. Therefore, we chose to study these relationships using data from patients treated in Ontario hospitals. Methods: We used the Ontario Cancer Registry from calendar years 1990-2000 to obtain data on patients who underwent surgery for breast, colon, lung or esophageal cancer or who underwent major liver surgery related to a cancer diagnosis between 1990 and 1995 in order to assess the influence of volume of procedures and teaching status of hospitals on in-hospital death rate and long-term survival. For each disease site and before observing patient outcomes data, volume cut-off points were selected to create volume groups with similar numbers of patients. Teaching hospitals were those directly affiliated with a medical school. Logistic regression and proportional hazards models were used to consider the clustering of data at the hospital level and to assess operative death and long-term survival. We also used 4 measures to gauge the degree of procedure regionalization across the province including (1) the number of hospitals performing a procedure; (2) the percentage of patients treated in teaching hospitals; (3) the percentage of rural patients treated in higher volume procedure hospitals; and (4) median distances travelled by patients to receive care. Results: The number of patients in our cohorts who underwent resection of the breast, colon, lung, esophagus or liver was 14 346, 8398, 2698, 629 and 362, respectively. Surgery in a high-volume versus a low-volume hospital did not have a statistically significant influence on the odds of operative death for patients who underwent colon, liver, lung or esophageal cancer resection. The risk of long-term death was increased in low-volume versus high-volume hospitals for patients who underwent resection of the breast (hazard ratio [HR] 1.2, 95% confidence interval [95% CI] 1.0-1.4, p < 0.05), lung (HR 1.3, 95% CI 1.1-1.6, p < 0.01) and liver (HR 1.7, 95% CI 1.0-2.7, p = 0.04). There were no significant differences in the odds of operative (in-hospital) death or risk of long-term death among patients treated in teaching compared with nonteaching hospitals. There was more regionalization of liver, lung and esophageal operations versus breast and colon operations. Conclusions: Increased hospital procedure volume correlated with improved long-term survival for patients in Ontario who underwent some, but not all, cancer resections, whereas hospital teaching status had no significant impact on patient outcomes. Across the province, further regionalization of care may help improve the quality of some cancer procedures. [ABSTRACT FROM AUTHOR]

Intermittent behaviour of economic dynamics is studied by a nonlinear model of business cycles. Numerical simulations show that after an economic system evolves from order to chaos, the system keeps its memory before the transition and its time series alternates episodically between periods of low-level (quiescent) and high-level (bursting) activities. This model of economic intermittency exhibits power-law spectrum similar to the nonlinear time series observed in financial markets. [ABSTRACT FROM AUTHOR]

We examine the dynamical roles of nonattracting chaotic sets known as chaotic saddles in an Alfvén wave system described by the driven-dissipative derivative nonlinear Schrödinger equation. These Alfvén chaotic saddles have gaps which are filled at the onset of chaos via a saddle-node bifurcation and at a chaotic transition via an interior crisis. It is shown that after an interior crisis an Alfvén chaotic attractor consists of two chaotic saddles connected by a set of coupling unstable periodic orbits. [ABSTRACT FROM AUTHOR]

A numerical study of an interior crisis of a large-amplitude Alfvén wave described by the driven-dissipative derivative nonlinear Schrödinger equation, in the low-dimensional limit, is reported. An example of Alfvén interior crisis is characterized using the unstable periodic orbits and their associated invariant stable and unstable manifolds in the Poincaré plane. We suggest that this type of chaotic transition can be observed in space and laboratory plasmas. [ABSTRACT FROM AUTHOR]

A new transition mechanism to Alfvén chaos via boundary crisis is reported. This crisis appears in a complex plasma region in the presence of a large number of coexisting attractors. We characterize an example of double boundary crises using the unstable periodic orbit determined from the numerical solution of the driven-dissipative derivative nonlinear Schrödinger equation, and demonstrate how the same unstable periodic orbit causes the appearance/disappearance of two chaotic attractors due to two successive homoclinic tangencies. [ABSTRACT FROM AUTHOR]

