Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.

The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disorder of unknown etiology that is characterized by a usual interstitial pneumonia pattern. Previous meta-analyses have reported associations between occupational exposures and IPF, but higher-quality studies have been published in recent years, doubling the number of studied patients. Objectives: To provide a contemporary and comprehensive assessment of the relationship between occupational exposures and IPF. Methods: We searched PubMed, Embase, and Web of Science through July 2023 to identify all publications on occupational exposure and IPF. We conducted a meta-analysis of the occupational burden, odds ratio (OR), and population attributable fraction (PAF) of exposures. Five exposure categories were analyzed: vapors, gas, dust, and fumes (VGDF); metal dust; wood dust; silica dust; and agricultural dust. A comprehensive bias assessment was performed. The study protocol was registered in the International Prospective Register of Systematic Reviews (identifier CRD42021267808). Results: Our search identified 23,942 publications. Sixteen publications contained relative risks needed to calculate pooled ORs and PAFs, and 12 additional publications reported an occupational burden within a case series. The proportion of cases with occupational exposures to VGDF was 44% (95% confidence interval [CI], 36-53%), with a range of 8-17% within more specific exposure categories. The pooled OR was increased for VGDF at 1.8 (95% CI, 1.3-2.4), with a pooled PAF of 21% (95% CI, 15-28%). ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust. The pooled ORs and PAFs within specific exposure categories ranged from 1.6 to 1.8 and from 4% to 14%, respectively. We identified some publication bias, but it was not sufficient to diminish the association between occupational exposures and IPF based on sensitivity analysis and bias assessment. Conclusions: Our findings indicate that 21% of IPF cases (or approximately one in five) could be prevented by removal of occupational exposure (alongside a pooled OR of 1.8). Additionally, 44% of patients with IPF report occupational exposure to VGDF. This meta-analysis suggests that a considerable number of cases of IPF are attributable to inhaled occupational exposures and warrant increased consideration in the clinical care of patients and future prevention efforts.

The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. METHODS: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. RESULTS: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997-1.000; p=0.245). CONCLUSIONS: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated.

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.

Mesothelioma mortality in Great Britain: how much longer will dockyards dominate?

OBJECTIVES: We aimed to investigate whether there has been a geographic shift in the distribution of mesothelioma deaths in Great Britain given the decline of shipbuilding and progressive exposure regulation. METHODS: We calculated age-adjusted mesothelioma mortality rates and estimated rate ratios for areas with and without a dockyard. We compared spatial autocorrelation statistics (Moran's I) for age-adjusted rates at local authority district level for 2002-2008 and 2009-2015. We measured the mean distance of the deceased's postcode to the nearest dockyard at district level and calculated the association of average distance to dockyard and district mesothelioma mortality using simple linear regression for men, for 2002-2008 and 2009-2015. RESULTS: District age-adjusted male mortality rates fell during 2002-2015 for 80 of 348 districts (23%), rose for 267 (77%) and were unchanged for one district; having one or more dockyards in a district was associated with rates falling (OR=2.43, 95% CI 1.22 to 4.82, p=0.02). The mortality rate ratio for men in districts with a dockyard, compared with those without a dockyard was 1.41 (95% CI 1.35 to 1.48, p<0.05) for 2002-2008 and 1.18 (95% CI 1.13 to 1.23, p<0.05) for 2009-2015. Spatial autocorrelation (measured by Moran's I) decreased from 0.317 (95% CI 0.316 to 0.319, p=0.001) to 0.312 (95% CI 0.310 to 0.314, p=0.001) for men and the coefficient of the association between distance to dockyard and district level age-adjusted male mortality (per million population) from -0.16 (95% CI -0.21 to -0.10, p<0.01) to -0.13 (95% CI -0.18 to -0.07, p<0.01) for men, when comparing 2002-2008 with 2009-2015. CONCLUSION: For most districts age-adjusted mesothelioma mortality rates increased through 2002-2015 but the relative contribution from districts with a dockyard fell. Dockyards remain strongly spatially associated with mesothelioma mortality but the strength of this association appears to be falling and mesothelioma deaths are becoming more dispersed.

The Occupational Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and European Respiratory Society Statement.

