Communication in Drug Development: "Translating" Scientific Discovery.

The discovery and development of new medicines that promote human health and potentially extend natural life remains a remarkably challenging endeavor. In this Commentary, we identify key elements of communication required to successfully translate promising biological findings to novel approved drug therapies and discuss the attendant challenges and opportunities.

From cancer genomics to precision oncology--tissue's still an issue.

Rapidly evolving genome technology has enabled extensive molecular analysis of limited tumor biopsy material, thereby facilitating the broader implementation of personalized cancer medicine. However, genomics-based patient stratification across diverse tumor types is unlikely to supplant tissue-of-origin considerations in addressing clinical needs, including the development and application of novel "rationally targeted" cancer therapies.

Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants.

BACKGROUND: The safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)-associated lower respiratory tract infection when administered in healthy infants are unclear. METHODS: In a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. RESULTS: A total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P = 0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P = 0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P = 0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group. CONCLUSIONS: Nirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and hemolysis.

The spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank by using magnetic resonance imaging and provide a reference range for spleen iron in an unselected population. Through genome-wide association study, we identify associations between spleen iron and regulatory variation at two hereditary spherocytosis genes, ANK1 and SPTA1. Spherocytosis-causing coding mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while these common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes that have been observed clinically. Our genetic study also identifies a signal that co-localizes with a splicing quantitative trait locus for MS4A7, and we show this gene is abundantly expressed in the spleen and in macrophages. The combination of deep learning and efficient image processing enables non-invasive measurement of spleen iron and, in turn, characterization of genetic factors related to the lytic phase of the erythrocyte life cycle and iron reuptake in the spleen.

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes.

BACKGROUND: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain. METHODS: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%. RESULTS: A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups. CONCLUSIONS: All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Age-Specific Resurgence in Invasive Pneumococcal Disease Incidence in the COVID-19 Pandemic Era and Its Association With Respiratory Virus and Pneumococcal Carriage Dynamics: A Time-Series Analysis.

Using multiple national surveillance systems, we found an increase in the incidence of invasive pneumococcal disease during after the relaxation of non-pharmaceutical interventions against COVID-19, which strongly varied by age. Age groups with higher incidence of respiratory syncytial virus and influenza also experienced higher increase in invasive pneumococcal disease incidence, with no change in pneumococcal carriage.

Thin seams and small mines are associated with higher exposures to respirable crystalline silica in US underground coal mines.

OBJECTIVES: Previous radiologic and histopathologic studies suggest respirable crystalline silica (RCS) overexposure has been driving the resurgence of pneumoconiosis among contemporary US coal miners, with a higher prevalence of severe disease in Central Appalachia. We sought to better understand RCS exposure among US underground coal miners. METHODS: We analysed RCS levels, as measured by respirable quartz, from coal mine dust compliance data from 1982 to 2021. RESULTS: We analysed 322 919 respirable quartz samples from 5064 US underground coal mines. Mean mine-level respirable quartz percentage and mass concentrations were consistently higher for Central Appalachian mines than the rest of the USA. Mean mine-level respirable quartz mass concentrations decreased significantly over time, from 0.116 mg/m3 in 1982 to as low as 0.017 mg/m3 for Central Appalachian mines, and from 0.089 mg/m3 in 1983 to 0.015 mg/m3 in 2020 for the rest of the USA. Smaller mine size, location in Central Appalachia, lack of mine safety committee and thinner coal seams were predictive of higher respirable quartz mass concentrations. CONCLUSIONS: These data substantially support the association between RCS overexposure and the resurgence of coal workers' pneumoconiosis in the USA, particularly in smaller mines in Central Appalachia.

Measuring lung diffusing capacity: an opportunity for improved medical surveillance and disability evaluation of coal miners.

OBJECTIVES: Spirometry is the primary lung function test utilised for medical surveillance and disability examination for coal mine dust lung disease. However, spirometry likely underestimates physiologic impairment. We sought to characterise abnormalities of single-breath diffusing capacity for carbon monoxide (DLCO) among a population of former coal miners. METHODS: Data from 3115 former coal miners evaluated at a West Virginia black lung clinic between 2006 and 2015 were retrospectively analysed to study the association between diffusion impairment (abnormally low DLCO), resting spirometry and the presence and severity of coal workers' pneumoconiosis on chest radiography. We developed ordinary least squares linear regression models to evaluate factors associated with per cent predicted DLCO (DLCOpp). RESULTS: Diffusion impairment was identified in 20.2% of subjects. Ten per cent of all miners with normal spirometry had diffusion impairment including 7.4% of never smokers. The prevalence of diffusion impairment increased with worsening radiographic category of pneumoconiosis. Mean DLCOpp decreased with increasing small opacity profusion subcategory in miners without progressive massive fibrosis. Linear regression analysis also showed significant decreases in DLCOpp with increasing small opacity profusion and presence of large opacities. CONCLUSIONS: Diffusion impairment is common among former coal miners, including among never smokers, miners without radiographic pneumoconiosis and miners with normal spirometry. These findings demonstrate the value of including DLCO testing in disability examinations of former coal miners and an important role for its use in medical surveillance of working miners to detect early chronic lung disease.

