Classifying Future Healthcare Utilization in COPD Using Quantitative CT Lung Imaging and Two-Step Feature Selection via Sparse Subspace Learning with the CanCOLD Study.

RATIONALE: Although numerous candidate features exist for predicting risk of higher risk of healthcare utilization in patients with chronic obstructive pulmonary disease (COPD), the process for selecting the most discriminative features remains unclear. OBJECTIVE: The objective of this study was to develop a robust feature selection method to identify the most discriminative candidate features for predicting healthcare utilization in COPD, and compare the model performance with other common feature selection methods. MATERIALS AND METHODS: In this retrospective study, demographic, lung function measurements and CT images were collected from 454 COPD participants from the Canadian Cohort Obstructive Lung Disease study from 2010-2017. A follow-up visit was completed approximately 1.5 years later and participants reported healthcare utilization. CT analysis was performed for feature extraction. A two-step hybrid feature selection method was proposed that utilized: (1) sparse subspace learning with nonnegative matrix factorization, and, (2) genetic algorithm. Seven commonly used feature selection methods were also implemented that reported the top 10 or 20 features for comparison. Performance was evaluated using accuracy. RESULTS: Of the 454 COPD participants evaluated, 161 (35%) utilized healthcare services at follow-up. The accuracy for predicting subsequent healthcare utilization for the seven commonly used feature selection methods ranged from 72%-76% with the top 10 features, and 77%-80% with the top 20 features. Relative to these methods, hybrid feature selection obtained significantly higher accuracy for predicting subsequent healthcare utilization at 82% ± 3% (p < 0.05). Selected features with the proposed method included: DLCO, FEV1, RV, FVC, TAC, LAA950, Pi-10, LAA856, LAC total hole count, outer area RB1, wall area RB1, wall area and Jacobian. CONCLUSION: The hybrid feature selection method identified the most discriminative features for classifying individuals with and without future healthcare utilization, and increased the accuracy compared to other state-of-the-art approaches.

Oncogene-driven non-small cell lung cancers in patients with a history of smoking lack smoking-induced mutations.

Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in non-smokers, alterations in these "non-smoking-related oncogenes" (NSROs) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared to typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC datasets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to regulation of the cell cycle. These findings suggest that, while the genomic landscape is similar between NSRO-driven NSCLC in smokers and non-smokers, smoking still affects the tumor phenotype independently of genomic alterations.

Haemodynamic compensations for exercise tissue oxygenation in early stages of COPD: an integrated cardiorespiratory assessment study.

BACKGROUND: Cardiovascular comorbidities are increasingly being recognised in early stages of chronic obstructive pulmonary disease (COPD) yet complete cardiorespiratory functional assessments of individuals with mild COPD or presenting with COPD risk factors are lacking. This paper reports on the effectiveness of the cardiocirculatory-limb muscles oxygen delivery and utilisation axis in smokers exhibiting no, or mild to moderate degrees of airflow obstruction using standardised cardiopulmonary exercise testing (CPET). METHODS: Post-bronchodilator spirometry was used to classify participants as 'ever smokers without' (n=88), with 'mild' (n=63) or 'mild-moderate' COPD (n=56). All underwent CPET with continuous concurrent monitoring of oxygen uptake (V'O2) and of bioimpedance cardiac output (Qc) enabling computation of arteriovenous differences (a-vO2). Mean values of Qc and a-vO2 were mapped across set ranges of V'O2 and Qc isolines to allow for meaningful group comparisons, at same metabolic and circulatory requirements. RESULTS: Peak exercise capacity was significantly reduced in the 'mild-moderate COPD' as compared with the two other groups who showed similar pulmonary function and exercise capacity. Self-reported cardiovascular and skeletal muscle comorbidities were not different between groups, yet disease impact and exercise intolerance scores were three times higher in the 'mild-moderate COPD' compared with the other groups. Mapping of exercise Qc and a-vO2 also showed a leftward shift of values in this group, indicative of a deficit in peripheral O2 extraction even for submaximal exercise demands. Concurrent with lung hyperinflation, a distinctive blunting of exercise stroke volume expansion was also observed in this group. CONCLUSION: Contrary to the traditional view that cardiovascular complications were the hallmark of advanced disease, this study of early COPD spectrum showed a reduced exercise O2 delivery and utilisation in individuals meeting spirometry criteria for stage II COPD. These findings reinforce the preventive clinical management approach to preserve peripheral muscle circulatory and oxidative capacities.

