In Situ Lung Dust Analysis by Automated Field Emission Scanning Electron Microscopy With Energy Dispersive X-ray Spectroscopy: A Method for Assessing Inorganic Particles in Lung Tissue From Coal Miners.

CONTEXT.­: Overexposure to respirable coal mine dust can cause severe lung disease including progressive massive fibrosis (PMF). Field emission scanning electron microscopy with energy dispersive x-ray spectroscopy (FESEM-EDS) has been used for in situ lung dust particle analysis for evaluation of disease etiology. Automating such work can reduce time, costs, and user bias. OBJECTIVE.­: To develop and test an automated FESEM-EDS method for in situ analysis of inorganic particles in coal miner lung tissue. DESIGN.­: We programmed an automated FESEM-EDS procedure to collect particle size and elemental data, using lung tissue from 10 underground coal miners with PMF and 4 control cases. A statistical clustering approach was used to establish classification criteria based on particle chemistry. Data were correlated to PMF/non-PMF areas of the tissue, using corresponding brightfield microscopy images. Results for each miner case were compared with a separate corresponding analysis of particles recovered following tissue digestion. RESULTS.­: In situ analysis of miner tissues showed higher particle number densities than controls and densities were generally higher in PMF than non-PMF areas. Particle counts were typically dominated by aluminum silicates with varying percentages of silica. Compared to digestion results for the miner tissues, in situ results indicated lower density of particles (number per tissue volume), larger size, and a lower ratio of silica to total silicates-probably due to frequent particle clustering in situ. CONCLUSIONS.­: Automated FESEM-EDS analysis of lung dust is feasible in situ and could be applied to a larger set of mineral dust-exposed lung tissues to investigate specific histologic features of PMF and other dust-related occupational diseases.

Assessment of Dosing Strategies for Pediatric Drug Products.

Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing. Therefore, we sought to understand the landscape of pediatric drug dosing by characterizing the dosing strategies from drug products recently approved for pediatric indications identified using FDA Drug Databases and analyze the impact of body size descriptors (age, body surface area, weight) on drug pharmacokinetics for several selected antipsychotics approved in pediatric patients. Our review of these pediatric databases revealed a dependence on body size-guided dosing, with 68% of dosing in pediatric drug labelings being dependent on knowing either the age, body surface area, or weight of the patient to guide dosing for pediatric patients. This dependence on body size-guided dosing drives the need for special consideration when dosing a drug in overweight and obese patients. Exploratory pharmacokinetic analyses in antipsychotics illustrate possible effects of drug exposure when applying different dosing strategies for this class of drugs. Future efforts should aim to further understand the pediatric drug dosing and obesity paradigm across pediatric age ranges and drug classes to optimize drug development and clinical care for this patient population.

Pathologic Findings in Severe Coal Workers' Pneumoconiosis in Contemporary US Coal Miners.

CONTEXT.­: The pathology of coal workers' pneumoconiosis (CWP) and its most severe form-progressive massive fibrosis (PMF)-in US coal miners has changed in recent years. Severe disease is occurring in younger miners and has been linked to an increase in silica dust exposure. OBJECTIVE.­: To update the description of the pathologic features of CWP in contemporary miners compared to historical miners. DESIGN.­: This study is a retrospective expert classification of lung tissue from 85 historical and contemporary coal miners with PMF. Significant pathologic features were scored by using a standardized instrument with consensus achieved for major findings, including newly defined categories of PMF as coal-type, mixed-type, and silica-type. RESULTS.­: Pathologic features associated with silica dust exposure, including silica-type PMF, mineral dust alveolar proteinosis (MDAP), and immature (early stage) silicotic nodules were increased in contemporary miners. Detailed descriptions of the pathology of contemporary CWP with illustrative figures are provided. CONCLUSIONS.­: Silica-related pathologies are more common in contemporary miners. Severe forms of CWP can be detected by subtyping PMF lesions (if present) or by identification of mature and immature silicotic nodules, coal mine dust-related alveolar proteinosis, and severe inflammation in coal miners' lungs. Silica-type PMF cases showed significantly higher levels of MDAP than either mixed- or coal-type PMF (P < .001). High profusion of birefringent silica/silicate particles was observed more frequently in cases with immature (early stage) silicotic nodules (P = .04). Severe inflammation was also significantly increased in contemporary miners (P = .03). Our findings underscore the urgent need to revise current exposure limits and monitoring of respirable crystalline silica in US coal mines.

