What role for asbestos in idiopathic pulmonary fibrosis? Findings from the IPF job exposures case-control study.

BACKGROUND: Asbestos has been hypothesised as the cause of the recent global increase in the incidence of 'idiopathic' pulmonary fibrosis (IPF). Establishing this has important diagnostic and therapeutic implications. The association between occupational asbestos exposure and IPF, and interaction with a common (minor allele frequency of 9% in European populations) genetic variant associated with IPF, MUC5B rs35705950, is unknown. METHODS: Multicentre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 UK hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was assessed at interview using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs35705950 was investigated using a genetic dominant model. RESULTS: 327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls had cumulative exposure estimates ≥25 fibre ml⁻¹ years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1 (95% CI 0.8 to 1.4; p=0.6) and there was no gene-environment interaction (p=0.3). Ever smoking was associated with IPF, OR 1.4 (95% CI 1 to 1.9; p=0.04) and interacted with occupational asbestos exposure, OR 1.9 (95% CI 1 to 3.6; p=0.04). In a further non-specified analysis, when stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs35705950. CONCLUSION: Occupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. Exposure to asbestos and smoking interact to increase IPF risk in carriers of a common genetic variant, the minor allele of MUC5B rs35705950. TRIAL REGISTRATION NUMBER: NCT03211507.

Chronic Obstructive Pulmonary Disease and Work: The Continuing Narrative.

It has long been recognized that harmful inhaled workplace exposures can contribute to the development of chronic obstructive pulmonary disease (COPD). This article, intended for the clinician, summarizes some of this evidence and some areas of controversy. Current estimates based on pooled epidemiological analyses of population-based studies identify that approximately 14% of the burden of COPD (and 13% of the burden of chronic bronchitis) is attributable to such exposures. In addition to these approaches, various studies implicate specific exposures as contributing. Certain of these relating to cadmium, coal, and respirable crystalline silica are discussed in more detail. Despite this amassed evidence to date supporting associations between COPD and workplace exposures, there have been surprisingly few studies that have attempted to assess the attribution by experts of an occupational cause in cases of COPD. One study, using hypothetical cases of COPD, noted that while expert physicians were willing to make such an occupational link, this was only likely in cases with light smoking histories and a priori defined heavy occupational exposures. Relatively recent data relating to computed tomography (CT) scan appearances may give the clinician a further guide. Several studies from populations have now linked potentially harmful occupational exposures specifically with the presence of emphysema on CT scanning. It will be of interest to see if this finding, along with other clinical attributes of cases such as smoking and family histories, exclusion of asthma, genetic data, and the nature of workplace exposures, will increase the future diagnosis by clinicians of occupational COPD. In the interim, while better diagnostic approaches are developed, we suggest that consideration of an occupational cause is an important part of the clinical investigation of cases of COPD. Finally, we suggest that evidence-based workplace preventive strategies for occupational COPD should be informed by knowledge of which exposures are most important to reduce, and whether and when intervention to reduce exposure at an individual worker level is warranted.

Improvement of quantitative structure-activity relationship (QSAR) tools for predicting Ames mutagenicity: outcomes of the Ames/QSAR International Challenge Project.

The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.

Emerging trends in the UK incidence of occupational asthma: should we be worried?

While 15% of adult-onset asthma is estimated to have an occupational cause, there has been evidence of a downward trend in occupational asthma incidence in several European countries since the start of this millennium. However, recent data from The Health and Occupation Reporting network in the UK have suggested a possible reversal of this downward trend since 2014. We present these data and discuss possible explanations for this observed change in incidence trend. A high index of suspicion of occupational causation in new-onset asthma cases continues to be important, whether or not the recently observed increase in occupational asthma incidence in the UK is real or artefactual.

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.

Working within a spiritual framework.

Chris Barber, Visiting Lecturer (Learning Disabilities), Birmingham City University ( chris.barber@bcu.ac.uk ), offers tips for nurses on supporting patients in the spiritual aspects of their lives.

Assessment and Reproducibility of Quantitative Structure-Activity Relationship Models by the Nonexpert.

Model reliability is generally assessed and reported as an intrinsic component of quantitative structure-activity relationship (QSAR) publications; it can be evaluated using defined quality criteria such as the Organisation for Economic Cooperation and Development (OECD) principles for the validation of QSARs. However, less emphasis is afforded to the assessment of model reproducibility, particularly by users who may wish to use model outcomes for decision making, but who are not QSAR experts. In this study we identified a range of QSARs in the area of absorption, distribution, metabolism, and elimination (ADME) prediction and assessed their adherence to the OECD principles, as well as investigating their reproducibility by scientists without expertise in QSAR. Here, 85 papers were reviewed, reporting over 80 models for 31 ADME-related endpoints. Of these, 12 models were identified that fulfilled at least 4 of the 5 OECD principles and 3 of these 12 could be readily reproduced. Published QSAR models should aim to meet a standard level of quality and be clearly communicated, ensuring their reproducibility, to progress the uptake of the models in both research and regulatory landscapes. A pragmatic workflow for implementing published QSAR models and recommendations to modellers, for publishing models with greater usability, are presented herein.