Radio emissions from the solar active regions can be generated by nonlinear coupling of Langmuir waves with Alfvén waves. Multi-wavelength observations can be used to provide evidence for Langmuir-Alfvén turbulence in the solar atmosphere.To search for other articles by the author(s) go to: http://adsabs.harvard.edu/abstract_service.html [ABSTRACT FROM PUBLISHER]

We perform a two-parameter bifurcation study of the driven-damped regularized long-wave equation by varying the amplitude and phase of the driver. Increasing the amplitude of the driver brings the system to the regime of spatiotemporal chaos (STC), a chaotic state with a large number of degrees of freedom. Several global bifurcations are found, including codimension-two bifurcations and homoclinic bifurcations involving three-tori and the manifolds of steady waves, leading to the formation of chaotic saddles in the phase space. We identify four distinct routes to STC; they depend on the phase of the driver and involve boundary and interior crises, intermittency, the Ruelle-Takens scenario, the Feigenbaum cascade, an embedded saddle-node, homoclinic, and other bifurcations. This study elucidates some of the recently reported dynamical phenomena. [ABSTRACT FROM AUTHOR]

We study general multifractal properties of tidal gauge and long-wave time series which show a well defined transition between two states, as is the case of sea level when a tsunami arrives. We adopt a method based on discrete wavelets, called wavelet leaders, which has been successfully used in a wide range of applications from image analysis to biomedical signals. First, we analyze an empirical time series of tidal gauge from the tsunam event of 27 February 2010 in Chile. Then, we study a numerical solution of the driven-damped regularize long-wave equation (RLWE) which displays on-off intermittency. Both time series are characterized by a sudden change between two sharply distinct dynamical states. Our analysis suggests a correspondence between the pre-and post-tsunami states (ocean background) and the on state in the RLWE, and also between the tsunami state (disturbed ocean) and the off state in the RLWE. A qualitative similarity in their singularity spectra is observed, and since the RLWE is used to model shallow water dynamics, this result could imply an underlying dynamical similarity. [ABSTRACT FROM AUTHOR]

Background: Intimate Partner Violence (IPV) exposes women and children to a wide range of challenges across housing, employment, social connections, and child well-being and is a public health issue. IPV survivors are at heightened risk of housing insecurity and homelessness. Emergency shelters have historically offered respite and support, but the emergence of second-stage shelters provides longer-term solutions. Despite their significance, there has been a lack of comprehensive research on second-stage shelters. This study focuses on understanding the needs of IPV survivors accessing second-stage shelters, aiming to illuminate unexplored aspects of support. To examine the current published peer-reviewed literature and gray literature on second-stage shelters, a scoping review was conducted., Methods: This scoping review used the method suggested by Arksey & O'Malley (2005) and considered all studies that focused on women who had experienced IPV and were accessing transitional housing/second-stage shelters., Results: Sixteen articles, mainly from the USA and published between 1985 and 2022, were included in the analysis. The findings highlighted themes of (1) a safe(r) place, with the subtheme of 'gated' communities, and (2) programming and services, with the subtheme of does one size fit all? and (3) insider support, with subthemes of paid insider support and peer insider support., Conclusions: Housing instability was evident, and the need for multiple and individualized tailored options of programming and support along with housing security was identified. Second-stage housing policy and practice implications are addressed which illuminate unexplored aspects of support., (© 2024. The Author(s).)

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase ( erm ) genes. Beginning in 2018, we detected high-level inducible clarithromycin resistance (MICs of ≥16μg/mL) in clinical isolates of Mycobacterium chelonae, an RGM species not previously known to contain erm genes. Using whole-genome sequencing, we identified a novel plasmid-mediated erm gene. This gene, designated erm (55) P , exhibits <65% amino acid identity to previously described RGM erm genes. Two additional chromosomal erm (55) alleles, with sequence identities of 81% to 86% to erm (55) P , were also identified and designated erm (55) C and erm (55) T . The erm (55) T is part of a transposon. The erm (55) P allele variant is located on a putative 137-kb conjugative plasmid, pMchErm55. Evaluation of 133 consecutive isolates from 2020 to 2022 revealed 5 (3.8%) with erm (55). The e rm (55) P gene was also identified in public data sets of two emerging pathogenic pigmented RGM species: Mycobacterium iranicum and Mycobacterium obuense, dating back to 2008. In both species, the gene appeared to be present on plasmids homologous to pMchErm55. Plasmid-mediated macrolide resistance, not described previously for any NTM species, appears to have spread to multiple RGM species. This has important implications for antimicrobial susceptibility guidelines and treatment of RGM infections. Further spread could present serious consequences for treatment of other macrolide-susceptible RGM. Additional studies are needed to determine the transmissibility of pMchErm55 and the distribution of erm (55) among other RGM species., Competing Interests: The authors declare no conflict of interest.

