Low-Level Respirable Crystalline Silica and Silicosis: Long-Term Follow-Up of Vermont Granite Workers.

The lifetime risk of silicosis associated with low-level occupational exposure to respirable crystalline silica remains unclear because most previous radiographic studies included workers with varying exposure concentrations and durations. This study assessed the prevalence of silicosis after lengthy exposure to respirable crystalline silica at levels ≤ 0.10 mg/m3. Vermont granite workers employed any time during 1979-1987 were traced and chest radiographs were obtained for 356 who were alive in 2017 and residing in Vermont. Work history, smoking habits and respiratory symptoms were obtained by interview, and exposure was estimated using a previously developed job-exposure matrix. Associations between radiographic findings, exposure, and respiratory symptoms were assessed by ANOVA, chi-square tests and binary regression. Fourteen workers (3.9%) had radiographic evidence of silicosis, and all had been employed ≥30 years. They were more likely to have been stone cutters or carvers and their average exposure concentrations and cumulative exposures to respirable crystalline silica were significantly higher than workers with similar durations of employment and no classifiable parenchymal abnormalities. This provides direct evidence that workers with long-term exposure to low-level respirable crystalline silica (≤0.10 mg/m3) are at risk of developing silicosis.

Dopamine depletion weakens direct pathway modulation of SNr neurons.

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson's disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway's influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.

Introducing the STReaC (Spike Train Response Classification) toolbox.

Background: This work presents a toolbox that implements methodology for automated classification of diverse neural responses to optogenetic stimulation or other changes in conditions, based on spike train recordings. New Method: The toolbox implements what we call the Spike Train Response Classification algorithm (STReaC), which compares measurements of activity during a baseline period with analogous measurements during a subsequent period to identify various responses that might result from an event such as introduction of a sustained stimulus. The analyzed response types span a variety of patterns involving distinct time courses of increased firing, or excitation, decreased firing, or inhibition, or combinations of these. Excitation (inhibition) is identified from a comparative analysis of the spike density function (interspike interval function) for the baseline period relative to the corresponding function for the response period. Results: The STReaC algorithm as implemented in this toolbox provides a user-friendly, tunable, objective methodology that can detect a variety of neuronal response types and associated subtleties. We demonstrate this with single-unit neural recordings of rodent substantia nigra pars reticulata (SNr) during optogenetic stimulation of the globus pallidus externa (GPe). Comparison with existing methods: In several examples, we illustrate how the toolbox classifies responses in situations in which traditional methods (spike counting and visual inspection) either fail to detect a response or provide a false positive. Conclusions: The STReaC toolbox provides a simple, efficient approach for classifying spike trains into a variety of response types defined relative to a period of baseline spiking.

Asian Intensive Reader of Pneumoconiosis program: examination for certification during 2008-2020.

This study examined physicians' participation and performance in the examinations administered by the Asian Intensive Reader of Pneumoconiosis (AIR Pneumo) program from 2008 to 2020 and compared radiograph readings of physicians who passed with those who failed the examinations. Demography of the participants, participation trends, pass/fail rates, and proficiency scores were summarized; differences in reading the radiographs for pneumoconiosis of physicians who passed the examinations and those who failed were evaluated. By December 2020, 555 physicians from 20 countries had taken certification examinations; the number of participants increased in recent years. Reported background specialty training and work experience varied widely. Passing rate and mean proficiency score for participants who passed were 83.4% and 77.6 ± 9.4 in certification, and 76.8% and 88.1 ± 4.5 in recertification examinations. Compared with physicians who passed the examinations, physicians who failed tended to classify test radiographs as positive for pneumoconiosis and read a higher profusion; they likely missed large opacities and pleural plaques and had a lower accuracy in recognizing the shape of small opacities. Findings suggest that physicians who failed the examination tend to over-diagnose radiographs as positive for pneumoconiosis with higher profusion and have difficulty in correctly identifying small opacity shape.

Cupolets in a chaotic neuron model.