The social contexts of behaviors and relationships: The relation of classroom and cyber victimization to number of classroom and cyber friends.

Behaviors and relationships exist within a variety of social contexts. More specifically for the current research, victimization and friendships occur in classrooms and, increasingly, in online virtual contexts. The current research examined how the number of classroom friends and number of cyber friends related to the extent of classroom victimization and extent of cyber victimization. Research has demonstrated the importance of face-to-face friendships in relation to being a victim; much less is known about the role of cyber friends in relation to being a cyber victim or how these relationships may play a role in cross-context victimization. Participants were 350 children from Grades 3 through 5 (188 girls and 162 boys). Children indicated classroom friends on a classroom roster, reported the number of their cyber friends, and indicated the extent of their cyber victimization. Peers nominated classmates for classroom victimization behaviors. A path analysis revealed that number of classroom friends was negatively associated with both extent of classroom victimization and extent of cyber victimization. Number of cyber friends was positively associated with extent of cyber victimization and was negatively related to extent of classroom victimization. Discussion of results includes the construction, use, and adaptation of social skills within and between social contexts.

Resting diffusing capacity and severity of radiographic disease predict gas exchange abnormalities with exercise in former US coal miners.

BACKGROUND: The US Department of Labor (DOL) does not fund diffusing capacity (DLCO) or metabolic measurements from cardiopulmonary exercise testing (CPET) for coal miners' disability evaluations. Although exercise arterial blood gas testing is covered, many miners are unable to perform maximal tests, and sampling at peak exercise can be challenging. We explored the relationship between resting DLCO, radiographic disease severity, and CPET abnormalities in former US coal miners. METHODS: We analyzed data from miners evaluated between 2005 and 2015. Multivariable linear and logistic regression analyses were used to examine relationships between percent predicted (pp) forced expiratory volume in 1 s (FEV1pp), DLCOpp, VO2maxpp, A-a oxygen gradient (A-a)pp, dead space fraction (Vd/Vt), disabling oxygen tension (PO2), and radiographic findings of pneumoconiosis. RESULTS: Data from 2015 male coal miners was analyzed. Mean tenure was 28 years (SD 8.6). Thirty-twopercent had an abnormal A-a gradient (>150 pp), 20% had elevated Vd/Vt (>0.33), and 34% a VO2max < 60 pp. DLCOpp strongly predicted a disabling PO2, with an odds ratio (OR) of 2.33 [2.09-2.60], compared to 1.18 [1.08-1.29] for FEV1. Each increase in subcategory of small opacity (simple) pneumoconiosis increased the odds of a disabling PO2 by 42% [1.29-1.57], controlling for age, body mass index, pack-years of tobacco smoke exposure, and years of coal mine employment. CONCLUSIONS: DLCO is the best resting pulmonary function test predictor of CPET abnormalities. Radiographic severity of pneumoconiosis was also associated with CPET abnormalities. These findings support funding DLCO testing for impairment and suggest the term "small opacity" should replace "simple" pneumoconiosis to reflect significant associations with impairment.

Poor adherence to dust, noise and safety regulations predict injury rates in underground coal mines.

BACKGROUND: While safety in US coal mining has improved over the past two decades, general occupational health research shows that risk of injury varies across individual worksites and is influenced by worksite safety cultures and practices. METHODS: In this longitudinal study, we evaluated whether mine-level characteristics reflecting poor adherence to health and safety regulations in underground coal mines are associated with higher acute injury rates. We aggregated Mine Safety and Health Administration (MSHA) data by year for each underground coal mine for the period 2000-2019. Data included part-50 injuries, mine characteristics, employment and production, dust sampling, noise sampling, and violations. Multivariable hierarchical generalised estimating equations (GEE) models were developed. RESULTS: Based on the final GEE model, despite an average annual decline in injury rates by 5.5%, the following indicators of inadequate adherence to health and safety regulations were associated with increased average annual injury rates: +2.9% for each 10% increase in dust samples exceeding the permissible exposure limit; +0.6% for each 10% increase of permitted 90 dBA 8-hour noise exposure dose; +2.0% for every 10 substantial-significant MSHA violations in a year; +1.8% for each rescue/recovery procedure violation; +2.6% for each safeguard violation. If a fatality occurred in a mine, injury rates increased by 11.9% in the same year, but declined by 10.4% in the following year. The presence of safety committees was associated with a 14.5% decline in injury rates. DISCUSSION: In US underground coal mines, injury rates are associated with poor adherence to dust, noise and safety regulations.

Increased odds of mortality from non-malignant respiratory disease and lung cancer are highest among US coal miners born after 1939.

OBJECTIVES: Coal miners suffer increased mortality from non-malignant respiratory diseases (NMRD), including pneumoconioses and chronic obstructive pulmonary disease, compared with the US population. We characterised mortality trends from NMRD, lung cancer and ischaemic heart disease (IHD) using data from the Federal Black Lung Program, National Coal Workers' Health Surveillance Program and the National Death Index. METHODS: We compared mortality ORs (MORs) for NMRD, lung cancer and IHD in former US coal miners to US white males. MORs were computed for the study period 1979-2017 by birth cohort (<1920, 1920-1929, 1930-1939, ≥1940), with a subanalysis restricted to Central Appalachia. RESULTS: The study population totalled 235 550 deceased miners, aged >45 years. Odds of death from NMRD and lung cancer across all miner birth cohorts averaged twice those of US males. In Central Appalachia, MORs significantly increased across birth cohorts. There was an eightfold increase in odds of death from NMRD among miners born after 1940 (MORBC≥1940 8.25; 95% CI 7.67 to 8.87). Miners with progressive massive fibrosis (PMF) were younger at death than those without PMF (74 vs 78 years; p<0.0001). We observed a pattern of reduced MORs from IHD in coal miners compared with national and regional counterparts. CONCLUSION: US coal miners have excess mortality from NMRD and lung cancer compared with total US and Appalachian populations. Mortality is highest in the most recent birth cohorts, perhaps reflecting increased rates of severe pneumoconiosis.

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.

Global Trends in Occupational Lung Disease.

Lung diseases caused by workplace exposure are too often mis- or underdiagnosed due in part to nonexistent or inadequate health surveillance programs for workers. Many of these diseases are indistinguishable from those that occur in the general population and are not recognized as being caused at least in part by occupational exposures. More than 10% of all lung diseases are estimated to result from workplace exposures. This study reviews recent estimates of the burden of the most important occupational lung diseases using data published by United Nations specialized agencies as well as the Global Burden of Disease studies. We focus on occupational chronic respiratory disease of which chronic obstructive lung disease and asthma are the most significant. Among occupational cancers, lung cancer is the most common, and is associated with more than 10 important workplace carcinogens. Classic occupational interstitial lung diseases such as asbestosis, silicosis, and coal workers' pneumoconiosis still comprise a substantial burden of disease in modern industrial societies, while other occupational causes of pulmonary fibrosis and granulomatous inflammation are frequently misclassified as idiopathic. Occupational respiratory infections gained prominence during the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic, eclipsing influenza and tuberculosis and other less common workplace infectious agents. The most significant risks are workplace exposures to particulate matter, gases, and fumes as well as occupational carcinogens and asthmagens. We present data on the burden of disease measured by deaths attributable to occupational respiratory disease as well as disability-adjusted years of life lost. Where available, prevalence and incidence data are also presented. These diseases are unique in that they are theoretically 100% preventable if appropriate exposure controls and workplace medical surveillance are implemented. This remains a continuing challenge globally and requires steadfast commitment on the part of government, industry, organized labor, and the medical profession.

Structural basis for the activation and inhibition of the UCH37 deubiquitylase.

The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to the proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the roles of UCH37 in the unrelated proteasome and INO80 complexes.

Improved Molecular Diagnosis and Culture of the Emerging Heteropathotype Enterohemorrhagic Escherichia coli O80:H2 Using Its Non-Melibiose-Fermenting and Antibiotic-Resistance Properties.