Introduction: Low pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5-8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown., Methods and Analysis: In this multicentre pilot randomised controlled trial, infants <29 weeks' gestational age (GA) who either: (A) fail treatment with traditional nCPAP or (B) being extubated from invasive mechanical ventilation with mean airway pressure ≥10 cmH2O, will be randomised to receive either high nCPAP (positive end-expiratory pressure 9-15 cmH2O) or NIPPV (target mean Paw 9-15 cmH2O). Primary outcome is feasibility of the conduct of a larger, definitive trial as assessed by rates of recruitment and protocol violations. The main secondary outcome is failure of assigned treatment within 7 days postrandomisation. Multiple other clinical outcomes including bronchopulmonary dysplasia will be ascertained. All randomised participants will be analysed using intention to treat. Baseline and demographic variables as well as outcomes will be summarised and compared using univariate analyses, and a p<0.05 will be considered significant., Ethics and Dissemination: The trial has been approved by the respective research ethics boards at each institution (McMaster Children's Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness., Trial Registration Number: NCT03512158., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The development and approval of COVID-19 vaccines have generated optimism for the end of the COVID-19 pandemic and a return to normalcy. However, vaccine hesitancy, often fueled by misinformation, poses a major barrier to achieving herd immunity., Objective: We aim to investigate Twitter users' attitudes toward COVID-19 vaccination in Canada after vaccine rollout., Methods: We applied a weakly supervised aspect-based sentiment analysis (ABSA) technique, which involves the human-in-the-loop system, on COVID-19 vaccination-related tweets in Canada. Automatically generated aspect and opinion terms were manually corrected by public health experts to ensure the accuracy of the terms and make them more domain-specific. Then, based on these manually corrected terms, the system inferred sentiments toward the aspects. We observed sentiments toward key aspects related to COVID-19 vaccination, and investigated how sentiments toward "vaccination" changed over time. In addition, we analyzed the most retweeted or liked tweets by observing most frequent nouns and sentiments toward key aspects., Results: After applying the ABSA system, we obtained 170 aspect terms (eg, "immunity" and "pfizer") and 6775 opinion terms (eg, "trustworthy" for the positive sentiment and "jeopardize" for the negative sentiment). While manually verifying or editing these terms, our public health experts selected 20 key aspects related to COVID-19 vaccination for analysis. The sentiment analysis results for the 20 key aspects revealed negative sentiments related to "vaccine distribution," "side effects," "allergy," "reactions," and "anti-vaxxer," and positive sentiments related to "vaccine campaign," "vaccine candidates," and "immune response." These results indicate that the Twitter users express concerns about the safety of vaccines but still consider vaccines as the option to end the pandemic. In addition, compared to the sentiment of the remaining tweets, the most retweeted or liked tweets showed more positive sentiment overall toward key aspects (P<.001), especially vaccines (P<.001) and vaccination (P=.009). Further investigation of the most retweeted or liked tweets revealed two opposing trends in Twitter users who showed negative sentiments toward vaccines: the "anti-vaxxer" population that used negative sentiments as a means to discourage vaccination and the "Covid Zero" population that used negative sentiments to encourage vaccinations while critiquing the public health response., Conclusions: Our study examined public sentiments toward COVID-19 vaccination on tweets over an extended period in Canada. Our findings could inform public health agencies to design and implement interventions to promote vaccination., (©Hyeju Jang, Emily Rempel, Ian Roe, Prince Adu, Giuseppe Carenini, Naveed Zafar Janjua. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.03.2022.)

