Individuals with Recurrent Low Back Pain Exhibit Significant Changes of Paraspinal Muscle Performance after Lumbar Multifidus Intramuscular Fine Wire Electrode Insertion

STUDY DESIGN: Case control study. BACKGROUND: Recurrent low back pain (RLBP) is associated with paraspinal muscle dysfunction. Intramuscular electromyography (EMG) is a common tool for studying activation of the deep lumbar paraspinal muscles such as multifidi muscles, but it is currently currently unclear how muscle performance and activation are affected by the pain and micro-injury associated with intramuscular fine-wire electrode (IFWE) insertion and how it interacts with the presence of RLBP. OBJECTIVES: The purpose of this study was to examine how IFWE insertion into the lumbar multifidus affects paraspinal muscle strength and endurance in subjects with and without RLBP. METHODS: Forty subjects aged 18 - 40 were recruited; 20 subjects with a history of RLBP were compared with a group of 20 age-matched controls with no RLBP. Paraspinal extensor strength and endurance were measured under three conditions over three testing days. On Day 1, the baseline condition (BL), we obtained preliminary measures of discomfort, force production, endurance, and muscle activation. On Days 2 and 3, the participants randomly alternated between the two experimental conditions: (i) a wire-in condition (WI) in which the IFWE was inserted and remained within the muscle and (ii) a wire-out condition (WO) in which the IFWE was inserted and immediately removed. Participants were blinded to the order of the fine-wire conditions. Subjective pain levels were recorded via the Visual Analog Scale at specific time points throughout the testing protocol. RESULTS: Individuals with RLBP showed a significant decrease in strength in both conditions that involved IFWE insertion. Controls showed no significant difference in strength across conditions. Both groups exhibited similar performance in the endurance test. CONCLUSION: Our findings indicate IFWE insertion into lumbar multifidus may lead to reduced peak spinal extensor muscle force production in individuals with a history of RLBP compared to healthy controls

Individuals with Recurrent Low Back Pain Exhibit Significant Changes in Paraspinal Muscle Strength after Intramuscular Fine Wire Electrode Insertion

Objective To examine how insertion and presence of intramuscular fine‐wire electromyography electrodes (IFWE) in lumbar multifidus affect paraspinal muscle strength, endurance, and activation in persons with and without recurrent lower back pain (RLBP) during activities that require high levels of muscle contraction. Design Case‐control with randomization of conditions. Setting Clinical Research Laboratory. Participants Forty participants age 18‐40 were recruited (18 female; mean age = 25.5 yr); 20 with a history of RLBP were compared to a matching control group of 20 without RLBP. Interventions Each participant was tested under three conditions over three sessions. On Session 1, the baseline condition, we assessed muscle performance without IFWE insertion. On Sessions 2 and 3, participants were randomly alternated between two experimental conditions: a) wire‐in, in which the IFWE was inserted and remained within the muscle during testing, and b) wire‐out, in which the IFWE was inserted and immediately removed. Main Outcome Measures Lumbar spinal extensor peak strength, endurance, and normalized EMG amplitude during the endurance test. Results Individuals with RLBP showed a significant decrease in peak strength during conditions that involved IFWE insertion and tend to experience more pain during muscle testing. Both groups exhibited similar levels of performance and muscle activation during the endurance test. Conclusion Our findings indicate that individuals with RLBP exhibited reduced lumbar extensor strength in response to IFWE insertion to the deep paraspinal muscles. This behavior is different from those without RLBP. Researchers should carefully consider the use of IFWE electromyography in individuals with RLBP during high exertion activities

Life Beyond the Solar System: Remotely Detectable Biosignatures

For the first time in human history, we will soon be able to apply to the scientific method to the question "Are We Alone?" The rapid advance of exoplanet discovery, planetary systems science, and telescope technology will soon allow scientists to search for life beyond our Solar System through direct observation of extrasolar planets. This endeavor will occur alongside searches for habitable environments and signs of life within our Solar System. While these searches are thematically related and will inform each other, they will require separate observational techniques. The search for life on exoplanets holds potential through the great diversity of worlds to be explored beyond our Solar System. However, there are also unique challenges related to the relatively limited data this search will obtain on any individual world

Rewriting the just war tradition: just war in classical Greek political thought and practice

The just war tradition is the predominant western framework for thinking about the ethics of contemporary war. Political and military leaders frequently invoke its venerable lineage to lend ballast to their arguments for or against particular wars. How we understand the history of just war matters, then, for it subtends how that discourse is deployed today. Conventional accounts of the just war trace its origins to the writings of Saint Augustine in the 4th century CE. This discounts the possibility that just war ideas were in circulation prior to this, in the classical world. This article contests this omission. It contends that ideas homologous to a range of core jus ad bellum, jus in bello, and jus post bellum principles were evident in classical Greek political thought and practice. This finding challenges scholars to re-consider not only the common view that the just war is, at root, a Christian tradition, but also the relation between victory and just war, the nature of the ties binding just war and Islamic jihad, and an innovative approach to the comparative ethics of war

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource