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.

Segregation of Amine Oxide Surfactants in PVA Films.

The vertical depth distributions of amine oxide surfactants, N,N-dimethyldodecyl amine N-oxide (DDAO) and N,N-dimethyltetradecyl amine N-oxide (DTAO), in poly(vinyl alcohol) (PVA) films were explored using neutron reflectometry (NR). In both binary and plasticized films, the two deuterated surfactants formed a single monolayer on the film surface with the remaining surfactant homogeneously distributed throughout the bulk of the film. Small-angle neutron scattering and mechanical testing revealed that these surfactants acted like plasticizers in the bulk, occupying the amorphous regions of PVA and reducing its glass-transition temperature. NR revealed little impact of plasticizer (glycerol) incorporation on the behavior of these surfactants in PVA. The surfactant molecular area in the segregated monolayer was smaller for DTAO than for DDAO, indicating that the larger molecule was more densely packed at the surface. Surface tension was used to assess the solution behavior of these surfactants and the effect of glycerol incorporation. Determination of molecular area of each surfactant on the solution surface revealed that the structures of the surface monolayers are remarkably consistent when water is placed by the solid PVA. Incorporation of glycerol caused a decrease of molecular area for DDAO and increase in molecular area for DTAO both in solution and in PVA. This suggests that the head group interactions, which normally limit the minimum area per adsorbed molecule, are modified by the length of the alkyl tail.

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.

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 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.

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

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.

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.

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Thermoresponsive Block Copolymer Core-Shell Nanoparticles with Tunable Flow Behavior in Porous Media.

With the purpose of investigating new polymeric materials as potential flow modifiers for their future application in enhanced oil recovery (EOR), a series of amphiphilic poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) [P(DEGMA-co-OEGMA)]-based core-shell nanoparticles were prepared by aqueous reversible addition-fragmentation chain transfer-mediated polymerization-induced self-assembly. The developed nano-objects were shown to be thermoresponsive, demonstrating a reversible lower-critical solution temperature (LCST)-type phase transition with increasing solution temperature. Characterization of their thermoresponsive nature by variable-temperature UV-vis and dynamic light scattering analyses revealed that these particles reversibly aggregate when heated above their LCST and that the critical transition temperature could be accurately tuned by simply altering the molar ratio of core-forming monomers. Sandpack experiments were conducted to evaluate their pore-blocking performance at low flow rates in a porous medium heated at temperatures above their LCST. This analysis revealed that particles aggregated in the sandpack column and caused pore blockage with a significant reduction in the porous medium permeability. The developed aggregates and the increased pressure generated by the blockage were found to remain stable under the injection of brine and were observed to rapidly dissipate upon reducing the temperature below the LCST of each formulation. Further investigation by double-column sandpack analysis showed that the blockage was able to reform when re-heated and tracked the thermal front. Moreover, the rate of blockage formation was observed to be slower when the LCST of the injected particles was higher. Our investigation is expected to pave the way for the design of "smart" and versatile polymer technologies for EOR applications in future studies.

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.

Cardiac resynchronization therapy in mild heart failure: a review of the REVERSE and MADIT-CRT trials.

Cardiac resynchronization therapy has become part of the treatment strategy for advanced, symptomatic heart failure, but newly published trials show that more patients than previously realized may benefit from this therapy, including those with mild heart failure symptoms. The REVERSE and MADIT-CRT trials showed that cardiac resynchronization therapy reduces risk of hospitalization for heart failure and leads to beneficial reverse remodeling of the left ventricle in mild heart failure, especially in patients with prolonged QRS complexes. Ongoing studies aim to expand the indications for this therapy even further, including in patients with normal ejection fractions and a need for frequent ventricular pacing. The current body of evidence favors cardiac resynchronization therapy in patients with a depressed ejection fraction and prolonged QRS, even with minimal or no heart failure symptoms.

Occupational Contributions to Interstitial Lung Disease.