Enterohemorrhagic Escherichia coli (EHEC) O80:H2, belonging to sequence type ST301, is among the main causes of hemolytic and uremic syndrome in Europe, a major concern in young children. Aside from the usual intimin and Shiga toxin virulence factors (VFs), this emerging serotype possesses a mosaic plasmid combining extra-intestinal VF- and antibiotic resistance-encoding genes. This hybrid pathotype can be involved in invasive infections, a rare occurrence in EHEC infections. Here, we aimed to optimize its detection, improve its clinical diagnosis, and identify its currently unknown reservoir. O80:H2 EHEC strains isolated in France between 2010 and 2018 were phenotypically and genetically analyzed and compared with non-O80 strains. The specificity and sensitivity of a PCR test and a culture medium designed, based on the molecular and phenotypic signatures of O80:H2 EHEC, were assessed on a collection of strains and stool samples. O80:H2 biotype analysis showed that none of the strains (n = 137) fermented melibiose versus 5% of non-O80 EHEC (n = 19/352). This loss of metabolic function is due to deletion of the entire melibiose operon associated with the insertion of a 70-pb sequence (70mel), a genetic scar shared by all ST301 strains. This metabolic hallmark was used to develop a real-time PCR test (100% sensitivity, 98.3% specificity) and a melibiose-based culture medium including antibiotics, characterized by 85% specificity and sensitivity for clinical specimens. These new tools may facilitate the diagnosis of this atypical clone, help the food industry to identify the reservoir and improve our epidemiological knowledge of this threatening and emerging clone.

High-affinity free ubiquitin sensors for quantifying ubiquitin homeostasis and deubiquitination.

Ubiquitin (Ub) conjugation is an essential post-translational modification that affects nearly all proteins in eukaryotes. The functions and mechanisms of ubiquitination are areas of extensive study, and yet the dynamics and regulation of even free (that is, unconjugated) Ub are poorly understood. A major impediment has been the lack of simple and robust techniques to quantify Ub levels in cells and to monitor Ub release from conjugates. Here, we describe avidity-based fluorescent sensors that address this need. The sensors bind specifically to free Ub, have dissociation constant Kd values down to 60 pM and, together with a newly developed workflow, allow us to distinguish and quantify the pools of free, protein-conjugated and thioesterified forms of Ub from cell lysates. Alternatively, free Ub in fixed cells can be visualized microscopically by staining with a sensor. Real-time assays using the sensors afford unprecedented flexibility and precision to measure deubiquitination of virtually any (poly)Ub conjugate.

Estimating the impact of donor programs on child mortality in low- and middle-income countries: a synthetic control analysis of child health programs funded by the United States Agency for International Development.

BACKGROUND: Significant levels of funding have been provided to low- and middle-income countries for development assistance for health, with most funds coming through direct bilateral investment led by the USA and the UK. Direct attribution of impact to large-scale programs funded by donors remains elusive due the difficulty of knowing what would have happened without those programs, and the lack of detailed contextual information to support causal interpretation of changes. METHODS: This study uses the synthetic control analysis method to estimate the impact of one donor's funding (United States Agency for International Development, USAID) on under-five mortality across several low- and middle-income countries that received above average levels of USAID funding for maternal and child health programs between 2000 and 2016. RESULTS: In the study period (2000-16), countries with above average USAID funding had an under-five mortality rate lower than the synthetic control by an average of 29 deaths per 1000 live births (year-to-year range of - 2 to - 38). This finding was consistent with several sensitivity analyses. CONCLUSIONS: The synthetic control method is a valuable addition to the range of approaches for quantifying the impact of large-scale health programs in low- and middle-income countries. The findings suggest that adequately funded donor programs (in this case USAID) help countries to reduce child mortality to significantly lower rates than would have occurred without those investments.

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.

Prevalence and severity of abnormal lung function among US former coal miners with and without radiographic coal workers' pneumoconiosis.

OBJECTIVES: Examination of lung function abnormalities among coal miners has historically focused on actively working miners. This likely underestimates the true burden of chronic respiratory disease. The objective of this study was to characterise patterns and severity of lung function impairment among a population of former coal miners. METHODS: Cross-sectional data from 2568 former coal miners evaluated at eight US Black Lung clinics in a 12-month period were retrospectively analysed for patterns of prebronchodilator spirometric abnormality and severity of lung function impairment. Spirometry data from a subset of former miners with chest radiographs were analysed based on the presence and severity of coal workers' pneumoconiosis (CWP). RESULTS: Abnormal spirometry was identified in 56.6% of subjects. The age-standardised prevalence of airflow obstruction among miners aged ≥45 years was 18.9% overall and 12.2% among never smokers. Among 1624 subjects who underwent chest radiography, the prevalence and severity of abnormal spirometry increased with worsening radiographic category for pneumoconiosis. Of never-smoking former miners without radiographic CWP, 39.0% had abnormal spirometry; 25.1% had abnormally low forced expiratory volume in 1 s (FEV1), and 17.1% had moderate to severe FEV1 impairment. CONCLUSIONS: Abnormal spirometry is common among former coal miners. While ever-smoking former miners had higher rates of airflow obstruction, never-smoking former miners also demonstrated clinically significant airflow obstruction, including those without radiographic pneumoconiosis. These findings demonstrate the importance of recognising physiological as well as imaging manifestations of coal mine dust lung diseases in former miners.