Understanding the impact of distance and disadvantage on lung cancer care and outcomes: a study protocol.

BACKGROUND: Lung cancer is the third most common cancer in the UK and the leading cause of cancer mortality globally. NHS England guidance for optimum lung cancer care recommends management and treatment by a specialist team, with experts concentrated in one place, providing access to specialised diagnostic and treatment facilities. However, the complex and rapidly evolving diagnostic and treatment pathways for lung cancer, together with workforce limitations, make achieving this challenging. This place-based, behavioural science-informed qualitative study aims to explore how person-related characteristics interact with a person's location relative to specialist services to impact their engagement with the optimal lung pathway, and to compare and contrast experiences in rural, coastal, and urban communities. This study also aims to generate translatable evidence to inform the evidence-based design of a patient engagement intervention to improve lung cancer patients' and informal carers' participation in and experience of the lung cancer care pathway. METHODS: A qualitative cross-sectional interview study with people diagnosed with lung cancer < 6 months before recruitment (in receipt of surgery, radical radiotherapy, or living with advanced disease) and their informal carers. Participants will be recruited purposively from Barts Health NHS Trust and United Lincolnshire Hospitals NHS Trusts to ensure a diverse sample across urban and rural settings. Semi-structured interviews will explore factors affecting individuals' capability, opportunity, and motivation to engage with their recommended diagnostic and treatment pathway. A framework approach, informed by the COM-B model, will be used to thematically analyse facilitators and barriers to patient engagement. DISCUSSION: The study aligns with the current policy priority to ensure that people with cancer, no matter where they live, can access the best quality treatments and care. The evidence generated will be used to ensure that lung cancer services are developed to meet the needs of rural, coastal, and urban communities. The findings will inform the development of an intervention to support patient engagement with their recommended lung cancer pathway. PROTOCOL REGISTRATION: The study received NHS Research Ethics Committee (Ref: 23/SC/0255) and NHS Health Research Authority (IRAS ID 328531) approval on 04/08/2023. The study was prospectively registered on Open Science Framework (16/10/2023; https://osf.io/njq48 ).

A systematic review on the qualitative experiences of people living with lung cancer in rural areas.

PURPOSE: To synthesize the qualitative literature exploring the experiences of people living with lung cancer in rural areas. METHODS: Searches were performed in MEDLINE, CINAHL, and PsycINFO. Articles were screened independently by two reviewers against pre-determined eligibility criteria. Data were synthesized using Thomas and Harden's framework for the thematic synthesis of qualitative research. The CASP qualitative checklist was used for quality assessment and the review was reported in accordance with the ENTREQ and PRISMA checklists. RESULTS: Nine articles were included, from which five themes were identified: (1) diagnosis and treatment pathways, (2) travel and financial burden, (3) communication and information, (4) experiences of interacting with healthcare professionals, (5) symptoms and health-seeking behaviors. Lung cancer diagnosis was unexpected for some with several reporting treatment delays and long wait times regarding diagnosis and treatment. Accessing treatment was perceived as challenging and time-consuming due to distance and financial stress. Inadequate communication of information from healthcare professionals was a common concern expressed by rural people living with lung cancer who also conveyed dissatisfaction with their healthcare professionals. Some were reluctant to seek help due to geographical distance and sociocultural factors whilst others found it challenging to identify symptoms due to comorbidities. CONCLUSIONS: This review provides a deeper understanding of the challenges faced by people with lung cancer in rural settings, through which future researchers can begin to develop tailored support to address the existing disparities that affect this population.

Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study.

BACKGROUND: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter. OBJECTIVES: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection. METHODS: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months. RESULTS: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively. CONCLUSIONS: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.

Developing a specialist-nurse-led 'COPD in-reach service'.

AIM: To develop and implement a respiratory clinical-nurse-specialist-led chronic obstructive pulmonary disease (COPD) 'in-reach service' for an emergency admission unit within a large acute county hospital. METHOD: Data collected during the service development were compared with existing data when no COPD in-reach service was available. Data were compared on average length of stay, readmission rates, 'early assisted discharge' and patient experience. FINDINGS: The COPD in-reach service reduced average length of stay for COPD patients by 2.53 days and readmission rates were reduced by an average of 4.5 per month; 17% of patients were discharged on an early assisted discharge scheme, and overall patients felt more prepared and ready for discharge. CONCLUSION: The COPD in-reach service has been proven to be of great benefit both financially and in terms of patient experience.