Background: An infodemic is an overflow of information of varying quality that surges across digital and physical environments during an acute public health event. It leads to confusion, risk-taking, and behaviors that can harm health and lead to erosion of trust in health authorities and public health responses. Owing to the global scale and high stakes of the health emergency, responding to the infodemic related to the pandemic is particularly urgent. Building on diverse research disciplines and expanding the discipline of infodemiology, more evidence-based interventions are needed to design infodemic management interventions and tools and implement them by health emergency responders., Objective: The World Health Organization organized the first global infodemiology conference, entirely online, during June and July 2020, with a follow-up process from August to October 2020, to review current multidisciplinary evidence, interventions, and practices that can be applied to the COVID-19 infodemic response. This resulted in the creation of a public health research agenda for managing infodemics., Methods: As part of the conference, a structured expert judgment synthesis method was used to formulate a public health research agenda. A total of 110 participants represented diverse scientific disciplines from over 35 countries and global public health implementing partners. The conference used a laddered discussion sprint methodology by rotating participant teams, and a managed follow-up process was used to assemble a research agenda based on the discussion and structured expert feedback. This resulted in a five-workstream frame of the research agenda for infodemic management and 166 suggested research questions. The participants then ranked the questions for feasibility and expected public health impact. The expert consensus was summarized in a public health research agenda that included a list of priority research questions., Results: The public health research agenda for infodemic management has five workstreams: (1) measuring and continuously monitoring the impact of infodemics during health emergencies; (2) detecting signals and understanding the spread and risk of infodemics; (3) responding and deploying interventions that mitigate and protect against infodemics and their harmful effects; (4) evaluating infodemic interventions and strengthening the resilience of individuals and communities to infodemics; and (5) promoting the development, adaptation, and application of interventions and toolkits for infodemic management. Each workstream identifies research questions and highlights 49 high priority research questions., Conclusions: Public health authorities need to develop, validate, implement, and adapt tools and interventions for managing infodemics in acute public health events in ways that are appropriate for their countries and contexts. Infodemiology provides a scientific foundation to make this possible. This research agenda proposes a structured framework for targeted investment for the scientific community, policy makers, implementing organizations, and other stakeholders to consider., Competing Interests: Conflicts of Interest: AA, EA, JNA, SB, SCB, CC, JL, RL, AM, PNN, TN, TDP, AR, and BY are staff of the World Health Organization; NA, AI, AK, SK, PP, DP, and EW are staff members of the US Centers for Disease Control and Prevention; LE and AW are staff members of the European Centre for Disease Prevention and Control. RH is staff of UNICEF. These authors alone are responsible for the views expressed in this paper, and they do not represent the views of their organizations. BS participated in the conference while being staff of WHO. SB consults for WHO in data analysis for emergency preparedness and supported the work described in the paper during his consultancy contract. IB is Director of WHO Collaborating Center on information systems for health, which supports WHO with broader digital health analytics and policy analysis. The center has supported Pan American Health Organization (PAHO)/WHO with infodemic analytics during COVID-19. LMB works for Immunize Canada/Canadian Public Health Association, which has received educational grants/funding from Merck Canada, Pfizer Canada, Pfizer Global, Moderna Canada, Seqirus, Sanofi Canada, GSK Canada and the Public Health Agency of Canada (PHAC). These funds are not related to the paper. AB has received funding from Carlsberg Foundation for a research project about online hostility for which she is project co-primary investigator. This project is not related to the deliberation described in this publication., (©Neville Calleja, AbdelHalim AbdAllah, Neetu Abad, Naglaa Ahmed, Dolores Albarracin, Elena Altieri, Julienne N Anoko, Ruben Arcos, Arina Anis Azlan, Judit Bayer, Anja Bechmann, Supriya Bezbaruah, Sylvie C Briand, Ian Brooks, Lucie M Bucci, Stefano Burzo, Christine Czerniak, Manlio De Domenico, Adam G Dunn, Ullrich K H Ecker, Laura Espinosa, Camille Francois, Kacper Gradon, Anatoliy Gruzd, Beste Sultan Gülgün, Rustam Haydarov, Cherstyn Hurley, Santi Indra Astuti, Atsuyoshi Ishizumi, Neil Johnson, Dylan Johnson Restrepo, Masato Kajimoto, Aybüke Koyuncu, Shibani Kulkarni, Jaya Lamichhane, Rosamund Lewis, Avichal Mahajan, Ahmed Mandil, Erin McAweeney, Melanie Messer, Wesley Moy, Patricia Ndumbi Ngamala, Tim Nguyen, Mark Nunn, Saad B Omer, Claudia Pagliari, Palak Patel, Lynette Phuong, Dimitri Prybylski, Arash Rashidian, Emily Rempel, Sara Rubinelli, PierLuigi Sacco, Anton Schneider, Kai Shu, Melanie Smith, Harry Sufehmi, Viroj Tangcharoensathien, Robert Terry, Naveen Thacker, Tom Trewinnard, Shannon Turner, Heidi Tworek, Saad Uakkas, Emily Vraga, Claire Wardle, Herman Wasserman, Elisabeth Wilhelm, Andrea Würz, Brian Yau, Lei Zhou, Tina D Purnat. Originally published in JMIR Infodemiology (https://infodemiology.jmir.org), 15.09.2021.)

