Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Background Anatomical lung resection offers the best prospect of long-term survival in patients with non-small cell lung cancer (NSCLC). However, some patients with significant dyspnoea, impaired performance status (PS), borderline or poor pulmonary function are considered inoperable and instead referred for radiotherapy, chemotherapy or palliative care. The aims of the study were to determine whether pre-operative pulmonary physiotherapy (Prehab), by improving clinical parameters, (i) makes patients suitable for surgery who were considered inoperable on subjective criteria of dyspnoea >3 and PS >2, and objective criteria of diffusing capacity for carbon monoxide (DLCO) <50%; and (ii) thereby allows them to safely receive curative surgery with reduced morbidity and mortality. Methods From January 2017 to December 2018 a total of 306 patients were prospectively and sequentially assessed for Prehab and 216 patients with lung cancer studied. Their mean age (95% CI) was 71.7 ± 1.1 years, 50.5% ( n = 109) were men and they received Prehab over 39.0 ± 7.0 days averaging 3.1 ± 0.6 sessions. Their dyspnoea scores, PS, level of activity, six minute walk test (6MWT) and frailty index prior to and following Prehab were determined. Following surgery the post-operative length of hospital stay (LOHS), complications and mortality at 30 days, 90 days and 1 year determined. Similar outcomes were determined for (i) high-risk patients with dyspnoea scores >3 and PS >2, and compared with low-risk patients having dyspnoea scores <2 and PS <2 (subjective criteria); and (ii) high-risk patients with DLCO <50% and compared with low-risk patients with DLCO >80% (objective criteria). Findings In the total cohort following Prehab, there was significant improvement in the dyspnoea scores <2 / ≥2 (40%/60% prior to Prehab vs. 65%/35% following Prehab, p = 0.00002), PS <2 / ≥2 (45%/55% prior to vs. 62%/38% following Prehab, p = 0.003), frailty index ≤3 / >3 (49%/51% vs 70%/30%, p = 0.0006), and 6MWT (306.6 ± 6.8 m vs 354.8 ± 52.7 m, p = 0.04). Post-operative major complication rates were 8.7%; median LOHS was 7 (IQR 6) days; hospital mortality at 30 days 1.3%, 90 days 4.7% and 1 year 16%. Using subjective criteria of dyspnoea scores >3 and PS >2, 100% of high-risk patients were considered inoperable. Following optimization with Prehab 84.2% of the high-risk patients were ready to proceed with radical treatment and 52.6% with surgery, and subsequently 42.8% of patients underwent surgery. Likewise, 78.8% of patients with DLCO <50% were considered inoperable. Following Prehab 86.5% of high-risk patients were ready to proceed with radical treatment and 59.1% with surgery, and 54.6% of high-risk patients underwent surgery. In each category there were no significant differences in complications, LOHS or mortality rates between the high-risk a...
BackgroundThe aim was to complete a feasibility study that would test the methods of the main trial, that will investigate whether early thoracic and shoulder girdle exercises reduce chronic pain in patients with blunt chest wall trauma, when compared with normal care.MethodsA single centre, parallel, feasibility randomised controlled trial was completed at a University Teaching Hospital in Wales between June and September 2019. Adult patients with blunt chest wall trauma, admitted to hospital for greater than 24 hours, with no concurrent, immediately life-threatening injuries, were included. The intervention was a simple physiotherapy programme comprising thoracic and shoulder girdle exercises. Feasibility outcome measures included: primary outcomes: (1) 80% or more of identified eligible patients were approached for potential recruitment to the trial (2) 30% or less of approached, eligible patients dissented to participate in the trial; secondary outcomes: (3) follow-up data for patient secondary outcomes can be collected for 80% or more of patients, (4) there should be no greater than 10% increase in serious adverse events in the intervention group compared with the control group.ResultsA total of 19/19 (100%) patients were deemed eligible for the trial and were approached for participation, 5/19 (26%) eligible patients declined to participate in the trial, follow-up data were collected for n=10/14 (71%) patients and there were no serious adverse events reported in either group.ConclusionsWe have demonstrated that a fully powered randomised clinical trial of the EarLy Exercise in blunt Chest wall Trauma Trial is feasible.Trial registration numberISRCTN16197429
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