Historical shift in pathological type of progressive massive fibrosis among coal miners in the USA.

BACKGROUND: Pneumoconiosis among coal miners in the USA has been resurgent over the past two decades, despite modern dust controls and regulatory standards. Previously published studies have suggested that respirable crystalline silica (RCS) is a contributor to this disease resurgence. However, evidence has been primarily indirect, in the form of radiographic features. METHODS: We obtained lung tissue specimens and data from the National Coal Workers' Autopsy Study. We evaluated specimens for the presence of progressive massive fibrosis (PMF) and used histopathological classifications to type these specimens into coal-type, mixed-type and silica-type PMF. Rates of each were compared by birth cohort. Logistic regression was used to assess demographic and mining characteristics associated with silica-type PMF. RESULTS: Of 322 cases found to have PMF, study pathologists characterised 138 (43%) as coal-type, 129 (40%) as mixed-type and 55 (17%) as silica-type PMF. Among earlier birth cohorts, coal-type and mixed-type PMF were more common than silica-type PMF, but their rates declined in later birth cohorts. In contrast, the rate of silica-type PMF did not decline in cases from more recent birth cohorts. More recent year of birth was significantly associated with silica-type PMF. CONCLUSIONS: Our findings demonstrate a shift in PMF types among US coal miners, from a predominance of coal- and mixed-type PMF to a more commonly encountered silica-type PMF. These results are further evidence of the prominent role of RCS in the pathogenesis of pneumoconiosis among contemporary US coal miners.

Pathology and Mineralogy of the Pneumoconioses.

Pneumoconioses represent the spectrum of lung diseases caused by inhalation of respirable particulate matter small enough (typically <5-µm diameter) to reach the terminal airways and alveoli. Pneumoconioses primarily occur in occupational settings where workers perform demanding and skilled manual labor including mining, construction, stone fabrication, farming, plumbing, electronics manufacturing, shipyards, and more. Most pneumoconioses develop after decades of exposure, though shorter latencies can occur from more intense particulate matter exposures. In this review, we summarize the industrial exposures, pathologic findings, and mineralogic features of various well-characterized pneumoconioses including silicosis, silicatosis, mixed-dust pneumoconiosis, coal workers' pneumoconiosis, asbestosis, chronic beryllium disease, aluminosis, hard metal pneumoconiosis, and some less severe pneumoconioses. We also review a general framework for the diagnostic work-up of pneumoconioses for pulmonologists including obtaining a detailed occupational and environmental exposure history. Many pneumoconioses are irreversible and develop due to excessive cumulative respirable dust inhalation. Accurate diagnosis permits interventions to minimize ongoing fibrogenic dust exposure. A consistent occupational exposure history coupled with typical chest imaging findings is usually sufficient to make a clinical diagnosis without the need for tissue sampling. Lung biopsy may be required when exposure history, imaging, and testing are inconsistent, there are unusual or new exposures, or there is a need to obtain tissue for another indication such as suspected malignancy. Close collaboration and information-sharing with the pathologist prior to biopsy is of great importance for diagnosis, as many occupational lung diseases are missed due to insufficient communication. The pathologist has a broad range of analytic techniques including bright-field microscopy, polarized light microscopy, and special histologic stains that may confirm the diagnosis. Advanced techniques for particle characterization such as scanning electron microscopy/energy dispersive spectroscopy may be available in some centers.

Mining Tenure and Job Duties Differ Among Contemporary and Historic Underground Coal Miners With Progressive Massive Fibrosis.