This paper reports the first finding of cupolets in a chaotic Hindmarsh-Rose neural model. Cupolets (chaotic, unstable, periodic, orbit-lets) are unstable periodic orbits that have been stabilized through a particular control scheme by applying a binary control sequence. We demonstrate different neural dynamics (periodic or chaotic) of the Hindmarsh-Rose model through a bifurcation diagram where the external input current, I, is the bifurcation parameter. We select a region in the chaotic parameter space and provide the results of numerical simulations. In this chosen parameter space, a control scheme is applied when the trajectory intersects with either of the two control planes. The type of the control is determined by a bit in a binary control sequence. The control is either a small microcontrol (0) or a large macrocontrol (1) that adjusts the future dynamics of the trajectory by a perturbation determined by the coding function r ( x ). We report the discovery of many cupolets with corresponding control sequences and comment on the differences with previously reported cupolets in the double scroll system. We provide some examples of the generated cupolets and conclude by discussing potential implications for biological neurons.

Inter-observer agreement and accuracy in classifying radiographs for pneumoconiosis among Asian physicians taking AIR Pneumo certification examination.

This study examined inter-observer agreement and diagnostic accuracy in classifying radiographs for pneumoconiosis among Asian physicians taking the AIR Pneumo examination. We compared agreement and diagnostic accuracy for parenchymal and pleural lesions across residing countries, specialty training, and work experience using data on 93 physicians. Physicians demonstrated fair to good agreement with kappa values 0.30 (95% CI: 0.20-0.40), 0.29 (95% CI: 0.23-0.36), 0.59 (95% CI: 0.52-0.67), and 0.65 (95% CI: 0.55-0.74) in classifying pleural plaques, small opacity shapes, small opacity profusion, and large opacities, respectively. Kappa values among Asian countries ranging from 0.25 to 0.55 (pleural plaques), 0.47 to 0.73 (small opacity profusion), and 0.55 to 0.69 (large opacity size). The median Youden's J index (interquartile range) for classifying pleural plaque, small opacity, and large opacity was 61.1 (25.5), 76.8 (29.3), and 88.9 (23.3), respectively. Radiologists and recent graduates showed superior performance than other groups regarding agreement and accuracy in classifying all types of lesions. In conclusion, Asian physicians taking the AIR Pneumo examination were better at classifying parenchymal lesions than pleural plaques using the ILO classification. The degree of agreement and accuracy was different among countries and was associated with background specialty training.

Transmission of delta band (0.5-4 Hz) oscillations from the globus pallidus to the substantia nigra pars reticulata in dopamine depletion.

Parkinson's disease (PD) and animal models of PD feature enhanced oscillations in several frequency bands in the basal ganglia (BG). Past research has emphasized the enhancement of 13-30 Hz beta oscillations. Recently, however, oscillations in the delta band (0.5-4 Hz) have been identified as a robust predictor of dopamine loss and motor dysfunction in several BG regions in mouse models of PD. In particular, delta oscillations in the substantia nigra pars reticulata (SNr) were shown to lead oscillations in motor cortex (M1) and persist under M1 lesion, but it is not clear where these oscillations are initially generated. In this paper, we use a computational model to study how delta oscillations may arise in the SNr due to projections from the globus pallidus externa (GPe). We propose a network architecture that incorporates inhibition in SNr from oscillating GPe neurons and other SNr neurons. In our simulations, this configuration yields firing patterns in model SNr neurons that match those measured in vivo. In particular, we see the spontaneous emergence of near-antiphase active-predicting and inactive-predicting neural populations in the SNr, which persist under the inclusion of STN inputs based on experimental recordings. These results demonstrate how delta oscillations can propagate through BG nuclei despite imperfect oscillatory synchrony in the source site, narrowing down potential targets for the source of delta oscillations in PD models and giving new insight into the dynamics of SNr oscillations.

Outcomes of Idiopathic Pulmonary Fibrosis Improve with Obesity: A Rural Appalachian Experience.

