The underlying mechanisms by which Post-Traumatic Growth is associated with cardiovascular health in male UK military personnel: The ADVANCE cohort study.

Post-Traumatic Growth (PTG) is associated with good cardiovascular health, but the mechanisms of this are poorly understood. This cross-sectional analysis assessed whether factors of PTG (Appreciation of Life (AOL), New Possibilities (NP), Personal Strength (PS), Relating to Others (RTO) and Spiritual Change (SC)) are associated with cardiovascular health in a cohort of 1006 male UK military personnel (median age 34). The findings suggest AOL, PS and RTO are associated with better cardiovascular health through cardiometabolic effects (lower levels of triglycerides, and total cholesterol) and haemodynamic functioning (lower diastolic blood pressure), but not inflammation. However, NP and SC were associated with poorer cardiovascular health through cardiometabolic effects (lower levels of high-density lipoproteins and higher levels of total cholesterol) and AOL had a non-linear association with low-density lipoproteins. These findings suggest that the relationship between PTG and cardiovascular functioning is complex and in need of further scrutiny.

Pain after combat injury in male UK military personnel deployed to Afghanistan.

BACKGROUND: Chronic pain after injury poses a serious health burden. As a result of advances in medical technology, ever more military personnel survive severe combat injuries, but long-term pain outcomes are unknown. We aimed to assess rates of pain in a representative sample of UK military personnel with and without combat injuries. METHODS: We used data from the ADVANCE cohort study (ISRCTN57285353). Individuals deployed as UK armed forces to Afghanistan were recruited to include those with physical combat injuries, and a frequency-matched uninjured comparison group. Participants completed self-reported questionnaires, including 'overall' pain intensity and self-assessment of post-traumatic stress disorder, anxiety, and depression. RESULTS: A total of 579 participants with combat injury, including 161 with amputations, and 565 uninjured participants were included in the analysis (median 8 yr since injury/deployment). Frequency of moderate or severe pain was 18% (n=202), and was higher in the injured group (n=140, 24%) compared with the uninjured group (n=62, 11%, relative risk: 1.1, 95% confidence interval [CI]: 1.0-1.2, P<0.001), and lower in the amputation injury subgroup (n=31, 19%) compared with the non-amputation injury subgroup (n=109, 26%, relative risk: 0.9, 95% CI: 0.9-1.0, P=0.034). Presence of at least moderate pain was associated with higher rates of post-traumatic stress (RR: 3.7, 95% CI: 2.7-5.0), anxiety (RR: 3.2, 95% CI: 2.4-4.3), and depression (RR: 3.4, 95% CI: 2.7-4.5) after accounting for injury. CONCLUSION: Combat injury, but not amputation, was associated with a higher frequency of moderate to severe pain intensity in this cohort, and pain was associated with adverse mental health outcomes.

Occupational exposure to particulate matter and staff sickness absence on the London underground.

The London Underground (LU) employs over 19,000 staff, some of whom are exposed to elevated concentrations of particulate matter (PM) within the network. This study quantified the occupational exposure of LU staff to subway PM and investigated the possible association with sickness absence (SA). A job exposure matrix to quantify subway PM2.5 staff exposure was developed by undertaking measurement campaigns across the LU network. The association between exposure and SA was evaluated using zero-inflated mixed-effects negative binomial models. Staff PM2.5 exposure varied by job grade and tasks undertaken. Drivers had the highest exposure over a work shift (mean: 261 µg/m3), but concentrations varied significantly by LU line and time the train spent subway. Office staff work in office buildings separate to the LU network and are unexposed to occupational subway PM2.5. They were found to have lower rates of all-cause and respiratory infection SA compared to non-office staff, those who work across the LU network and are occupational exposed to subway PM2.5. Train drivers on five out of eight lines showed higher rates of all-cause SA, but no dose-response relationship was seen. Only drivers from one line showed higher rates of SAs from respiratory infections (incidence rate ratio: 1.24, 95% confidence interval 1.10-1.39). Lower-grade customer service (CS) staff showed higher rates of all-cause and respiratory infection SA compared to higher grade CS staff. Doctor-certified chronic respiratory and cardiovascular SAs were associated with occupational PM2.5 exposure in CS staff and drivers. While some groups with higher occupational exposure to subway PM reported higher rates of SA, no evidence suggests that subway PM is the main contributing factor to SA. This is the largest subway study on health effects of occupational PM2.5 exposure and may have wider implications for subway workers, contributing to safer working environments.

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.

Assessing the Feasibility of a Multifaceted Intervention Package for Improving Respiratory Health of Textile Workers: Findings From the MultiTex Pilot Study in Karachi, Pakistan.