Muramyl dipeptide causes mitochondrial dysfunction and intestinal inflammatory cytokine responses in rats.

INTRODUCTION: Intestinal flora and the translocation of its products, such as muramyl dipeptide (MDP), are common causes of sepsis. MDP is a common activator of the intracellular pattern recognition receptor NOD2, and MDP translocation can cause inflammatory damage to the small intestine and systemic inflammatory responses in rats. Therefore, this study investigated the effects of MDP on the intestinal mucosa and distant organs during sepsis and the role of the NOD2/AMPK/LC3 pathway in MDP-induced mitochondrial dysfunction in the intestinal epithelium. METHODS: Fifty male Sprague Dawley rats were randomly divided into five treatment groups: lipopolysaccharide (LPS) only, 1.5 and 15 mg/kg MDP + LPS, and 1.5 and 15 mg/kg MDP + short-peptide enteral nutrition (SPEN) + LPS. The total caloric intake was the same per group. The rats were euthanized 24 hours after establishing the model, and peripheral blood and small intestinal mucosal and lung tissues were collected. RESULTS: Compared to the LPS group, both MDP + LPS groups had aggravated inflammatory damage to the intestinal mucosal and lung tissues, increased IL-6 and MDP production, increased NOD2 expression, decreased AMPK and LC3 expression, increased mitochondrial reactive oxygen species production, and decreased mitochondrial membrane potential. Compared to the MDP + LPS groups, the MDP + SPEN+LPS groups had decreased IL-6 and MDP production, increased AMPK and LC3 protein expression, and protected mitochondrial and organ functions. CONCLUSIONS: MDP translocation reduced mitochondrial autophagy by regulating the NOD2/AMPK/LC3 pathway, causing mitochondrial dysfunction. SPEN protected against MDP-induced impairment of intestinal epithelial mitochondrial function during sepsis.

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

BACKGROUND: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. METHODS: This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. RESULTS: The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p < .0001). CONCLUSIONS: ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

Abnormal Exertional Breathlessness on Cardiopulmonary Cycle Exercise Testing in Relation to Self-Reported and Physiologic Responses in Chronic Airflow Limitation.

BACKGROUND: Exertional breathlessness is a cardinal symptom of cardiorespiratory disease. RESEARCH QUESTION: How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)? STUDY DESIGN AND METHODS: An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated. RESULTS: We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV1/FVC, 57.3% ± 8.2%; FEV1, 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET. INTERPRETATION: Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting construct validity of abnormal exertional breathlessness.

Airway tree caliber heterogeneity and airflow obstruction among older adults.

Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomical locations (trachea-to-subsegments) and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height, and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. Among 2,505 MESA Lung participants (means ± SD age: 69 ± 9 yr; 53% female, mean airway tree caliber: 99 ± 10% predicted, airway tree caliber heterogeneity: 14 ± 5%; median follow-up: 6.1 yr), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV1 (adjusted mean difference: -125 mL, 95%CI: -171,-79), lower FEV1/FVC (adjusted mean difference: -0.01, 95%CI: -0.02,-0.01), and higher odds of COPD (adjusted odds ratio: 1.42, 95%CI: 1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV1 and FEV1/FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry.NEW & NOTEWORTHY In this study, by leveraging two community-based samples and a case-control study of heavy smokers, we show that among older adults, airway tree caliber heterogeneity quantified by CT is associated with airflow obstruction and COPD independent of age, sex, height, race-ethnicity, and dysanapsis. These observations suggest that airway tree caliber heterogeneity is a structural trait associated with low baseline lung function and normal decline trajectory that is relevant to COPD.

Physiological Characterization of Preserved Ratio Impaired Spirometry in the CanCOLD Study: Implications for Exertional Dyspnea and Exercise Intolerance.

Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV1 < 80% predicted and FEV1/FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/[Formula: see text]o2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P < 0.001) and lower [Formula: see text]o2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with [Formula: see text]o2peak (r = 0.65; P < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with www.clinicaltrials.gov (NCT00920348).

A fully automated pipeline for the extraction of pectoralis muscle area from chest computed tomography scans.

Background: Computed tomography (CT)-derived pectoralis muscle area (PMA) measurements are prognostic in people with or at-risk of COPD, but fully automated PMA extraction has yet to be developed. Our objective was to develop and validate a PMA extraction pipeline that can automatically: 1) identify the aortic arch slice; and 2) perform pectoralis segmentation at that slice. Methods: CT images from the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study were used for pipeline development. Aorta atlases were used to automatically identify the slice containing the aortic arch by group-based registration. A deep learning model was trained to segment the PMA. The pipeline was evaluated in comparison to manual segmentation. An external dataset was used to evaluate generalisability. Model performance was assessed using the Dice-Sorensen coefficient (DSC) and PMA error. Results: In total 90 participants were used for training (age 67.0±9.9 years; forced expiratory volume in 1 s (FEV1) 93±21% predicted; FEV1/forced vital capacity (FVC) 0.69±0.10; 47 men), and 32 for external testing (age 68.6±7.4 years; FEV1 65±17% predicted; FEV1/FVC 0.50±0.09; 16 men). Compared with manual segmentation, the deep learning model achieved a DSC of 0.94±0.02, 0.94±0.01 and 0.90±0.04 on the true aortic arch slice in the train, validation and external test sets, respectively. Automated aortic arch slice detection obtained distance errors of 1.2±1.3 mm and 1.6±1.5 mm on the train and test data, respectively. Fully automated PMA measurements were not different from manual segmentation (p>0.05). PMA measurements were different between people with and without COPD (p=0.01) and correlated with FEV1 % predicted (p<0.05). Conclusion: A fully automated CT PMA extraction pipeline was developed and validated for use in research and clinical practice.

Prevalence of chronic cough, its risk factors and population attributable risk in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study.

Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition. Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors. Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job. Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors. Funding: Wellcome Trust.

Dysanapsis is not associated with exertional dyspnoea in healthy male and female never-smokers aged 40 years and older.

In healthy adults, airway-to-lung (i.e., dysanapsis) ratio is lower and dyspnoea during exercise at a given minute ventilation (V̇E) is higher in females than in males. We investigated the relationship between dysanapsis and sex on exertional dyspnoea in healthy adults. We hypothesized that females would have a smaller airway-to-lung ratio than males and that exertional dyspnoea would be associated with airway-to-lung ratio in males and females. We analyzed data from n = 100 healthy never-smokers aged ≥40 years enrolled in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study who underwent pulmonary function testing, a chest computed tomography scan, and cardiopulmonary exercise testing. The luminal area of the trachea, right main bronchus, left main bronchus, right upper lobe, bronchus intermedius, left upper lobe, and left lower lobe were 22%-37% smaller (all p < 0.001) and the airway-to-lung ratio (i.e., average large conducting airway diameter relative to total lung capacity) was lower in females than in males (0.609 ± 0.070 vs. 0.674 ± 0.082; p < 0.001). During exercise, there was a significant effect of V̇E, sex, and their interaction on dyspnoea (all p < 0.05), indicating that dyspnoea increased as a function of V̇E to a greater extent in females than in males. However, after adjusting for age and total lung capacity, there were no significant associations between airway-to-lung ratio and measures of exertional dyspnoea, regardless of sex (all r < 0.34; all p > 0.05). Our findings suggest that sex differences in airway size do not contribute to sex differences in exertional dyspnoea.

Normative Reference Equations for Breathlessness Intensity during Incremental Cardiopulmonary Cycle Exercise Testing.