OBJECTIVES: Obesity can be an independent predictor of fibrosis in tissues, including the liver, heart, and skin. We evaluated a rural Appalachian cohort of idiopathic pulmonary fibrosis (IPF) for its relation to obesity. METHODS: Using American Thoracic Society 2018 diagnostic guidelines, an IPF cohort was systematically identified at an Appalachian academic medical center (2015-2019). The cohort was categorized in subgroups of body mass index (BMI) <30 or BMI ≥30 kg/m2. Demographics, clinical variables, and treatment details were collected retrospectively and evaluated for their associations with obesity. RESULTS: In our IPF cohort (N = 138), a usual interstitial pneumonia pattern was less prevalent in the obese group (n = 49) relative to the nonobese group (69% vs 85%, respectively). The obese group was younger (mean age 73.27 ± 9.12 vs 77.97 ± 9.59 years) and had a higher prevalence of hypertension (90% vs 72%), hyperlipidemia (83% vs 68%), diabetes mellitus (47% vs 25%), sleep-disordered breathing (47% vs 25%), chronic pain disorders (28% vs 15%), and deep vein thrombosis (19% vs 7%). An increased proportion of obese-IPF patients was seen at a tertiary or an interstitial lung disease center, with more surgical lung biopsies performed and incident diagnosis (ie, within 6 months of presentation) assigned. Only a minority of patients underwent lung transplantation (3.6%), all of them from the obese-IPF subgroup. Approximately 30% of the total IPF cohort died, with a lower mortality observed in the obese group (35% vs 20%, P = 0.017). An increasing BMI predicted a better survival in the total IPF cohort (BMI 25-29.9, 20-24.9, and <20 had mortality rates of 20%, 47%, and 75%, respectively; P < 0.001). CONCLUSIONS: Our study represents a first known effort to develop an IPF cohort in a rural Appalachian region. Although they shared an increased burden of comorbidities, the obese subgroup showed less advanced fibrosis with a lower mortality rate relative to nonobese subgroup, suggesting a potential "obesity paradox" in IPF. The study findings significantly advance our understanding of challenges posed by IPF in a rural population that also suffers from an alarming rate of obesity. We highlight the need for the multidisciplinary management of these patients and prospective studies to better define this complex relation.

Sigmoidal synaptic learning produces mutual stabilization in chaotic FitzHugh-Nagumo model.

This paper investigates the interaction between two coupled neurons at the terminal end of a long chain of neurons. Specifically, we examine a bidirectional, two-cell FitzHugh-Nagumo neural model capable of exhibiting chaotic dynamics. Analysis of this model shows how mutual stabilization of the chaotic dynamics can occur through sigmoidal synaptic learning. Initially, this paper begins with a bifurcation analysis of an adapted version of a previously studied FitzHugh-Nagumo model that indicates regions of periodic and chaotic behaviors. Through allowing the synaptic properties to change dynamically via neural learning, it is shown how the system can evolve from chaotic to stable periodic behavior. The driving factor between this transition is representative of a stimulus coming down a long neural pathway. The result that two chaotic neurons can mutually stabilize via a synaptic learning implies that this may be a mechanism whereby neurons can transition from a disordered, chaotic state to a stable, ordered periodic state that persists. This approach shows that even at the simplest level of two terminal neurons, chaotic behavior can become stable, sustained periodic behavior. This is achieved without the need for a large network of neurons.

Utility of FDG PET/CT for assessment of lung nodules identified during low dose computed tomography screening.