Working with a patient with an autism spectrum condition.

Chris Barber, Visiting Lecturer (Learning Disabilities), Birmingham City University ( chris.barber@bcu.ac.uk ), offers tips for nurses working with adults with autism spectrum conditions.

Chest physician-reported, work-related, long-latency respiratory disease in Great Britain.

Much of the current burden of long-latency respiratory disease (LLRD) in Great Britain is attributed to historical asbestos exposure. However, continuing exposure to other agents, notably silica, also contributes to disease burden. The aim of this study was to investigate the incidence of work-related LLRD reported by chest physicians in Great Britain, including variations by age, gender, occupation and suspected agent.LLRD incidence and incidence rate ratios by occupation were estimated (1996-2014). Mesothelioma cases by occupation were compared with proportional mortality ratios.Cases were predominantly in men (95%) and 92% of all cases were attributed to asbestos. Annual average incidence rates (males) per 100 000 were: benign pleural disease, 7.1 (95% CI 6.0-8.2); mesothelioma, 5.4 (4.8-6.0); pneumoconiosis, 1.9 (1.7-2.2); lung cancer, 0.8 (0.6-1.0); chronic obstructive pulmonary disease (COPD), 0.3 (0.2-0.4). Occupations with a particularly high incidence of LLRD were miners and quarrymen (COPD), plumbers and gas fitters (asbestosis), and shipyard and dock workers (all other categories). There was a clear concordance between cases of SWORD mesothelioma and proportional mortality ratios by occupation.Occupationally caused LLRD continues to contribute to a significant disease burden. Many cases are attributable to past exposure to agents such as asbestos and silica, but the potential for occupational exposures persists.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Evaluation of a statistics-based Ames mutagenicity QSAR model and interpretation of the results obtained.

The relative wealth of bacterial mutagenicity data available in the public literature means that in silico quantitative/qualitative structure activity relationship (QSAR) systems can readily be built for this endpoint. A good means of evaluating the performance of such systems is to use private unpublished data sets, which generally represent a more distinct chemical space than publicly available test sets and, as a result, provide a greater challenge to the model. However, raw performance metrics should not be the only factor considered when judging this type of software since expert interpretation of the results obtained may allow for further improvements in predictivity. Enough information should be provided by a QSAR to allow the user to make general, scientifically-based arguments in order to assess and overrule predictions when necessary. With all this in mind, we sought to validate the performance of the statistics-based in vitro bacterial mutagenicity prediction system Sarah Nexus (version 1.1) against private test data sets supplied by nine different pharmaceutical companies. The results of these evaluations were then analysed in order to identify findings presented by the model which would be useful for the user to take into consideration when interpreting the results and making their final decision about the mutagenic potential of a given compound.

Establishing best practise in the application of expert review of mutagenicity under ICH M7.

The ICH M7 guidelines for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals allows for the consideration of in silico predictions in place of in vitro studies. This represents a significant advance in the acceptance of (Q)SAR models and has resulted from positive interactions between modellers, regulatory agencies and industry with a shared purpose of developing effective processes to minimise risk. This paper discusses key scientific principles that should be applied when evaluating in silico predictions with a focus on accuracy and scientific rigour that will support a consistent and practical route to regulatory submission.

Old age and people on the autism spectrum: a focus group perspective.

Until recently, the focus of many within the 'autism service industry' has been on children and young adults who are on the autism spectrum where 'service transition' usually refers specifically to the transition from children to adult service provision. This article explores 'service transition' from the opposite end of the age scale, that of old age, and incorporates the views of older adults who are on the autism spectrum. In order to design and provide a service that is 'fit for purpose', training of health professionals and consulting with people on the autism spectrum is crucial.

The impact of nuance DAX ambient listening AI documentation: a cohort study.