OBJECTIVE: To characterize differences in mining jobs and tenure between contemporary (born 1930+, working primarily with modern mining technologies) and historic coal miners with progressive massive fibrosis (PMF). METHODS: We classified jobs as designated occupations (DOs) and non-DOs based on regulatory sampling requirements. Demographic, occupational characteristics, and histopathological PMF type were compared between groups. RESULTS: Contemporary miners ( n = 33) had significantly shorter mean total (30.4 years vs 37.1 years, P = 0.0006) and underground (28.8 years vs 35.8 years, P = 0.001) mining tenure compared with historic miners ( n = 289). Silica-type PMF was significantly more common among miners in non-DOs (30.1% vs 15.8%, P = 0.03) and contemporary miners (58.1% vs 15.2%, P < 0.0001). CONCLUSIONS: Primary jobs changed over time with the introduction of modern mining technologies and likely changed exposures for workers. Elevated crystalline silica exposures are likely in non-DOs and require attention.

Heterogeneity of Airway Smooth Muscle Remodeling in Asthma.

Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodeling. Objectives: To determine the distribution of ASM remodeling in mild-severe asthma. Methods: The ASM area was measured in nine airway levels in three bronchial pathways in cases of nonfatal (n = 30) and fatal asthma (n = 20) and compared with control cases without asthma (n = 30). Correlations of ASM area within and between bronchial pathways were calculated. Asthma cases with 12 large and 12 small airways available (n = 42) were classified on the basis of the presence or absence of ASM remodeling (more than two SD of mean ASM area of control cases, n = 86) in the large or small airway or both. Measurements and Main Results: ASM remodeling varied widely within and between cases of nonfatal asthma and was more widespread and confluent and more marked in fatal cases. There were weak correlations of ASM between levels within the same or separate bronchial pathways; however, predictable patterns of remodeling were not observed. Using mean data, 44% of all asthma cases were classified as having no ASM remodeling in either the large or small airway despite a three- to 10-fold increase in the number of airways with ASM remodeling and 81% of asthma cases having ASM remodeling in at least one large and small airway. Conclusions: ASM remodeling is related to asthma severity but is heterogeneous within and between individuals and may contribute to the heterogeneous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodeling.

Living with COVID-19: Subjective Well-Being in the Second Phase of the Pandemic.

While there is ample evidence of the decline in mental health among youth during the onset of the COVID-19 pandemic, less is known about the determinants of recovery, which is the focus of this study. Drawing on a stress process framework, this study examines the associations of changes in direct, pandemic-related, and indirect, lockdown-related stressors with life satisfaction. A novel representative, longitudinal sample of British 16-25-year-olds is used, drawing on 6 data collections between February 2021 to May 2022 (N = 6000, 51% female, 24% ethnic minority, 46% in work, 35% with higher education). Using linear fixed-effects regression models, the findings suggest a substantial improvement in life satisfaction among youth. An increasing frequency of social contacts, receding worries about career prospects and job skills learning contributed significantly to increases in life satisfaction, whereas direct, health-related COVID-19 stressors did not affect life satisfaction. Sub-group analysis suggests that women's, adolescents', and students' life satisfaction responded more strongly to the stressors considered in this study. The findings highlight the positive effects of less stringent lockdown restrictions, economic recovery, and opportunities for job skills learning on youth's happiness.

Pathology and Mineralogy Demonstrate Respirable Crystalline Silica Is a Major Cause of Severe Pneumoconiosis in U.S. Coal Miners.