Rationale: Cardiopulmonary exercise testing (CPET) is the gold standard to evaluate exertional breathlessness, a common and disabling symptom. However, the interpretation of breathlessness responses to CPET is limited by a scarcity of normative data. Objectives: We aimed to develop normative reference equations for breathlessness intensity (Borg 0-10 category ratio) response in men and women aged ⩾40 years during CPET, in relation to power output (watts), oxygen uptake, and minute ventilation. Methods: Analysis of ostensibly healthy people aged ⩾40 years undergoing symptom-limited incremental cycle CPET (10 W/min) in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study. Participants had smoking histories <5 pack-years and normal lung function and exercise capacity. The probability of each Borg 0-10 category ratio breathlessness intensity rating by power output, oxygen uptake, and minute ventilation (as an absolute or a relative value [percentage of predicted maximum]) was predicted using ordinal multinomial logistic regression. Model performance was evaluated by fit, calibration, and discrimination (C statistic) and externally validated in an independent sample (n = 86) of healthy Canadian adults. Results: We included 156 participants (43% women) from CanCOLD; the mean age was 65 (range, 42-91) years, and the mean body mass index was 26.3 (standard deviation, 3.8) kg/m2. Reference equations were developed for women and men separately, accounting for age and/or body mass. Model performance was high across all equations, including in the validation sample (C statistic for men = 0.81-0.92, C statistic for women = 0.81-0.96). Conclusions: Normative reference equations are provided to compare exertional breathlessness intensity ratings among individuals or groups and to identify and quantify abnormal breathlessness responses (scores greater than the upper limit of normal) during CPET.

The modified Borg/6-min walk distance ratio: a method to assess exertional breathlessness and leg discomfort using the 6-min walk test.

Background: The 6-min walk test (6MWT) is widely used to assess exercise capacity across chronic health conditions, but is currently not useful to assess symptoms, as the scores do not account for the 6-min walk distance (6MWD). We aimed to 1) develop normative reference equations for breathlessness and leg discomfort intensity expressed as modified Borg (mBorg)/6MWD ratios; and 2) validate the equations in people with COPD. Methods: Analysis of people aged ≥40 years who performed two 6MWTs (on a 20-m course) in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study: a healthy cohort (n=291; mean±sd age 67.5±9.4 years; 54% male) with normal 6MWD and lung function, and a COPD cohort (n=156; age 66.2±9.0 years; 56% male; forced expiratory volume in 1 s (FEV1)/forced vital capacity 56.6±8.2%; FEV1 74.4±18.6% pred). The mBorg score was calculated as the Borg 0-10 category ratio intensity rating of breathlessness or leg discomfort recorded at the end of the 6MWT +1 (range 1-11), to avoid zeros and yield ratios proportional to the symptom score and 6MWD-1. Results: Using data from the healthy cohort, sex-specific normative reference equations for breathlessness and leg discomfort mBorg/6MWD ratios were developed using multivariable linear regression, accounting for age, and body mass or body mass index. In the COPD cohort, abnormal breathlessness and leg discomfort (mBorg/6MWD>upper limit of normal) showed strong concurrent validity with worse airflow limitation, Medical Research Council breathlessness and COPD Assessment Test scores. Conclusion: Normative references for the mBorg/6MWD ratio are presented to assess breathlessness and leg discomfort responses to the 6MWT in COPD.

An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model.

Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources.

The Promise of Epigenetics Research in the Treatment of Appendiceal Neoplasms.

Appendiceal cancers (AC) are a rare and heterogeneous group of malignancies. Historically, appendiceal neoplasms have been grouped with colorectal cancers (CRC), and treatment strategies have been modeled after CRC management guidelines due to their structural similarities and anatomical proximity. However, the two have marked differences in biological behavior and treatment response, and evidence suggests significant discrepancies in their respective genetic profiles. In addition, while the WHO classification for appendiceal cancers is currently based on traditional histopathological criteria, studies have demonstrated that histomorphology does not correlate with survival or treatment response in AC. Due to their rarity, appendiceal cancers have not been studied as extensively as other gastrointestinal cancers. However, their incidence has been increasing steadily over the past decade, making it crucial to identify new and more effective strategies for detection and treatment. Recent efforts to map and understand the molecular landscape of appendiceal cancers have unearthed a wealth of information that has made it evident that appendiceal cancers possess a unique molecular profile, distinct from other gastrointestinal cancers. This review focuses on the epigenetic landscape of epithelial appendiceal cancers and aims to provide a comprehensive overview of the current state of knowledge of epigenetic changes across different appendiceal cancer subtypes, highlighting the challenges as well as the promise of employing epigenetics in the quest for the detection of biomarkers, therapeutic targets, surveillance markers, and predictors of treatment response and survival in epithelial appendiceal neoplasms.