OBJECTIVE: To assess the impact of the use of an ambient listening/digital scribing solution (Nuance Dragon Ambient eXperience (DAX)) on caregiver engagement, time spent on Electronic Health Record (EHR) including time after hours, productivity, attributed panel size for value-based care providers, documentation timeliness, and Current Procedural Terminology (CPT) submissions. MATERIALS AND METHODS: We performed a peer-matched controlled cohort study from March to September 2022 to evaluate the impact of DAX in outpatient clinics in an integrated healthcare system. Primary outcome measurements included provider engagement survey results, reported patient safety events related to DAX use, patients' Likelihood to Recommend score, number of patients opting out of ambient listening, change in work relative values units, attributed value-based primary care panel size, documentation completion and CPT code submission deficiency rates, and note turnaround time. RESULTS: A total of 99 providers representing 12 specialties enrolled in the study; 76 matched control group providers were included for analysis. Median utilization of DAX was 47% among active participants. We found positive trends in provider engagement, while non-participants saw worsening engagement and no practical change in productivity. There was a statistically significant worsening of after-hours EHR. There was no quantifiable effect on patient safety. DISCUSSION: Nuance DAX use showed positive trends in provider engagement at no risk to patient safety, experience, or clinical documentation. There were no significant benefits to patient experience, documentation, or measures of provider productivity. CONCLUSION: Our results highlight the potential of ambient dictation as a tool for improving the provider experience. Head-to-head comparisons of EHR documentation efficiency training are needed.

COPD causation and workplace exposures: an assessment of agreement among expert clinical raters.

BACKGROUND: Although occupational exposure is a known risk factor for Chronic Obstructive Pulmonary Disease (COPD), it is difficult to identify specific occupational contributors to COPD at the individual level to guide COPD prevention or for compensation. The aim of this study was to gain an understanding of how different expert clinicians attribute likely causation in COPD. METHODS: Ten COPD experts and nine occupational lung disease experts assigned occupational contribution ratings to fifteen hypothetical cases of COPD with varying combinations of occupational and smoking exposures. Participants rated the cause of COPD as the percentage contribution to the overall attribution of disease for smoking, occupational exposures and other causes. RESULTS: Increasing pack-years of tobacco smoking was associated with significantly decreased proportional occupational causation ratings. Increasing weighted occupational exposure was associated with increased occupational causation ratings by 0.28% per unit change. Expert background also contributed significantly to the proportion of occupational causation rated, with COPD experts rating on average a 9.4% greater proportion of occupational causation per case. CONCLUSION: Our findings support the notion that respiratory physicians are able to assign attribution to different sources of causation in COPD, taking into account both smoking and occupational histories. The recommendations on whether to continue to work in the same job also differ, the COPD experts being more likely to recommend change of work rather than change of work practice.

Asthma in the workplace: a case-based discussion and review of current evidence.

The relationship between asthma and the workplace is important to consider in all cases of adult asthma. Early identification of a cause in the workplace offers an opportunity to improve asthma control significantly and reduce the need for long-term medication if further exposures to the cause can be avoided. This typical but fictitious case is designed to give the reader clinical information in the order this would normally be received in clinical practice, with a real-time commentary about management decisions. Pertinent recent guidance is cited to stress the importance of evidence-based practice.

Use of bullying as a management tool in healthcare environments.

Bullying is very much an aspect of contemporary society and perhaps it always has been. Many may have experienced it from early childhood while at school, either as victims or perpetrators. The healthcare industry is, sadly, not immune from this phenomenon. This short article seeks to answer the question: 'Is bullying deliberately used as a management tool within the healthcare industry?' Although bullies exist in many healthcare environments, and there may be a culture of bullying in some of these work places, the proposition that some people actually use bullying as a management tool is more difficult to prove.

Investigation of a SARS-CoV-2 Outbreak at an Automotive Manufacturing Site in England.

Workplace-related outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to occur globally. The manufacturing sector presents a particular concern for outbreaks, and a better understanding of transmission risks are needed. Between 9 March and 24 April 2021, the COVID-19 (coronavirus disease 2019) Outbreak Investigation to Understand Transmission (COVID-OUT) study undertook a comprehensive investigation of a SARS-CoV-2 outbreak at an automotive manufacturing site in England. The site had a total of 266 workers, and 51 SARS-CoV-2 infections. Overall, ventilation, humidity, and temperature at the site were assessed to be appropriate for the number of workers and the work being conducted. The company had implemented a number of infection control procedures, including provision of face coverings, spacing in the work, and welfare areas to allow for social distancing. However, observations of worker practices identified lapses in social distancing, although all were wearing face coverings. A total of 38 workers, including four confirmed cases, participated in the COVID-OUT study. The majority of participants received COVID-19 prevention training, though 42.9% also reported that their work required close physical contact with co-workers. Additionally, 73.7% and 34.2% had concerns regarding reductions in future income and future unemployment, respectively, due to self-isolation. This investigation adds to the growing body of evidence of SARS-CoV-2 outbreaks from the manufacturing sector. Despite a layered COVID-19 control strategy at this site, cases clustered in areas of high occupancy and close worker proximity.