Rationale: The reasons for resurgent coal workers' pneumoconiosis and its most severe forms, rapidly progressive pneumoconiosis and progressive massive fibrosis (PMF), in the United States are not yet fully understood. Objectives: To compare the pathologic and mineralogic features of contemporary coal miners with severe pneumoconiosis with those of their historical counterparts. Methods: Lung pathology specimens from 85 coal miners with PMF were included for evaluation and analysis. We compared the proportion of cases with pathologic and mineralogic findings in miners born between 1910 and 1930 (historical) with those in miners born in or after 1930 (contemporary). Results: We found a significantly higher proportion of silica-type PMF (57% vs. 18%; P < 0.001) among contemporary miners compared with their historical counterparts. Mineral dust alveolar proteinosis was also more common in contemporary miners compared with their historical counterparts (70% vs. 37%; P < 0.01). In situ mineralogic analysis showed that the percentage (26.1% vs. 17.8%; P < 0.01) and concentration (47.3 × 108 vs. 25.8 × 108 particles/cm3; P = 0.036) of silica particles were significantly greater in specimens from contemporary miners compared with their historical counterparts. The concentration of silica particles was significantly greater when silica-type PMF, mineral dust alveolar proteinosis, silicotic nodules, or immature silicotic nodules were present (P < 0.05). Conclusions: Exposure to respirable crystalline silica appears causal in the unexpected surge of severe disease in contemporary miners. Our findings underscore the importance of controlling workplace silica exposure to prevent the disabling and untreatable adverse health effects afflicting U.S. coal miners.

Requirements and limitations of imaging airway smooth muscle throughout the lung in vivo.

Clinical visualization and quantification of the amount and distribution of airway smooth muscle (ASM) in the lungs of individuals with asthma has major implications for our understanding of airway wall remodeling as well as treatments targeted at the ASM. This paper theoretically investigates the feasibility of quantifying airway wall thickness (focusing on the ASM) throughout the lung in vivo by means of bronchoscopic polarization-sensitive optical coherence tomography (PS-OCT). Using extensive human biobank data from subjects with and without asthma in conjunction with a mathematical model of airway compliance, we define constraints that airways of various sizes pose to any endoscopic imaging technique and how this is impacted by physiologically relevant processes such as constriction, inflation and deflation. We identify critical PS-OCT system parameters and pinpoint parts of the airway tree that are conducive to successful quantification of ASM. We further quantify the impact of breathing and ASM contraction on the measurement error and recommend strategies for standardization and normalization.

Coal mine dust lung disease in miners killed in the Upper Big Branch disaster: a review of lung pathology and contemporary respirable dust levels in underground US coal mines.

OBJECTIVES: In 2010, 29 coal miners died due to an explosion at the Upper Big Branch (UBB) mine in West Virginia, USA. Autopsy examinations of 24 individuals with evaluable lung tissue identified 17 considered to have coal workers' pneumoconiosis (CWP). The objectives of this study were to characterise histopathological findings of lung tissue from a sample of UBB fatalities and better understand the respirable dust concentrations experienced by these miners at UBB relative to other US coal mines. METHODS: Occupational pulmonary pathologists evaluated lung tissue specimens from UBB fatalities for the presence of features of pneumoconiosis. Respirable dust and quartz samples submitted for regulatory compliance from all US underground coal mines prior to the disaster were analysed. RESULTS: Families of seven UBB fatalities provided consent for the study. Histopathologic evidence of CWP was found in all seven cases. For the USA, central Appalachia and UBB, compliance dust samples showed the geometric mean for respirable dust was 0.468, 0.420 and 0.518 mg/m3, respectively, and respirable quartz concentrations were 0.030, 0.038 and 0.061 mg/m3. After adjusting for quartz concentrations, UBB exceeded the US permissible exposure limit (PEL) for respirable dust in 28% of samples. CONCLUSIONS: Although higher than average respirable dust and quartz levels were observed at UBB, over 200 US underground coal mines had higher dust concentrations than UBB and over 100 exceeded the PEL more frequently. Together with lung histopathological findings among UBB fatalities, these data suggest exposures leading to CWP in the USA are more prevalent than previously understood.

Methods Used for Pediatric Dose Selection in Drug Development Programs Submitted to the US FDA 2012-2020.