Objective: To evaluate the physiological impact of high CPAP (≥9 cmH 2 O) vs. NIPPV at equivalent mean airway pressures., Study Design: In this cross-over study, preterm neonates on high CPAP or NIPPV were placed on the alternate mode. After 30 min, left and right ventricular cardiac output and work of breathing indices were assessed, following which patients were placed back on the original mode and a similar procedure ensued., Results: Fifteen infants with mean (SD) postmenstrual age 32.7 (3.0) weeks, and weight 1569 (564) grams were included. No differences in LVO [320 (63) vs. 331 (86) mL/kg/min, P = 0.46] or RVO [420 (135) vs. 437 (141) mL/kg/min, P = 0.19] were noted during high CPAP vs. NIPPV, along with no differences in work of breathing indices., Conclusion: High CPAP pressures did not adversely impact cardiac output or work of breathing compared to NIPPV at equivalent mean airway pressure., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments., Material and Methods: Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively., Results and Conclusion: Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18-21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification., Methods: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath)., Results: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%., Conclusions: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1168). DK reports personal fees from AstraZeneca, Bristol-Myers Squibb, and Pfizer outside the submitted work. ALV reports personal fees from Astra Zeneca, outside the submitted work. RL reports grants from Deutsche Forschungsgemeinschaft (DFG), Dietmar Hopp Stiftung, outside the submitted work. CPH reports grants from Siemens, Pfizer, MeVis, Boehringer Ingelheim, German Center for Lung Research, personal fees from Astellas, AstraZeneca, Basilea, Bayer, Boehringer Ingelheim, Bracco MEDA Pharma, Chiesi, Covidien, Essex, Fresenius, Gilead, Grifols, Intermune, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Schering-Plough, Siemens, other from GSK, outside the submitted work; in addition, CPH has a patent Method and Device For Representing the Microstructure of the Lungs, IPC8 Class: AA61B5055FI, PAN: 20080208038 issued. FH reports personal fees from Uptake, BTG, Olympus, Pulmonx, outside the submitted work. PC reports grants and personal fees from Novartis, Roche, AstraZeneca, Takeda, and personal fees from Pfizer, Chugai, Boehringer, outside the submitted work. TM reports grants and non-financial support from Roche Diagnostics GmbH, Penzberg, Germany, outside the submitted work; in addition, TM has a patent WO2019158460 pending, a patent WO2019211418 pending, a patent WO2019215223 pending, a patent EP3391053 issued, and a patent EP3365679 pending. MR reports personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Lilly, Celgene, Merck, Mirati, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, outside the submitted work. WW reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas, Illumina, Agilent, Siemens, Molecular Health and grants from Roche, MSD, BMS, Bruker, AstraZeneca, outside the submitted work. JB reports grants from German Cancer Aid, outside the submitted work. MT reports grants, personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, Takeda, Roche, personal fees and non-financial support from AbbVie, Boehringer Ingelheim, Celgene, Chugai, Lilly, Novartis, Pfizer, outside the submitted work. SP reports personal fees from Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda, Takeda, Bioinvent, Medscape, Phosphoplatin Therapeutics; non-financial support from Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, Phosphoplatin; outside the submitted work; all fees to Institution. PS reports personal fees from BMS, MSD, Incyte, Janssen, Amgen, Novartis, Roche and AstraZeneca outside the submitted work. AS reports grants and personal fees from Bayer, BMS, grants from Chugai and personal fees from Astra Zeneca, MSD, Takeda, Seattle Genetics, Novartis, Illumina, Thermo Fisher, Eli Lily, Takeda, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Social media is a rich source where we can learn about people's reactions to social issues. As COVID-19 has impacted people's lives, it is essential to capture how people react to public health interventions and understand their concerns., Objective: We aim to investigate people's reactions and concerns about COVID-19 in North America, especially in Canada., Methods: We analyzed COVID-19-related tweets using topic modeling and aspect-based sentiment analysis (ABSA), and interpreted the results with public health experts. To generate insights on the effectiveness of specific public health interventions for COVID-19, we compared timelines of topics discussed with the timing of implementation of interventions, synergistically including information on people's sentiment about COVID-19-related aspects in our analysis. In addition, to further investigate anti-Asian racism, we compared timelines of sentiments for Asians and Canadians., Results: Topic modeling identified 20 topics, and public health experts provided interpretations of the topics based on top-ranked words and representative tweets for each topic. The interpretation and timeline analysis showed that the discovered topics and their trend are highly related to public health promotions and interventions such as physical distancing, border restrictions, handwashing, staying home, and face coverings. After training the data using ABSA with human-in-the-loop, we obtained 545 aspect terms (eg, "vaccines," "economy," and "masks") and 60 opinion terms such as "infectious" (negative) and "professional" (positive), which were used for inference of sentiments of 20 key aspects selected by public health experts. The results showed negative sentiments related to the overall outbreak, misinformation and Asians, and positive sentiments related to physical distancing., Conclusions: Analyses using natural language processing techniques with domain expert involvement can produce useful information for public health. This study is the first to analyze COVID-19-related tweets in Canada in comparison with tweets in the United States by using topic modeling and human-in-the-loop domain-specific ABSA. This kind of information could help public health agencies to understand public concerns as well as what public health messages are resonating in our populations who use Twitter, which can be helpful for public health agencies when designing a policy for new interventions., (©Hyeju Jang, Emily Rempel, David Roth, Giuseppe Carenini, Naveed Zafar Janjua. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 10.02.2021.)

The oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions by creating a tumor-supporting environment in conjunction with cell autonomous mechanisms. However, how YAP controls organization of the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood. To investigate heterotypic cell communication, we dissected murine and human liver endothelial cell (EC) populations into liver sinusoidal endothelial cells (LSEC) and continuous endothelial cells (CEC) through histomorphological and molecular characterization. In YAP S127A -induced tumorigenesis, a gradual replacement of LSECs by CECs was associated with dynamic changes in the expression of genes involved in paracrine communication. The formation of new communication hubs connecting CECs and LSECs included the hepatocyte growth factor (Hgf)/c-Met signaling pathway. In hepatocytes and tumor cells, YAP/TEA domain transcription factor 4 (TEAD4)-dependent transcriptional induction of osteopontin (Opn) stimulated c-Met expression in EC with CEC phenotype, which sensitized these cells to the promigratory effects of LSEC-derived Hgf. In human hepatocellular carcinoma, the presence of a migration-associated tip-cell signature correlated with poor clinical outcome and the loss of LSEC marker gene expression. The occurrence of c-MET-expressing CECs in human liver cancer samples was confirmed at the single-cell level. In summary, YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs in which tumor cell-derived factors modify the cross-talk between LSECs and CECs via the HGF/c-MET axis. SIGNIFICANCE: YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs in which tumor cell-derived factors modify the cross-talk between EC subpopulations. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5502/F1.large.jpg., (©2020 American Association for Cancer Research.)

Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype (p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype (p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs.

Objective: When wrongfully convicted individuals are released from prison, at first glance, it is a triumph; however, anecdotal evidence from exonerees suggests that obtaining housing postrelease is often challenging. We empirically examined whether race (Study 1) or type of criminal offense (Study 2) influenced landlords' willingness to rent to exonerees compared to releasees (i.e., rightfully convicted individuals released from prison) and control (i.e., members of the public)., Hypotheses: We hypothesized that: (a) exonerees and releasees would receive fewer replies and fewer "yes" available responses compared to control, (b) Indigenous and Black renters would receive fewer replies and fewer "yes" available responses compared to White renters, and (c) individuals convicted of murder would receive fewer replies and fewer "yes" available responses compared to individuals convicted of robbery., Method: The authors responded to online apartment listings across Canada (Study 1) and in Toronto (Study 2) inquiring about unit availability. All rental inquiries were identical with the exception of criminal status and race (Study 1), and criminal status and criminal offense (Study 2)., Results: Results demonstrated that landlords were significantly less likely to respond (Study 1: OR = 4.32, 95% CI [3.28, 5.69]; Study 2: OR = 7.88, 95% CI [4.97, 12.48]), and indicate availability (Study 1: OR = 6.62, 95% CI [3.54, 12.38]; Study 2: OR = 21.53, 95% CI [7.07, 65.58]), to rental inquiries from exonerees and releasees compared to members of the public. For race, landlords were significantly less likely to respond to inquiries from Indigenous and Black renters compared to White renters (OR = 1.45, 95% CI [1.12, 1.86]), and those convicted of robbery compared to murder (OR = 1.69, 95% CI [.36, .97])., Conclusion: The barriers that exonerees face when attempting to secure housing postrelease are potentially as great as those facing releasees; however, exonerees do not receive assistance with reentry. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Inflammatory gene signatures are currently being explored as predictive biomarkers for immune checkpoint blockade, and particularly for the treatment of renal cell cancers. From a diagnostic point of view, the nCounter analysis platform and targeted RNA sequencing are emerging alternatives to microarrays and comprehensive transcriptome sequencing in assessing formalin-fixed and paraffin-embedded (FFPE) cancer samples. So far, no systematic study has analyzed and compared the technical performance metrics of these two approaches. Filling this gap, we performed a head-to-head comparison of two commercially available immune gene expression assays, using clear cell renal cell cancer FFPE specimens. We compared the nCounter system that utilizes a direct hybridization technology without amplification with an NGS assay that is based on targeted RNA-sequencing with preamplification. We found that both platforms displayed high technical reproducibility and accuracy (Pearson coefficient: ≥0.96, concordance correlation coefficient [CCC]: ≥0.93). A density plot for normalized expression of shared genes on both platforms showed a comparable bi-modal distribution and dynamic range. RNA-Seq demonstrated relatively larger signaling intensity whereas the nCounter system displayed higher inter-sample variability. Estimated fold changes for all shared genes showed high correlation (Spearman coefficient: 0.73). This agreement is even better when only significantly differentially expressed genes were compared. Composite gene expression profiles, such as an interferon gamma (IFNg) signature, can be reliably inferred by both assays. In summary, our study demonstrates that focused transcript read-outs can reliably be achieved by both technologies and that both approaches achieve comparable results despite their intrinsic technical differences., (© 2020 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals, Inc.)