We piloted the development and implementation of a multifaceted intervention package for improving respiratory health among textile workers using a pre-post design at six mills in Karachi. The intervention, implemented following a baseline survey (n = 498), included health and safety training of workers and managers, promotion of cotton dust control measures, and the provision of facemasks. Follow-up surveys were conducted at 1, 6, and 12 months post-intervention. Knowledge, attitude, and practice (KAP) scores and respiratory symptoms were assessed through a questionnaire and spirometry was conducted. The intervention was provided to 230 workers and led to an improvement in KAP scores that was more likely among workers with a higher educational status, spinners, smokers, those with a permanent employment status, working in morning shifts, and with ⩾5 years of textile experience. We found the intervention acceptable and feasible in these textile mills henceforth, trials are required to determine its effectiveness.

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.

A cluster randomised controlled trial to reduce respiratory effects of cotton dust exposure among textile workers: the MultiTex RCT study.

BACKGROUND: We determined the effectiveness of an intervention to reduce cotton dust-related respiratory symptoms and improve lung function of textile workers. METHODS: We undertook a cluster randomised controlled trial at 38 textile mills in Karachi, Pakistan. The intervention comprised: training in occupational health for workers and managers, formation of workplace committees to promote a health and safety plan that included wet mopping and safe disposal of cotton dust, provision of simple face masks, and further publicity about the risks from cotton dust. Participating mills were randomised following baseline data collection. The impact of the intervention was measured through surveys at 3, 12 and 18 months using questionnaires, spirometry and dust measurements. The primary outcomes were 1) changes in prevalence of a composite respiratory symptom variable, 2) changes in post-bronchodilator percentage predicted forced expiratory volume in 1 s (FEV1) and 3) changes in cotton dust levels. These were assessed using two-level mixed effects linear and logistic regression. RESULTS: Of 2031 participants recruited at baseline, 807 (40%) were available at the third follow-up. At that point, workers in the intervention arm were more likely to report an improvement in respiratory symptoms (OR 1.58, 95% CI 1.06-2.36) and lung function (FEV1 % pred: ß 1.31%, 95% CI 0.04-2.57%). Personal dust levels decreased, more so in intervention mills, although we did not observe this in adjusted models due to the small number of samples. CONCLUSION: We found the intervention to be effective in improving the respiratory health of textile workers and recommend scaling-up of such simple and feasible interventions in low- and middle-income countries.

A systematic review of the prevalence of postamputation and chronic neuropathic pain associated with combat injury in military personnel.

ABSTRACT: Combat trauma can lead to widespread tissue damage and limb loss. This may result in chronic neuropathic and post amputation pain, including phantom limb pain (PLP) and residual limb pain (RLP). The military population is distinct with respect to demographic, injury, and social characteristics compared with other amputation and trauma cohorts. We undertook a systematic review of studies of military personnel, with a history of combat injury, that reported a prevalence of any type of postamputation pain or chronic neuropathic pain, identified from Embase and MEDLINE databases.Using the inverse variance method with a random-effects model, we undertook a meta-analysis to determine an overall prevalence and performed exploratory analyses to identify the effect of the type of pain, conflict, and time since injury on prevalence. Pain definitions and types of pain measurement tools used in studies were recorded. Thirty-one studies (14,738 participants) were included. The pooled prevalence of PLP, RLP, and chronic neuropathic pain were 57% (95% CI: 46-68), 61% (95% CI: 50-71), and 26% (95% CI: 10-54), respectively. Between-study heterogeneity was high (I 2 : 94%-98%). Characterisation of duration, frequency, and impact of pain was limited. Factors reported by included studies as being associated with PLP included the presence of RLP and psychological comorbidity. The prevalence of postamputation pain and chronic neuropathic pain after combat trauma is high. We highlight inconsistency of case definitions and terminology for pain and the need for consensus in future research of traumatic injury.

Relationship between combat-related traumatic injury and its severity to predicted cardiovascular disease risk: ADVANCE cohort study.