Dosing is a critical aspect of drug development in pediatrics that has led to trial failures and the inability to label the drug for pediatric use by the US Food and Drug Administration. Developing a structured approach for pediatric dose selection requires knowledge of the current approaches and their success or failure. This study describes the current experience with pediatric dosing methods from 2012 to 2020 and had 2 primary objectives: (1) to identify how the initial pediatric dose was selected and (2) to identify the pivotal dosing strategy used to identify the initially selected dose for safety and efficacy for pediatric clinical trials. Through September 2020, a total of 275 pediatric drug development programs were characterized for initial and pivotal dosing strategies. The success rate for labeling for pediatric use was 76.4%. The most common initial dosing strategy was previous experience with the product, followed by allometric scaling and exposure matching with adults. The most common pivotal dosing strategy was titration to target response in 33% of programs, with the second and third most common being pharmacokinetic/pharmacodynamic studies (30%) and exposure matching (20%), respectively. Additionally, about one-half of pediatric programs incorporated model-informed drug development. The emergence of titration to target response may signal a shift toward precision medicine in pediatric patients. Future work in pediatric drug dose selection should move toward the development of a structured pediatric dose selection approach.

Drug Safety in Labeling for Pediatric Drug Development and Dose Selection in Submissions to the US Food and Drug Administration.

Pediatric safety evaluations are an essential part of a pediatric drug development program. Communication of the results of these safety evaluations is primarily accomplished by labeling of the drug either during the initial pediatric drug development program, or during the postmarketing period after drug approval for pediatric patients. During drug development, the dose-adverse drug event (ADE) relationship is an important part of the evaluation, but a consideration for pediatric ADEs that are unrelated to drug dosage must be maintained. Examples of dose-related and non-dose-related ADEs are presented. The failure to label a product for pediatric use has been safety related for a number of development programs. The US Food and Drug Administration's Pediatric Advisory Committee is a primary source of the pediatric postmarketing safety review and has been associated with a number of labeling changes through its ongoing review process. Pediatric drug safety remains a critical part of the assessment of dose-effect relationship in the pediatric patient population during the drug development and postmarketing surveillance process.

Pathways from origins to destinations: Stability and change in the roles of cognition, private schools and educational attainment.

While much attention has been devoted to measuring levels of social mobility over time, less attention has been given to the possibility of changing pathways to social mobility. This paper examines pathways from social origins to socio-economic destinations in midlife for two British cohorts, born in 1958 and 1970 respectively, using Structural Equation Modelling (SEM). We address the roles of cognitive attainment, private schooling and educational attainment in mediating the link between social origins and destinations. Have these mechanisms become more or less important over time, in a context of structural change in the state schooling system and educational expansion? We find that private schools displayed greater academic selectivity and an increased link to high levels of educational attainment for the younger cohort. Essentially, private schools adapted to changing circumstances, becoming more academically selective and less socially selective, and more focused on educational credentials. Childhood social origins were less strongly linked to childhood cognitive scores in the younger cohort, but cognitive scores were also more weakly linked to educational attainment for this cohort. We also find a decreased association between social origins and educational attainment for the younger cohort. While the finding that educational inequalities weakened over this time period is positive, the lack of a corresponding reduction in the overall link between social origins and destinations suggests that reducing educational inequalities was not sufficient to increase social mobility when accompanied by countervailing changes in the role of private schools.

Evidence for Environmental-Human Microbiota Transfer at a Manufacturing Facility with Novel Work-related Respiratory Disease.