BACKGROUND: Many clinical guidelines recommend FDG PET/CT for the evaluation of pulmonary nodules ≥8 mm detected during low dose computed tomography (LDCT) lung cancer screening. However, its added value in this setting requires confirmation. We evaluated the clinical utility of FDG PET/CT, including incidental findings, during the evaluation of lung nodules detected on LDCT screening. METHODS: A retrospective cohort study was performed among 75 patients who completed FDG PET/CT between January 2010 and December 2017, after lung nodules > 8 mm had been detected on LDCT lung cancer screening. We report demographic variables, characteristics of the initial nodules on LDCT and FDG PET/CT, incidental findings on FDG PET/CT, as well as further work up performed and the influence of FDG PET/CT findings on management. RESULTS: Nodules were reported to be benign on FDG PET/CT in 38/75 (50.6%) patients. Physicians chose either radiological follow-up or no further work up in all 38. FDG PET/CT was indeterminate or suggested malignancy in 37 (49.3%) patients. Biopsy was performed in 32 (86%) of these patients. Incidental findings on FDG PET/CT were reported in 37/75 (49%) patients. Further work-up of incidental findings was performed in 21/75 (28%) of patients. CONCLUSIONS: In this study, for majority of individuals with lung nodules identified during LDCT lung cancer screening, FDG PET/CT results were able to guide physicians in choosing between routine follow up or invasive biopsies. Conversely, 28% of these patients required additional investigations to address incidental findings.

The National Institute for Occupational Safety and Health B Reader Certification Program-An Update Report (1987 to 2018) and Future Directions.

OBJECTIVE: The National Institute for Occupational Safety and Health (NIOSH) B Reader Program provides the opportunity for physicians to demonstrate proficiency in the International Labour Office (ILO) system for classifying radiographs of pneumoconioses. We summarize trends in participation and examinee attributes and performance during 1987 to 2018. METHODS: Since 1987, NIOSH has maintained details of examinees and examinations. Attributes of examinees and their examination performance were summarized. Simple linear regression was used in trend analysis of passing rates over time. RESULTS: The mean passing rate for certification and recertification for the study period was 40.4% and 82.6%, respectively. Since the mid-1990s, the number of B Readers has declined and the mean age and years certified have increased. CONCLUSIONS: To address the declining B Reader population, NIOSH is currently taking steps to modernize the program and offer more opportunities for training and testing.

Exposure‒response relationships for silicosis and its progression in industrial sand workers.

Objectives This study aimed to characterize the relationship between radiographic silicosis and exposure to respirable quartz and determine how exposure affects disease progression. Methods Surveillance chest radiographs from a cohort of 1902 workers were examined to identify 67 cases of radiographic silicosis and 167 matched controls. Exposures were estimated by linking work histories to a job exposure matrix (JEM) based on samples collected by the participating companies and historical estimates. Conditional logistic regression was used to examine exposure‒response relationships. Sequential radiographs from silicosis cases were used to assess associations between exposure and disease progression. Results Risk of silicosis increased with cumulative exposure [odds ratio (OR) 1.43 per 1 mg/m 3years, 95% confidence interval (CI) 1.23-1.66], average exposure concentration (OR 1.30 per 0.10 mg/m 3, 95% CI 1.11-1.51) and net exposure duration (OR 1.10 per year, 95% CI 1.05-1.16). Multivariate analyses indicated that the risk associated with cumulative exposure varied depending on exposure duration and concentration. Analysis of the time worked at differing exposure levels indicated that exposures ≤0.05 mg/m 3were not significantly associated with silicosis risk after adjustment for years worked at higher concentrations. Disease progression was related to subsequent exposure concentration, with a yearly increase in small opacity profusion of 0.052 subcategory per each 0.10 mg/m 3increase in concentration. Conclusions Workers with longer exposure at lower concentrations were at higher risk for silicosis than those with the same cumulative exposure who worked for a shorter time at higher concentrations. The rate of silicosis progression was related to subsequent exposure concentration.

Retrospective Assessment of Respirable Quartz Exposure for a Silicosis Study of the Industrial Sand Industry.