Historically well-recognized occupational threats such as coal workers pneumoconiosis, silicosis, and asbestosis remain important and are very likely underestimated in measures of global disease burden. Studies of occupational exposure related to idiopathic pulmonary fibrosis, the most common interstitial lung disease, are limited but there is moderate evidence for metal, wood, and stone dust being significant contributors. Vigilance is required to identify causes, such as hypersensitivity pneumonitis due to microbial contamination of metalworking fluid (now responsible for greater than 50% of occupational hypersensitivity pneumonitis cases in the United Kingdom) in an everchanging workplace environment.

Physician attire: physicians perspectives on attire in a community hospital setting among non-surgical specialties.

Background: Several studies have demonstrated a patient preference for physicians wearing a white coat associated with improved patient satisfaction. There are few studies on physicians' perceptions of attire mainly done in the outpatient and surgical specialties. Objective: Assess non-surgical physicians' perception of attire in the hospital and to identify if any difference in the choice of attire amongst generation X and millennial physicians. Methods: We surveyed 86 physicians in the hospital with six sets of pictures of commonly worn physician attires in the hospital setting with a two-part questionnaire. Key Results: Formal attire with a white coat was found to be most favored, followed by formal without a white coat. Casual attire without a white coat was the least preferred across the surveyed attributes. The results were similar in generation X and millennial physicians. Only 49% concordance was observed with what physicians preferred and what they wore. Conclusion: Our study showed that physicians felt wearing a white coat was the best to convey specific attributes like honesty, confidence, professionalism, among others, similar to prior studies done in patients. However, less than half of the physicians surveyed themselves followed the preferred attire.

Do doctors in dispensing practices with a financial conflict of interest prescribe more expensive drugs? A cross-sectional analysis of English primary care prescribing data.

OBJECTIVES: Approximately one in eight practices in primary care in England are 'dispensing practices' with an in-house dispensary providing medication directly to patients. These practices can generate additional income by negotiating lower prices on higher cost drugs, while being reimbursed at a standard rate. They, therefore, have a potential financial conflict of interest around prescribing choices. We aimed to determine whether dispensing practices are more likely to prescribe high-cost options for four commonly prescribed classes of drug where there is no evidence of superiority for high-cost options. DESIGN: A list was generated of drugs with high acquisition costs that were no more clinically effective than those with the lowest acquisition costs, for all four classes of drug examined. Data were obtained prescribing of statins, proton pump inhibitors (PPIs), angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEis). Logistic regression was used to calculate ORs for prescribing high-cost options in dispensing practices, adjusting for Index of Multiple Deprivation score, practice list size and the number of doctors at each practice. SETTING: English primary care. PARTICIPANTS: All general practices in England. MAIN OUTCOME MEASURES: Mean cost per dose was calculated separately for dispensing and non-dispensing practices. Dispensing practices can vary in the number of patients they dispense to; we, therefore, additionally compared practices with no dispensing patients, low, medium and high proportions of dispensing patients. Total cost savings were modelled by applying the mean cost per dose from non-dispensing practices to the number of doses prescribed in dispensing practices. RESULTS: Dispensing practices were more likely to prescribe high-cost drugs across all classes: statins adjusted OR 1.51 (95% CI 1.49 to 1.53, p<0.0001), PPIs OR 1.11 (95% CI 1.09 to 1.13, p<0.0001), ACEi OR 2.58 (95% CI 2.46 to 2.70, p<0.0001), ARB OR 5.11 (95% CI 5.02 to 5.20, p<0.0001). Mean cost per dose in pence was higher in dispensing practices (statins 7.44 vs 6.27, PPIs 5.57 vs 5.46, ACEi 4.30 vs 4.24, ARB 11.09 vs 8.19). For all drug classes, the more dispensing patients a practice had, the more likely it was to issue a prescription for a high-cost option. Total cost savings in England available from all four classes are £628 875 per month or £7 546 502 per year. CONCLUSIONS: Doctors in dispensing practices are more likely to prescribe higher cost drugs. This is the largest study ever conducted on dispensing practices, and the first contemporary research suggesting some UK doctors respond to a financial conflict of interest in treatment decisions. The reimbursement system for dispensing practices may generate unintended consequences. Robust routine audit of practices prescribing higher volumes of unnecessarily expensive drugs may help reduce costs.