Dietary sodium manipulation and asthma.

BACKGROUND: There is a wide geographical variation in the prevalence of asthma and observational studies have suggested that dietary sodium may play a role. OBJECTIVES: To assess the effect of dietary sodium manipulation on asthma control. SEARCH STRATEGY: We carried out a search using the Cochrane Airways Group asthma register. We searched the bibliographies of included randomised controlled trials (RCTs) for additional studies. We carried out the most recent search in November 2010. SELECTION CRITERIA: We considered only RCTs that involved dietary sodium reduction or increased sodium intake in patients with asthma. DATA COLLECTION AND ANALYSIS: Both review authors assessed study and extracted data. We conducted data analyses in RevMan 5 using mean differences and random effects. MAIN RESULTS: We identified a total of nine studies in relation to sodium manipulation and asthma, of which five were in people with asthma (318 participants), and four in people with exercise-induced asthma (63 participants). There were no significant benefits of salt restriction on the control of asthma. There was some evidence from the exercise-induced asthma studies that a low sodium diet may improve lung function after exercise and possibly baseline lung function, but this is based on findings from a very small numbers of participants. AUTHORS' CONCLUSIONS: This review did not find any evidence that dietary sodium reduction significantly improves asthma control. Although dietary sodium reduction may result in improvements in lung function in exercise-induced asthma, the clinical significance of this effect is unclear.

Impact of adopting low sodium diet on biomarkers of inflammation and coagulation: a randomised controlled trial.

BACKGROUND: A low sodium diet is an established intervention in the treatment of impaired renal function and hypertension which may modulate cardiovascular risk independent of recognised antihypertensive effects. Epidemiological data suggest that dietary sodium intake may be associated with systemic inflammation: another potential pathophysiological mechanism by which sodium intake may modify vascular disease. METHODS: We tested the hypothesis that adopting a low sodium diet may decrease biomarkers of systemic inflammation or coagulation using data from a randomised double-blind placebo-controlled trial. Participants (n=171; aged 18-65 years) in a randomised double-blind placebo-controlled trial of a low sodium diet for 6 weeks provided paired serum samples for analysis to assess the impact of adopting a low sodium diet on biomarkers of systemic inflammation and coagulation. RESULTS: There was a significant difference in 24-hour sodium urinary excretion between the low sodium intake and the normal sodium intake groups of 43 mmol (p<0.001). In the primary analysis there was no effect of adopting a low sodium diet on serum D-dimers, but high-sensitivity C-reactive protein (hsCRP) was reduced by 1.13 mg/L (95% confidence interval [95% CI], 0.03 to 2.22). However, after elimination of outlying high values for baseline serum hsCRP (>10 mg/L), this effect was attenuated (-0.47 mg/L; 95% CI, -1.25 to 0.31). CONCLUSIONS: Using data from a randomised double-blind placebo-controlled trial in asthma with objective confirmation of adherence to the low sodium diet, we report that adopting a low sodium diet for 6 weeks has no effect on measures of systemic inflammation or coagulation.

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

An evaluation of the use of bronchoconstriction induced by deep inspiration as a new epidemiological measure for asthma.

RATIONALE: Bronchoconstriction after deep inhalation is associated with increased severity of asthma and is also a predictor of length of hospital stay in individuals admitted with asthma exacerbations. We hypothesized that this effect may represent a new non-invasive method to assess bronchial reactivity and other measures of asthma control. METHODS: We used a cross-sectional study design recruiting participants 18 to 65 years of age with a physician diagnosis of asthma. All participants were asked to provide three serial peak expiratory flow rate (PEFR) measurements in the morning, and bronchial reactivity was measured up to a maximum inhaled dose of 24.5 micromoL methacholine on the same day. Participants also recorded their asthma symptoms score and bronchodilator use during the 7 days before measuring bronchial reactivity. RESULTS: A total of 127 people provided data for analysis. There was no significant relationship between bronchoconstriction after deep inhalation (as measured by three serial PEFR measurements) and either bronchial reactivity to methacholine, asthma symptoms, or bronchodilator use. CONCLUSIONS: Bronchoconstriction induced by deep inspiration does not appear to be a valid marker of airway hyperresponsiveness or asthma severity in adults with mild to moderate asthma.