A unique presentation of acute tophaceous gout in the lumbar spine causing cauda equina syndrome.

Gout is a common metabolic disease characterized by the deposition of monosodium urate (MSU) crystals and typically affects the peripheral joint, rarely involving the axial skeleton. We present a rare case of acute tophaceous gout in the lumbar spine causing cauda equina syndrome. A 60-year-old man with a history of gout and prior admissions for polyarticular gout flare presented with acute onset of bilateral lower limb numbness and weakness. He underwent surgical decompression with drainage of the epidural collection, with histology consistent with tophaceous gout. The patient made a full recovery postoperatively and was discharged uneventfully. Due to the high initial suspicion for gout, early spinal decompression surgery was performed, and the patient was started on medical therapy. Spinal tophaceous should be considered in the list of different diagnoses of spinal epidural masses especially in the context of a history of gouty arthritis.

Anti-fibrotic strategies and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) results from the dysregulated process of injury and repair, which promotes scarring of the lung tissue and deposition of collagen-rich extracellular matrix (ECM) components, that make the lung unphysiologically stiff. IPF presents a serious concern as its pathogenesis remains elusive, and current anti-fibrotic treatments are only effective in slowing rather than halting disease progression. The IPF disease pathogenesis is incompletely defined, complex and incorporates interplay between different fibrogenesis signaling pathways. Preclinical IPF experimental models used to validate drug candidates present significant limitations in modeling IPF pathobiology, with their limited time frame, simplicity and inaccurate representation of the disease and the mechanical influences of IPF. Potentially more accurate mimetic disease models that capture the cell-cell and cell-matrix interaction, such as 3D cultures, organoids and precision-cut lung slices (PCLS), may yield more meaningful clinical predictions for drug candidates. Recent advances in developing anti-fibrotic compounds have positioned drug towards targeting components of the fibrogenesis signaling pathway of IPF or the extracellular microenvironment. The major goals in this area of research focus on finding ways to reverse or halt the disease progression by utilizing more disease-relevant experimental models to improve the qualification of potential drug targets for treating pulmonary fibrosis.

CT Imaging With Machine Learning for Predicting Progression to COPD in Individuals at Risk.

BACKGROUND: Identifying individuals at risk of progressing to COPD may allow for initiation of treatment to potentially slow the progression of the disease or the selection of subgroups for discovery of novel interventions. RESEARCH QUESTION: Does the addition of CT imaging features, texture-based radiomic features, and established quantitative CT scan to conventional risk factors improve the performance for predicting progression to COPD in individuals who smoke with machine learning? STUDY DESIGN AND METHODS: Participants at risk (individuals who currently or formerly smoked, without COPD) from the Canadian Cohort Obstructive Lung Disease (CanCOLD) population-based study underwent CT imaging at baseline and spirometry at baseline and follow-up. Various combinations of CT scan features, texture-based CT scan radiomics (n = 95), and established quantitative CT scan (n = 8), as well as demographic (n = 5) and spirometry (n = 3) measurements, with machine learning algorithms were evaluated to predict progression to COPD. Performance metrics included the area under the receiver operating characteristic curve (AUC) to evaluate the models. DeLong test was used to compare the performance of the models. RESULTS: Among the 294 at-risk participants who were evaluated (mean age, 65.6 ± 9.2 years; 42% female; mean pack-years, 17.9 ± 18.7), 52 participants (23.7%) in the training data set and 17 participants (23.0%) in the testing data set progressed to spirometric COPD at follow-up (2.5 ± 0.9 years from baseline). Compared with machine learning models with demographics alone (AUC, 0.649), the addition of CT imaging features to demographics (AUC, 0.730; P < .05) or CT imaging features and spirometry to demographics (AUC, 0.877; P < .05) significantly improved the performance for predicting progression to COPD. INTERPRETATION: Heterogeneous structural changes occur in the lungs of individuals at risk that can be quantified using CT imaging features, and evaluation of these features together with conventional risk factors improves performance for predicting progression to COPD.