Rationale: Workplace inhalational hazards remain common worldwide, even though they are ameliorable. Previous American Thoracic Society documents have assessed the contribution of workplace exposures to asthma and chronic obstructive pulmonary disease on a population level, but not to other chronic respiratory diseases. The goal of this document is to report an in-depth literature review and data synthesis of the occupational contribution to the burden of the major nonmalignant respiratory diseases, including airway diseases; interstitial fibrosis; hypersensitivity pneumonitis; other noninfectious granulomatous lung diseases, including sarcoidosis; and selected respiratory infections. Methods: Relevant literature was identified for each respiratory condition. The occupational population attributable fraction (PAF) was estimated for those conditions for which there were sufficient population-based studies to allow pooled estimates. For the other conditions, the occupational burden of disease was estimated on the basis of attribution in case series, incidence rate ratios, or attributable fraction within an exposed group. Results: Workplace exposures contribute substantially to the burden of multiple chronic respiratory diseases, including asthma (PAF, 16%); chronic obstructive pulmonary disease (PAF, 14%); chronic bronchitis (PAF, 13%); idiopathic pulmonary fibrosis (PAF, 26%); hypersensitivity pneumonitis (occupational burden, 19%); other granulomatous diseases, including sarcoidosis (occupational burden, 30%); pulmonary alveolar proteinosis (occupational burden, 29%); tuberculosis (occupational burden, 2.3% in silica-exposed workers and 1% in healthcare workers); and community-acquired pneumonia in working-age adults (PAF, 10%). Conclusions: Workplace exposures contribute to the burden of disease across a range of nonmalignant lung conditions in adults (in addition to the 100% burden for the classic occupational pneumoconioses). This burden has important clinical, research, and policy implications. There is a pressing need to improve clinical recognition and public health awareness of the contribution of occupational factors across a range of nonmalignant respiratory diseases.

Better value digital health: the medium, the market and the role of openness.

The recent NHS 'hack days' have showcased the enthusiasm and talent of the junior doctor body as well as the potential of open source, open governance and small-medium enterprise. There still remains much scope for developing better value digital health services within the NHS. This article sets out the current state of NHS information technology (IT), how it fails to meet the needs of patients and professionals alike and suggests how better value digital health can be achieved.

No impact of rifamycin selection on tuberculosis treatment outcome in HIV coinfected patients.

Rifabutin has been substituted for rifampicin when treating tuberculosis (TB)/HIV coinfection. However, despite reports of anti-TB treatment failure and acquired rifamycin resistance, long-term clinical outcome data are lacking. Observational analyses performed in a UK TB/HIV cohort demonstrated no difference in severe adverse events, anti-TB treatment completion, relapse frequency or subsequent rifamycin resistance when rifampicin and rifabutin were compared, using different combinations of antiretroviral therapy. Our data support the wider use of rifabutin in TB/HIV coinfection.

Exercise associated hyponatraemia leading to tonic-clonic seizure.

A 34-year-old Filipino lady presented to the emergency department with breathlessness and muscle cramping following a Bikram yoga workout. The patient reported sweating excessively while performing 90 min of strenuous exertion in a humidified room heated to an ambient temperature of 40.6°C. After the workout she drank 3.5 litres of water before experiencing breathlessness, severe muscle cramps, nausea and general malaise. Initial investigations revealed severe hyponatraemia (120 mmol/l). Despite early sodium replacement the patient dropped her Glasgow coma scale to 9/15 and developed tonic clonic seizures, requiring intubation and admission to the intensive care unit. The hyponatraemia was slowly corrected on the intensive care unit and the patient made a full recovery over the course of 5 days. This case highlights the dangers of overzealous fluid replacement following severe exertion in a hot environment.

Open source, open standards, and health care information systems.

Recognition of the improvements in patient safety, quality of patient care, and efficiency that health care information systems have the potential to bring has led to significant investment. Globally the sale of health care information systems now represents a multibillion dollar industry. As policy makers, health care professionals, and patients, we have a responsibility to maximize the return on this investment. To this end we analyze alternative licensing and software development models, as well as the role of standards. We describe how licensing affects development. We argue for the superiority of open source licensing to promote safer, more effective health care information systems. We claim that open source licensing in health care information systems is essential to rational procurement strategy.

Gonococcal peritonitis diagnosed post laparotomy in a 38-year-old woman: a case report.

A 38-year-old South African lady with a background history of cervical intra-epithelial neoplasia and recent colposcopy presented to the emergency department with severe abdominal pain. Initial investigations were non-diagnostic and despite empirical antibiotic therapy the patient developed peritonism. Post-laprotomy the diagnosis of severe pelvic inflammatory disease and peritonitis secondary to infection with Neisseria Gonorrhoea was made.