Introduction: Tumor mutational burden (TMB) is a quantitative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment., Methods: A total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell carcinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classification, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated., Results: Sixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise comparisons revealing a Spearman's ρ greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation artifacts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points., Conclusions: This study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important parameters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the evaluation of such assays., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Retrospective data including subgroup analyses in clinical studies have sparked strong interest in developing tumor mutational burden (TMB) as a predictive biomarker for immune checkpoint blockade. While individual factors influencing panel sequencing based measurement of TMB (psTMB) have been discussed in the recent literature, an integrative study quantifying, comparing and combining all potential confounders is still missing., Material and Methods: We separated different potential confounders of psTMB measurement including "panel size", "germline mutation filtering", "biological variance" and "technical variance" and developed a specific error model for each of these factors. Published experimental psTMB data were fitted to the error models to quantify the contribution of each of the confounders. The total psTMB variance was obtained as sum over the variance contributions of each of the confounders., Results: Using a typical large panel (size 1-1.5 Mbp) total errors of 57 %, 42 %, 34 % and 28 % were observed for tumors with psTMB of 5, 10, 20 and 40 muts/Mbp. Even for large panels, the stochastic error connected to the panel size represented the largest of all contributions to the total psTMB variance, especially for tumors with TMB up to 20 muts/Mbp. Other sources of psTMB variability could be kept under control, but rigorous quality control, best practice laboratory workflows and optimized bioinformatics pipelines are essential., Conclusion: A statistical framework for the analysis of complex, genomic biomarkers was developed and applied to the analysis of psTMB variability. The methods developed here can support the analysis of other quantitative biomarkers and their implementation in clinical practice., Competing Interests: Declaration of Competing Interest Dr. Budczies has nothing to disclose. Dr. Kazdal reports personal fees from Pfizer Pharma GmbH, outside the submitted work. Dr. Allgäuer has nothing to disclose. Dr. Christopoulos reports personal fees from Roche, personal fees from Chugai, grants and personal fees from Novartis, grants from Takeda, outside the submitted work. Dr. Rempel has nothing to disclose. Mrs. Pfarr has nothing to disclose. Dr. Weichert reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas and grants from Roche, MSD, BMS, Bruker outside the submitted work. Dr. Fröhling reports personal fees from Amgen, grants from AstraZeneca, personal fees from Eli Lilly, grants from Pfizer, grants from PharmaMar, personal fees from Roche, personal fees from Bayer, outside the submitted work;. Dr. Thomas reports personal fees from AbbVie, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from Boehringer, grants and personal fees from Celgene, personal fees from Lilly, personal fees and non-financial support from MSD, personal fees and non-financial support from Novartis, grants and personal fees from Roche, personal fees from Takeda, grants from AstraZeneca, outside the submitted work. Dr. Peters reports personal fees from Abbvie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, personal fees from Boehringer-Ingelheim, personal fees from Bistrol-Myers Squibb, personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Foundation Medicine, personal fees from Illumina, personal fees from Janssen, personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack, personal fees from Novartis, personal fees from Pharma Mar, personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics and Takeda, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Merck Sharp and Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, non-financial support from Sponsored by Amgen, non-financial support from AstraZeneca, non-financial support from Boehringer-Ingelheim, non-financial support from Bristol-Meyers Squibb, non-financial support from Clovis, non-financial support from F. Hoffmann-La Roche, non-financial support from Illumina, non-financial support from Merck Sharp and Dohme, non-financial support from Merck Serono, non-financial support from Novartis, non-financial support from Pfizer, personal fees from Sanofi, personal fees from Bioinvent, personal fees from Blueprint Medicine, outside the submitted work. Dr. Endris reports personal fees from Thermo Fisher, personal fees from Astra Zeneca, outside the submitted work. Dr. Schirmacher reports grants from QuIP, during the conduct of the study; grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Roche, grants and personal fees from AstraZeneca, grants and personal fees from Novartis, personal fees from Chugai, personal fees from AbbVie, grants from Sanofi-Aventis, personal fees from Ipsen, grants and personal fees from Pfizer, grants from Illumina, grants from Thermo Fisher, outside the submitted work. Dr. Stenzinger reports other from Ilumina, during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Bristol-Myers Squibb, personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Illumina, personal fees from MSD, personal fees from Roche, grants from Chugai, outside the submitted work., (Copyright © 2020 Elsevier B.V. All rights reserved.)