Background: In 2016, the OSHA PEL for crystalline silica was reduced, renewing interest in evaluating risk of silicosis from occupational exposures. The industrial sand industry, which deals with high-purity quartz sands, is the setting for a current epidemiologic investigation of silicosis risk and progression. In support of that investigation, respirable quartz (RQ) exposures were retrospectively estimated for 67 workers with silicosis and 167 matched control workers from 21 industrial sand plants, in which some started work as early as 1929. Methods: A job exposure matrix (JEM) was constructed by integrating a modern (post-1970) RQ exposure database containing more than 40000 measurements with archival particle count exposure data from a 1947 survey. A simulation algorithm was used to develop a conversion factor to convert the archival particle count data into modern measures of RQ by randomly generating 100000 virtual dust particles of varying diameters corresponding to the size distributions of 14 archival particle size distribution samples. The equivalent respirable mass and particle counts of the virtual particles were calculated, totalled, and ratioed to derive the conversion factor. The JEM was integrated with individual job histories to calculate average and cumulative exposure for each case and control. Multiple exposure estimates were derived for unprotected exposures as well as for exposures adjusted for estimated respiratory protective equipment use and efficiency. Results: The mean of the count to respirable mass conversion factors derived from 14 archival particle size samples was 157 µg m-3 per mppcf (SD: 42; range: 96-263) with no statistical difference across process areas (drying, screening, vibrating, binning, bulk loading, bagging), P = 0.29. The JEM demonstrated an industry-wide decrease in prevailing exposures to RQ of up to about 2 orders of magnitude from the distant (1929) to the recent (2012) past. Unadjusted cumulative exposures for cases and controls were statistically different (P < 0.001) with respective medians (range) of 3764 µg m-3 year (221-25121) and 1595 µg m-3 year (0-16446). Adjustment of exposure for use of respiratory protection showed modest reductions in estimated exposure: median adjusted cumulative exposures assuming a protection factor of 5 were 86% and 77% of the unadjusted values for cases and controls, respectively. Conclusions: The industrial sand industry offers a unique setting for examination of silicosis risk because of the high silica content of industrial sand and a long history of radiographic silicosis surveillance of industry workers. However, the great majority of silicosis cases in this industry are found among former workers and are associated with exposures occurring in the distant past, which necessitates extensive retrospective exposure assessment and increases the likelihood of exposure misclassification. Nonetheless, the estimated cumulative exposures for silicosis cases and controls in this work were significantly different, with the median cumulative exposure for cases being more than twice that of their matched controls.

Assessment of physicians' proficiency in reading chest radiographs for pneumoconiosis, based on a 60-film examination set with two factors constituting eight indices.

Two hundred and thirty-three individuals read chest x-ray images (CXR) in the Asian Intensive Reader of Pneumoconiosis (AIR Pneumo) workshop. Their proficiency in reading CXR for pneumoconiosis was calculated using eight indices (X1-X8), as follows: sensitivity (X1) and specificity (X2) for pneumoconiosis; sensitivity (X3) and specificity (X4) for large opacities; sensitivity (X5) and specificity (X6) for pleural plaques; profusion increment consistency (X7); and consistency for shape differentiation (X8). For these eight indices, one-way analysis of variance (ANOVA) and Scheffe's multiple comparison were conducted on six groups, based on the participants' specialty: radiology, respiratory medicine, industrial medicine, public health, general internal medicine, and miscellaneous physicians. Our analysis revealed that radiologists had a significant difference in the mean scores of X3, X5, and X8, compared with those of all groups, excluding radiologists. In the factor analysis, X1, X3, X5, X7, and X8 constituted Factor 1, and X2, X4, and X6 constituted Factor 2. With regard to the factor scores of the six participant groups, the mean scores of Factor 1 of the radiologists were significantly higher than those of all groups, excluding radiologists. The two factors and the eight indices may be used to appropriately assess specialists' proficiency in reading CXR.

Derivation and Validation of a Prognostic Model to Predict 6-Month Mortality in an Intensive Care Unit Population.