BACKGROUND: This study investigated the relationship between combat-related traumatic injury (CRTI) and its severity and predicted cardiovascular disease (CVD) risk. MATERIAL AND METHODS: This was an analysis of comparative 10-year predicted CVD risk (myocardial infarction, stroke or CVD-death) using the QRISK®3 scoring-system among adults recruited into the Armed Services Trauma Rehabilitation Outcome (ADVANCE) cohort study. Participants with CRTI were compared to uninjured servicemen frequency-matched by age, sex, rank, deployment (Afghanistan 2003-2014) and role. Injury severity was quantified using the New Injury Severity Score (NISS). RESULTS: One thousand one hundred forty four adult combat veterans were recruited, consisting of 579 injured (161 amputees) and 565 uninjured men of similar age ethnicity and time from deployment/injury. Significant mental illness (8.5% vs 4.4%; p = 0.006) and erectile dysfunction (11.6% vs 5.8%; p < 0.001) was more common, body mass index (28.1 ± 3.9 vs 27.4 ± 3.4 kg/m2; p = 0.001) higher and systolic blood pressure variability (median [IQR]) (1.7 [1.2-3.0] vs 2.1 [1.2-3.5] mmHg; p = 0.008) lower among the injured versus uninjured respectively. The relative risk (RR) of predicted CVD (versus the population expected risk) was higher (RR:1.67 [IQR 1.16-2.48]) among the injured amputees versus the injured non-amputees (RR:1.60 [1.13-2.43]) and uninjured groups (RR:1.52 [1.12-2.34]; overall p = 0.015). After adjustment for confounders CRTI, worsening injury severity (higher NISS, blast and traumatic amputation) were independently associated with QRISK®3 scores. CONCLUSION: CRTI and its worsening severity were independently associated with increased predicted 10-year CVD risk.

Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of five birth cohorts.

BACKGROUND: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. OBJECTIVES: To demonstrate that a more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. METHODS: We derived six multidimensional variables of eczema spells from birth to 18 years of age (including duration, temporal sequencing and the extent of persistence/recurrence). Spells were defined as consecutive observations of eczema separated by no eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); preschool/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partitioning Around Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity and associated risk factors, including FLG mutations. RESULTS: Analysis of 7464 participants with complete data identified five clusters: (i) no eczema (51.0%); (ii) early transient eczema (21.6%); (iii) late-onset eczema (LOE; 8.1%); (iv) intermittent eczema (INT; 7.5%); and (v) persistent eczema (PE; 11.8%). There was very-high agreement between the assignment of individual children into clusters when using complete or imputed (n = 15 848) data (adjusted Rand index = 0.99; i.e. the clusters were very stable). Within-individual symptom patterns across clusters confirmed within-cluster homogeneity, with consistent patterns of symptoms among participants within each cluster and no overlap between the clusters. Clusters were characterized by differences in associations with risk factors (e.g. parental eczema was associated with all clusters apart from LOE; sensitization to inhalant allergens was associated with all clusters, with the highest risk in the PE cluster). All clusters apart from LOE were associated with FLG mutations. Of note, the strongest association was for PE [relative risk ratio (RRR) 2.70, 95% confidence interval (CI) 2.24-3.26; P < 0.001] followed by INT (RRR 2.29, 95% CI 1.82-2.88; P < 0.001). CONCLUSIONS: Clustering of multidimensional variables identified stable clusters with different genetic architectures. Using multidimensional variables may capture eczema development and derive stable and internally homogeneous clusters. However, deriving homogeneous symptom clusters does not necessarily mean that these are underpinned by completely unique mechanisms.

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.

The relationship between combat-related traumatic amputation and subclinical cardiovascular risk.

BACKGROUND: The relationship between acute combat-related traumatic injury (CRTI) to coronary flow reserve (CFR) and subclinical cardiovascular risk have not been examined and was the primary aim of this study. METHODS AND RESULTS: UK combat veterans from the ADVANCE cohort study (UK-Afghanistan War 2003-14) with traumatic limb amputations were compared to injured non-amputees and to a group of uninjured veterans from the same conflict. Subclinical cardiovascular risk measures included fasted blood atherogenic index of plasma (AIP), triglyceride-glucose index (TyG; insulin resistance), the neutrophil-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP; vascular inflammation), body mass index (BMI) and visceral fat volume (dual-energy X-ray absorptiometry) and 6-min walk distance (6MWD; physical performance). The subendocardial viability ratio (SEVR), to estimate CFR, was calculated using arterial pulse waveform analysis (Vicorder device). In total 1144 adult male combat veterans were investigated, comprising 579 injured (161 amputees, 418 non-amputees) and 565 uninjured men. AIP, TyG, NLR, hs-CRP, BMI, total body fat and visceral fat volume were significantly higher and the SEVR and 6MWD significantly lower in the amputees versus the injured-non-amputees and uninjured groups. The SEVR was lowest in those with above knee and multiple limb amputations. CRTI (ExpB 0.96; 95% CI 0.94-0.98: p < 0.0001) and amputation (ExpB 0.94: 95% CI 0.91-0.97: p < 0.0001) were independently associated with lower SEVR after adjusting for age, rank, ethnicity and time from injury. CONCLUSION: CRTI, traumatic amputation and its worsening physical deficit are associated with lower coronary flow reserve and heightened subclinical cardiovascular risk.