Rationale: Workers' exposure to metalworking fluid (MWF) has been associated with respiratory disease.Objectives: As part of a public health investigation of a manufacturing facility, we performed a cross-sectional study using paired environmental and human sampling to evaluate the cross-pollination of microbes between the environment and the host and possible effects on lung pathology present among workers.Methods: Workplace environmental microbiota were evaluated in air and MWF samples. Human microbiota were evaluated in lung tissue samples from workers with respiratory symptoms found to have lymphocytic bronchiolitis and alveolar ductitis with B-cell follicles and emphysema, in lung tissue samples from control subjects, and in skin, nasal, and oral samples from 302 workers from different areas of the facility. In vitro effects of MWF exposure on murine B cells were assessed.Measurements and Main Results: An increased similarity of microbial composition was found between MWF samples and lung tissue samples of case workers compared with control subjects. Among workers in different locations within the facility, those that worked in the machine shop area had skin, nasal, and oral microbiota more closely related to the microbiota present in the MWF samples. Lung samples from four index cases and skin and nasal samples from workers in the machine shop area were enriched with Pseudomonas, the dominant taxa in MWF. Exposure to used MWF stimulated murine B-cell proliferation in vitro, a hallmark cell subtype found in the pathology of index cases.Conclusions: Evaluation of a manufacturing facility with a cluster of workers with respiratory disease supports cross-pollination of microbes from MWF to humans and suggests the potential for exposure to these microbes to be a health hazard.

Airway remodelling with spatial correlations: Implications for asthma pathogenesis.

Airway remodelling is a cardinal feature of asthma in which airways undergo structural changes - in particular, increased airway smooth muscle mass and total airway wall area. Remodelling has long been thought to have functional consequences in asthma due to geometric effects that can increase airway narrowing and luminal occlusion. Prior studies have examined the distribution of remodelling between and within patients, but none have yet considered the possibility for spatial correlations in airway remodelling. That is, is remodelling clustered locally, or interrelated along proximal and distal locations of the bronchial tree? In view of recent interest regarding airway remodelling produced by mechanical stimuli, we developed a mathematical model to examine whether spatial correlations in airway remodelling could arise due to cycles of bronchoconstriction and mechanotransduction. Further, we compared modelling predictions to the spatial distribution of airway remodelling in lungs from subjects with and without asthma. Results indicate that spatial correlations in airway remodelling do exist in vivo, and cycles of bronchoconstriction and mechanotransduction are one plausible mechanism for their origin. These findings offer insights into the evolution of airway remodelling in asthma, which may inform strategies for treatment and prevention.

Efficacy of a Peruvian Botanical Remedy (Sabell A4+) for Treating Liver Disease and Protecting Gastric Mucosal Integrity.

The purpose of this study was to determine the efficacy of a Peruvian botanical formulation for treating disorders of hepatic function and gastric mucosal integrity. The formulation A4+ (Sabell Corporation) contains extracts of Curcuma longa rhizome, Cordia lutea flower, and Annona muricata leaf. Individually these plants have been used as traditional remedies for liver disease. We report the efficacy of A4+ and its components using a variety of in vitro and in vivo disease models. The methods used included tests for antioxidant, anti-inflammatory, and antiviral activity as well as mouse models of liver disease, including Concanavalin A-induced immune-mediated hepatitis and a bile duct ligation model for evaluating sickness behaviour associated with liver disease. Rat models were used to evaluate the gastric mucosal protective property of A4+ following indomethacin challenge and to evaluate its anti-inflammatory action in an "air pouch" model. In all tests, A4+ proved to be more effective than placebo. A4+ was antioxidant and anti-inflammatory and diminished Hepatitis C virus replication in vitro. In animal models, A4+ was shown to protect the liver from immune-mediated hepatitis, improve behavioural function in animals with late stage liver disease, and protect the rat gastric mucosa from ulceration following NSAID exposure. We conclude that A4+ ameliorated many aspects of liver injury, inhibited hepatitis C virus replication, and protected the gastric mucosa from NSAIDs. These varied beneficial properties appear to result from positive interactions between the three constituent herbs.

Fatty airways: implications for obstructive disease.

Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in individuals with and without asthma.Transverse airway sections were sampled in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities.BMI ranged from 15 to 45 kg·m-2 and was greater in nonfatal asthma cases (p<0.05). Adipose tissue was identified in the outer wall of large airways (Pbm >6 mm), but was rarely seen in small airways (Pbm <6 mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm >12 mm, p<0.01), and with neutrophils in control subjects (Pbm >6 mm, p=0.04).These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology.