Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

A Resource Building Virtual Care Programme: improving symptoms and social functioning among female and male rural veterans

Background: Veterans have higher rates of PTSD and depression compared to the general population and experience substantial functional impairment. Impairment in social functioning has been a significant concern among Veterans, particularly rural Veterans, who have limited access to mental health care and are at risk for social isolation. Objective: A mixed-method study was implemented to evaluate the feasibility and effectiveness of webSTAIR, a web-based skills training programme, paired with home-based telehealth sessions. It was hypothesized that the programme would lead not only to reductions in PTSD and depression but also to improvements in social functioning. Method: Participants were 80 trauma-exposed Veterans enrolled in rural-serving VHA facilities with clinically elevated symptoms of either PTSD or depression. The study directed substantial outreach efforts to rural women Veterans and those who have experienced military sexual trauma (MST). Results: Significant improvements were obtained with PTSD and depression symptoms as well as in social functioning, emotion regulation, and interpersonal problems at post-treatment and 3-month follow-up. Ratings of therapeutic alliance were high as were reports of overall satisfaction in the programme. There were no differences by gender or MST status in symptom outcomes or satisfaction. Conclusions: The results support the feasibility and effectiveness of this integrated telehealth web-based skills training programme for both male and female Veterans as well as for those with and without MST. The focus on resource building and improved functioning make this programme of particular interest. Further testing is warranted

Comparing the Ratio of Therapist Support to Internet Sessions in a Blended Therapy Delivered to Trauma-Exposed Veterans: Quasi-experimental Comparison Study

BackgroundBlended models of therapy, which incorporate elements of both internet and face-to-face methods, have been shown to be effective, but therapists and patients have expressed concerns that fewer face-to-face therapy sessions than self-guided internet sessions may be associated with lower therapeutic alliance, lower program completion rates, and poorer outcomes. ObjectiveA multisite quasi-experimental comparison study with a noninferiority design implemented in routine clinical care was used to assess webSTAIR, a 10-module blended therapy derived from STAIR (skills training in affective and interpersonal regulation) for trauma-exposed individuals delivered with 10 weekly therapist sessions (termed Coach10) compared to 5 biweekly sessions (Coach5). It was hypothesized that Coach5 would be as good as Coach10 in a range of outcomes. MethodsA total of 202 veterans were enrolled in the study with 101 assigned to Coach5 and 101 to Coach10. Posttraumatic stress disorder (PTSD) symptoms, depression, emotion regulation, interpersonal problems, and social functioning measures were collected pre-, mid-, and posttreatment, and at a 3-month follow-up. Noninferiority analyses were conducted on symptom outcome measures. Comparisons were made of continuous and categorical measures regarding participant and therapist activities. ResultsParticipants reported moderate to severe levels of baseline PTSD, depression, or both. Significant reductions were obtained in all symptom measures posttreatment and at the 3-month follow up. Coach5 was not inferior to Coach10 in any outcome. Therapeutic alliance was at an equivalently high level across the 2 treatment conditions; completion rates and web usage were similar. Total session time was substantially less for the Coach5 therapists than the Coach10 therapists. Both programs were associated with a low, but equal number of therapist activities related to scheduling and crisis or motivational sessions. ConclusionsA blended model delivered with 5 sessions of therapist support was noninferior to 10 sessions in individuals with moderate to severe symptoms. Future studies identifying patient characteristics as moderators of outcomes with high versus low doses of therapist support will help create flexible, technology-based intervention programming