RATIONALE: Identification of terminally ill patients in the intensive care unit (ICU) would facilitate decision making and timely palliative care. OBJECTIVES: To develop and validate a patient-specific integrated prognostic model to predict 6-month mortality in medical ICU patients. METHODS: A longitudinal prospective cohort study of temporally split samples of 1,049 consecutive medical ICU patients in a tertiary care hospital was performed. For each patient, we collected demographic data, Acute Physiology and Chronic Health Evaluation III score, Charlson comorbidity index, intensivist response to a surprise question (SQ; "Would I be surprised if this patient died in the next 6 months?") on admission, and vital status at 6 months. RESULTS: Between November 2013 and May 2015, derivation and validation cohorts of 500 and 549 consecutive patients were studied to develop a multivariate logistic regression model. In the multivariate logistic regression model, Charlson comorbidity index (P = 0.033), Acute Physiology and Chronic Health Evaluation III score (P < 0.001), and SQ response (P < 0.001) were predictors of vital status at 6 months. The odds of dying within 6 months were significantly higher when the SQ was answered "no" than when it was answered "yes" (odds ratio, 7.29; P < 0.001). The c-statistic for the derivation and validation cohorts were 0.832 (95% confidence interval, 0.795-0.870) and 0.84 (95% confidence interval, 0.806-0.875), respectively. CONCLUSIONS: Our integrated prognostic model, which includes the SQ, has strong discrimination and calibration to predict 6-month mortality in medical ICU patients. This model can aid clinicians in identifying ICU patients who may benefit from the integration of palliative care into their treatment.

Toward personalized medicine of lung cancer: response to nontargeted therapy in invasive pulmonary adenocarcinoma as a function of tumor cell differentiation.

We evaluated clinical parameters, histomorphology, and thyroid transcription factor 1 (TTF-1) immunoreactivity in 40 epidermal growth factor receptor (EGFR) mutation- and anaplastic lymphoma kinase (ALK) rearrangement-negative invasive pulmonary adenocarcinomas. Tumors were histomorphologically quantitated by a pulmonary pathologist and TTF-1 immunohistochemistry applied. EGFR mutation and ALK rearrangement status was determined with polymerase chain reaction/DNA sequencing and fluorescence in situ hybridization, respectively. Treatment response was related to type of treatment (P < .005) and clinical stage (P = .001). EGFR mutation- and ALK rearrangement-negative pulmonary adenocarcinomas containing papillary/micropapillary histology showed greater morphologic heterogeneity (P < .001), greater TTF-1 immunoreactivity (P = .004), and were more common in treatment responders (P < .05). These findings support that patients with pulmonary adenocarcinomas that are subject to nontargeted therapies may respond to treatment as a function of tumor cell differentiation with TTF-1 as a potential biomarker of this response.

Proficiency in reading pneumoconiosis radiographs examined by the 60-film set with 4-factor structuring 8-index.

29 physicians (A1-Group) and 24 physicians (A2-Group) attending the 1st and 2nd "Asian Intensive Reader of Pneumoconiosis" (AIR Pneumo) training course, respectively, and 22 physicians (B-Group) attending the Brazilian training course took the examination of reading the 60-film set. The objective of the study was firstly to investigate the factor structure of physicians' proficiency of reading pneumoconiosis chest X-ray, and secondly to examine differences in factor scores between groups. Reading results in terms of the 8-index of all examinees (Examinee Group) were subjected to the exploratory factor analysis. A 4-factor was analyzed to structure the 8-index: the specificity for pneumoconiosis, specificity for large opacities, specificity for pleural plaque and shape differentiation for small opacities loaded on the Factor 1; the sensitivity for pneumoconiosis and sensitivity for large opacities loaded on the Factor 2; the sensitivity for pleural plaque loaded on the Factor 3; the profusion increment consistency loaded on the Factor 4. 4-Factor scores were compared between each other of the three groups. The Factor 2 scores in A1 and A2 groups were significantly higher than in B-Group. Four factors could reflect four aspects of reading proficiency of pneumoconiosis X-ray, and it was suggested that 4-factor scores could also assess the attained skills appropriately.