Exhaled carbon monoxide in asthmatic adults with bronchial reactivity: a prospective study.

HYPOTHESIS: We hypothesized that eCO may permit non-invasive assessment of disease activity in adults with asthma and bronchial reactivity. METHODS: A total of 209 participants 18 to 65 years of age with a diagnosis of asthma and bronchial reactivity provided data for analysis. The association between eCO and bronchial reactivity, forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), peak expiratory flow rate measurements (PEFR), asthma symptoms score, and bronchodilator use cross-sectionally and within-subject change in eCO were analyzed in relation to change in these variables over 6 weeks. RESULTS: There was no difference in eCO in those who were taking inhaled corticosteroids and those who were not (p = 0.33). There was also no cross-sectional or within-in subject association between eCO and bronchial reactivity, FEV(1), FVC, PEFR, symptoms score, or bronchodilator use. CONCLUSIONS: In a population of adults with bronchial reactivity, eCO has no or very limited potential as a biomarker of asthma activity.

The impact of statins, ACE inhibitors and gastric acid suppressants on pneumonia mortality in a UK general practice population cohort.

BACKGROUND: Pneumonia is a common diagnosis in general practice in the United Kingdom. Previous studies suggest that commonly prescribed drugs in general practice may influence pneumonia mortality. AIM: We investigated whether statins, angiotensin converting enzyme inhibitors (ACEIs), proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H(2)RAs) have an impact on short-term and long-term mortality in pneumonia cases. DESIGN OF STUDY: Population-based cohort study SETTTING: United Kingdom METHODS: Data on 3681 pneumonia cases above the age of 40 years were obtained from a comprehensive database called the health improvement network (THIN) which has computerised medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses. RESULTS: Current statin use was associated with a 67% decrease in 30-day mortality (adj. HR: 0.33, 95% CI: 0.19-0.58) and a 55% decrease in long-term mortality (adj. HR: 0.45, 95% CI: 0.32-0.62) over a median follow-up of 2.8 years as compared to no-use. Current ACEI use decreased the 30-day mortality risk by nearly 38% as compared to no-use (adj. HR: 0.62, 95% CI: 0.47-0.82) but was not associated with long-term mortality. No significant impact on mortality was observed for either gastric acid suppressant. CONCLUSION: The use of statins is associated with a lower risk of short- and long-term mortality following pneumonia whereas the use of ACEIs is associated with a decreased mortality risk only in the short-term.

Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study.

PURPOSE: Previous studies have shown that treatment with gastric acid suppressants may be associated with an increased risk of pneumonia whilst the use of statins and ACE inhibitors (ACEI) may decrease the risk of acquiring pneumonia. The evidence is conflicting however. Our aim was to investigate the effect of these drugs on pneumonia using population-based data from the UK. METHODS: We conducted a general population-based case-control study using the health improvement network (THIN), a comprehensive UK general practice database. Conditional multiple logistic regression was used to assess the association between the exposures and pneumonia. RESULTS: After adjusting for potential confounders, a current prescription for statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.78, 95% CI 0.65-0.94). Similarly, a current prescription for ACEI was associated with a reduction in the risk of pneumonia (adjusted OR 0.75, 95% CI 0.65-0.86). Contrary to previous study results we did not find a significant association between current prescription for histamine 2 receptor antagonist (H(2)RA) and pneumonia risk (adjusted OR 1.14, 95% CI 0.92-1.40) but current prescriptions for proton pump inhibitors (PPI) were associated with an increased risk of pneumonia (adjusted OR 1.55, 95% CI 1.38-1.77). CONCLUSIONS: Statins and ACE inhibitors were associated with a lower risk of pneumonia but these effects were smaller than those observed in previous studies. People prescribed a PPI, but not an H(2)RA at an increased risk of acquiring pneumonia.

Does a low sodium diet improve asthma control? A randomized controlled trial.

RATIONALE: Observational studies and initial randomized trials have indicated that a low sodium diet may improve asthma control. OBJECTIVES: We tested the hypothesis that a low sodium diet would improve asthma control over a 6-week period. METHODS: Participants with a physician diagnosis of asthma and measurable bronchial reactivity to methacholine entered a randomized double-blind placebo-controlled trial. All adopted a low sodium diet and were randomized to receive either 80 mmol/day of oral sodium supplements (normal sodium intake) or matched placebo (low sodium intake) for 6 weeks. The primary outcome was change in bronchial reactivity to methacholine; secondary outcomes were change in lung function, morning and evening peak expiratory flow, asthma symptoms score, daily bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire score, and atopy. MEASUREMENTS AND MAIN RESULTS: A total of 220 individuals entered the study, of whom 199 completed the protocol. In the low sodium-intake group, mean daily urinary sodium excretion decreased by 20 mmol (SD, 64 mmol) and in the normal-sodium-intake group increased by 28 mmol (SD, 74 mmol). There were no differences between the two groups in the primary or secondary outcome measures; the mean difference in bronchial reactivity between the low- and normal-intake groups was -0.03 doubling doses of methacholine (95% confidence interval, -0.60 to 0.53). CONCLUSIONS: The use of a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity to methacholine.

Pneumonia mortality in a UK general practice population cohort.

BACKGROUND: Pneumonia is a common diagnosis in general practice in the United Kingdom and yet there is little known about the short- and long-term prognosis of people with a diagnosis of pneumonia in general practice. We investigated the short- and long-term survival of people with pneumonia diagnosed in general practice as compared to the general population for all ages. METHODS: This was a general population-based cohort study. Data was obtained from a comprehensive general practice database called The Health Improvement Network (THIN) database which has computerized medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses. RESULTS: For pneumonia cases the 30-day mortality was 18.5% and the 3-year mortality was 30.8%. The equivalent figures for the general population controls were 0.4% and 10.3% respectively. The adjusted hazard ratio (HR) for all-cause mortality (for total follow-up time) in pneumonia cases vs. general population was 4.64 (95% CI 4.35-4.95). For the first 30 days the risk of mortality in cases was 46 times more (adj. HR 45.90, 95% CI 36.80-55.20). Even in the period of follow-up 91 days after diagnosis cases were almost 20% more likely to die compared to general population (adj. HR 1.19, 95% CI 1.08-1.31). CONCLUSION: People in general practice who have a diagnosis of pneumonia have a markedly increased mortality in the short-term but some increase in mortality persists during longer-term follow-up.

Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.

BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Does a low sodium diet modify heart rate variability? A randomised placebo-controlled double-blind trial.

BACKGROUND: Increased heart rate variability (HRV) is associated with a low risk of mortality, as is consuming a low sodium diet. As the survival benefits of a low sodium diet may be mediated partly by an increase in HRV, we have tested the hypothesis that adopting a low sodium diet increases HRV. METHODS: We used a randomised double-blind placebo-controlled trial design. Participants were aged 18-65 years old, had a physician diagnosis of asthma. All adopted a low sodium diet and they were randomised to receive either 80 mmol/day of oral sodium supplements (normal sodium intake - NSI) or matched placebo (low sodium intake-LSI) for 6 weeks. The primary outcome was change in SDNN (standard deviation of the N-N intervals); secondary outcomes were changes in other time domain and frequency domain measures of HRV. RESULTS: In those allocated to the LSI, mean daily urinary sodium excretion decreased by 22 mmol; and in those allocated to the NSI mean daily urinary sodium excretion increased by 31 mmol. There were no differences between the two groups for either the primary or secondary outcome measures. The mean difference in change in SDNN between those who received the LSI compared to the NSI was -2.7 ms (95% Confidence Intervals CI; -18.0 to +12.6). CONCLUSIONS: Adopting a low sodium diet does not have an impact on SDNN over a 6 weeks period. Future studies should aim to achieve a larger change in dietary sodium intake for a longer duration than 6 weeks.