Association Between Combat-Related Traumatic Injury and Skeletal Health: Bone Mineral Density Loss Is Localized and Correlates With Altered Loading in Amputees: the Armed Services Trauma Rehabilitation Outcome (ADVANCE) Study.

The association between combat-related traumatic injury (CRTI) and bone health is uncertain. A disproportionate number of lower limb amputees from the Iraq and Afghanistan conflicts are diagnosed with osteopenia/osteoporosis, increasing lifetime risk of fragility fracture and challenging traditional osteoporosis treatment paradigms. The aim of this study is to test the hypotheses that CRTI results in a systemic reduction in bone mineral density (BMD) and that active traumatic lower limb amputees have localized BMD reduction, which is more prominent with higher level amputations. This is a cross-sectional analysis of the first phase of a cohort study comprising 575 male adult UK military personnel with CRTI (UK-Afghanistan War 2003 to 2014; including 153 lower limb amputees) who were frequency-matched to 562 uninjured men by age, service, rank, regiment, deployment period, and role-in-theatre. BMD was assessed using dual-energy X-ray absorptiometry (DXA) scanning of the hips and lumbar spine. Femoral neck BMD was lower in the CRTI than the uninjured group (T-score -0.08 versus -0.42 p = .000). Subgroup analysis revealed this reduction was significant only at the femoral neck of the amputated limb of amputees (p = 0.000), where the reduction was greater for above knee amputees than below knee amputees (p < 0.001). There were no differences in spine BMD or activity levels between amputees and controls. Changes in bone health in CRTI appear to be mechanically driven rather than systemic and are only evident in those with lower limb amputation. This may arise from altered joint and muscle loading creating a reduced mechanical stimulus to the femur resulting in localized unloading osteopenia. This suggests that interventions to stimulate bone may provide an effective management strategy. © 2023 Crown copyright and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

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.

ADVANCE-TBI study protocol: traumatic brain injury outcomes in UK military personnel serving in Afghanistan between 2003 and 2014 - a longitudinal cohort study.

INTRODUCTION: Outcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort. METHODS AND ANALYSIS: The ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3-5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions. ETHICS AND DISSEMINATION: The ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Ethics Committee (ref: 2126/MODREC/22). Findings will be disseminated via publications in peer-reviewed journals and presentations at conferences.

Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: A prospective cohort study.

BACKGROUND AND OBJECTIVE: Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. METHODS: In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. RESULTS: 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. CONCLUSION: In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death.

The underlying mechanisms by which PTSD symptoms are associated with cardiovascular health in male UK military personnel: The ADVANCE cohort study.

Post-Traumatic Stress Disorder (PTSD) has been identified as an independent risk factor for cardiovascular disease, but the mechanisms of this relationship are not well understood. This study investigates the associations between PTSD symptom clusters (hyperarousal, intrusive thoughts, avoidance behaviours and emotional numbing) and mechanisms of cardiovascular disease including cardiometabolic effects, inflammation, and haemodynamic functioning. In the ADVANCE study cohort of UK male military personnel, 1111 participants were assessed for PTSD via questionnaire and cardiovascular risk via venous blood sampling, pulse wave analysis and dual energy x-ray absorptiometry between 2015 and 2020. Variable selection procedures were conducted to assess which of the symptom clusters if any were associated with cardiovascular risk outcomes. Associations were confirmed via robust regression modelling. Avoidance behaviours were associated with greater systolic Blood Pressure (BP) (Adjusted Coefficient (AC) 0.640 (95% Confidence Interval (CI) 0.065, 1.149). Emotional numbing was associated with greater estimated glucose disposal rate (AC -0.021 (95%CI -0.036, -0.005). Hyperarousal was associated with greater levels of (log)triglycerides (exponentiated-AC 1.009 (95%CI 1.002, 1.017). Intrusive thoughts were associated with greater visceral adipose tissue (AC 0.574 (95%CI 0.020, 1.250). Nonlinear relationships were observed between emotional numbing with heart rate and intrusive thoughts with systolic BP. Limited evidence is present for symptom associations with lipoproteins and pulse wave velocity. No associations were observed between PTSD symptom clusters and high sensitivity c-reactive protein, diastolic BP, total cholesterol, or haemoglobin fasting glucose. In conclusion, symptom clusters of PTSD were associated with increased cardiovascular risk via cardiometabolic and haemodynamic functioning mechanisms, but not inflammation.

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.